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Sample records for cancer cell death

  1. Glutathione in Cancer Cell Death

    International Nuclear Information System (INIS)

    Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy

  2. Glutathione in Cancer Cell Death

    Energy Technology Data Exchange (ETDEWEB)

    Ortega, Angel L. [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 17 Av. Blasco Ibanez, 46010 Valencia (Spain); Mena, Salvador [Green Molecular SL, Pol. Ind. La Coma-Parc Cientific, 46190 Paterna, Valencia (Spain); Estrela, Jose M., E-mail: jose.m.estrela@uv.es [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 17 Av. Blasco Ibanez, 46010 Valencia (Spain)

    2011-03-11

    Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy.

  3. Regulation of cell death in cancer - possible implications for immunotherapy

    OpenAIRE

    Simone eFulda

    2013-01-01

    Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is e...

  4. Colorectal Cancer Stem Cells and Cell Death

    International Nuclear Information System (INIS)

    Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes, conventional anticancer therapies have to be replaced with specific approaches targeting CSCs. In this review we provide strong support that BMP4 is an innovative therapeutic approach to prevent colon cancer growth increasing differentiation markers expression and apoptosis. Recent data suggest that in colorectal CSCs, protection from apoptosis is achieved by interleukin-4 (IL-4) autocrine production through upregulation of antiapoptotic mediators, including survivin. Consequently, IL-4 neutralization could deregulate survivin expression and localization inducing chemosensitivity of the colon CSCs pool

  5. Nerve Growth Factor in Cancer Cell Death and Survival

    International Nuclear Information System (INIS)

    One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer

  6. Gossypol Induced Cell Death in DU 145 Prostate Cancer Cells

    OpenAIRE

    Kennelly, Susan

    2010-01-01

    Cancer Biology Tumourigenesis is a multistep process which includes the transformation of healthy cells into extremely malignant cells, caused by the disruption of normal tissue homeostasis. Hanahan and Weinberg propose that there are a common set of 'acquired capabilities' that most if not all cancers posses's in order to survive and proliferate despite changes in their normal cell physiology during cancer development (Hanahan and Weinberg, 2000). These "Hallmarks of Cancer", according to...

  7. Mechanism of heavy ion radiation-induced cancer cell death

    International Nuclear Information System (INIS)

    We previously reported that the carbon beam triggers apoptosis in radio-resistant cancer cell lines via extracellular signal-regulated kinase (ERK)- and mitochondrial Bcl-2 family protein-dependant mechanism. Here, we further examined the further apoptosis-inducing mechanism of carbon beam in two glioma cell lines (T98G, U251). ERK1/2 knockdown experiments revealed that ERK regulates this apoptosis-inducing machinery upstream of mitochondria. Furthermore, we also found that both T98G cell and U251 cell stably expressing dominant-negative ERK2 suppress cell death induced by carbon beam irradiation. We also found proapoptotic PUMA and antiapoptotic Bcl-2 dynamically chang their expression levels corresponding to ERK activation after CB irradiation in U251 cell, and knockdown of PUMA decreased CB-induced U251 cell death. These data suggest that kinase action of ERK is essential for CB-induced glioma cell death, and proapoptotic PUMA and antiapoptotic Bcl-2 might be downstream targets of ERK in CB-induced glioma cell death mechanism. (author)

  8. Selective Induction of Cancer Cell Death by Targeted Granzyme B

    Directory of Open Access Journals (Sweden)

    Robert A. Jabulowsky

    2013-02-01

    Full Text Available The potential utility of immunotoxins for cancer therapy has convincingly been demonstrated in clinical studies. Nevertheless, the high immunogenicity of their bacterial toxin domain represents a critical limitation, and has prompted the evaluation of cell-death inducing proteins of human origin as a basis for less immunogenic immunotoxin-like molecules. In this review, we focus on the current status and future prospects of targeted fusion proteins for cancer therapy that employ granzyme B (GrB from cytotoxic lymphocytes as a cytotoxic moiety. Naturally, this serine protease plays a critical role in the immune defense by inducing apoptotic target cell death upon cleavage of intracellular substrates. Advances in understanding of the structure and function of GrB enabled the generation of chimeric fusion proteins that carry a heterologous cell binding domain for recognition of tumor-associated cell surface antigens. These hybrid molecules display high selectivity for cancer cells, with cell killing activities similar to that of corresponding recombinant toxins. Recent findings have helped to understand and circumvent intrinsic cell binding of GrB and susceptibility of the enzyme to inhibition by serpins. This now allows the rational design of optimized GrB derivatives that avoid sequestration by binding to non-target tissues, limit off-target effects, and overcome resistance mechanisms in tumor cells.

  9. Necroptosis: an alternative cell death program defending against cancer.

    Science.gov (United States)

    Chen, Dongshi; Yu, Jian; Zhang, Lin

    2016-04-01

    One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL) protein. Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID:26968619

  10. Targeted cancer cell death induced by biofunctionalized magnetic nanowires

    KAUST Repository

    Contreras, Maria F.

    2014-02-01

    Magnetic micro and nanomaterials are increasingly interesting for biomedical applications since they possess many advantageous properties: they can become biocompatible, they can be functionalized to target specific cells and they can be remotely manipulated by magnetic fields. The goal of this study is to use antibody-functionalized nickel nanowires (Ab-NWs) as an alternative method in cancer therapy overcoming the limitations of current treatments that lack specificity and are highly cytotoxic. Ab-NWs have been incubated with cancer cells and a 12% drop on cell viability was observed for a treatment of only 10 minutes and an alternating magnetic field of low intensity and low frequency. It is believed that the Ab-NWs vibrate transmitting a mechanical force to the targeted cells inducing cell death. © 2014 IEEE.

  11. Curcumin induces apoptosis-independent death in oesophageal cancer cells.

    LENUS (Irish Health Repository)

    O'Sullivan-Coyne, G

    2009-10-06

    Background:Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines.Methods:MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting.Results:Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2\\/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug.Conclusion:Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.British Journal of Cancer advance online publication, 6 October 2009; doi:10.1038\\/sj.bjc.6605308 www.bjcancer.com.

  12. Curcumin induces apoptosis-independent death in oesophageal cancer cells.

    LENUS (Irish Health Repository)

    O'Sullivan-Coyne, G

    2012-01-31

    BACKGROUND: Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines. METHODS: MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting. RESULTS: Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2\\/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug. CONCLUSION: Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.

  13. Activation of ERK signaling and induction of colon cancer cell death by piperlongumine

    OpenAIRE

    Randhawa, H; Kibble, K; Zeng, H.; Moyer, MP; Reindl, KM

    2013-01-01

    Piperlongumine (PPLGM) is a bioactive compound isolated from long peppers that shows selective toxicity towards a variety of cancer cell types including colon cancer. The signaling pathways that lead to cancer cell death in response to PPLGM exposure have not been previously identified. Our objective was to identify the intracellular signaling mechanisms by which PPLGM leads to enhanced colon cancer cell death. We found that PPLGM inhibited the growth of colon cancer cells in time- and concen...

  14. Unlocking Pandora's box: personalising cancer cell death in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Fennell Dean A

    2012-06-01

    Full Text Available Abstract Evasion of apoptosis is a hallmark of tumorigenesis and a recognised cause of multidrug resistance. Over the last decade, insights into how apoptosis might be exploited in non-small cell lung cancer (NSCLC and how cancer therapeutics might be used to engage apoptotic signalling in a personalised manner have changed markedly. We are now in the wake of a paradigm shift in stratified therapeutic approaches related to NSCLC. At the heart of this shift in thinking is the emerging knowledge that even the most drug-resistant cancers exhibit a functional death pathway and, critically, that this pathway can be efficiently engaged, leading to clinical benefit. This review will summarise current knowledge of mitochondrial apoptotic pathway dysfunction in NSCLC and how the next generation of targeted therapeutics might be used to exploit deficiencies in apoptotic signalling in a personalised manner to improve clinical outcome and predict therapeutic benefit.

  15. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    OpenAIRE

    Xuanbin Wang; Yibin Feng; Ning Wang; Fan Cheung; Hor Yue Tan; Sen Zhong; Charlie Li; Seiichi Kobayashi

    2014-01-01

    Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and...

  16. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E; Issinger, Olaf-Georg; Stenvang, Jan

    2007-01-01

    future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells are...... parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for...

  17. The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Cheng Guangming

    2009-07-01

    Full Text Available Abstract Background Increased serum level of parathyroid hormone (PTH was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells. Methods Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential. Results In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,. Conclusion Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.

  18. Activation of ERK signaling and induction of colon cancer cell death by piperlongumine.

    Science.gov (United States)

    Randhawa, H; Kibble, K; Zeng, H; Moyer, M P; Reindl, K M

    2013-09-01

    Piperlongumine (PPLGM) is a bioactive compound isolated from long peppers that shows selective toxicity towards a variety of cancer cell types including colon cancer. The signaling pathways that lead to cancer cell death in response to PPLGM exposure have not been previously identified. Our objective was to identify the intracellular signaling mechanisms by which PPLGM leads to enhanced colon cancer cell death. We found that PPLGM inhibited the growth of colon cancer cells in time- and concentration-dependent manners, but was not toxic toward normal colon mucosal cells at concentrations below 10 μM. Acute (0-60 min) and prolonged (24h) exposure of HT-29 cells to PPLGM resulted in phosphorylation of ERK. To investigate whether ERK signaling was involved in PPLGM-mediated cell death, we treated HT-29 cells with the MEK inhibitor U0126, prior to treating with PPLGM. We found that U0126 attenuated PPLGM-induced activation of ERK and partially protected against PPLGM-induced cell death. These results suggest that PPLGM works, at least in part, through the MEK/ERK pathway to result in colon cancer cell death. A more thorough understanding of the molecular mechanisms by which PPLGM induces colon cancer cell death will be useful in developing therapeutic strategies to treat colon cancer. PMID:23603476

  19. AB158. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

    Science.gov (United States)

    He, Zhenhua; Wang, Zhiping

    2016-01-01

    Objective Although it is well known that apoptosis contributes to cancer cell death, the role of autophagy in cancer cell death has remained in dispute. Atorvastatin has been suggested to exhibit anti-cancer effects. The present study aimed to examine atorvastatin-induced autophagy-associated cell death and the autophagy-associated gene expression profile in the PC3 prostate carcinoma cell line. Methods The atorvastatin-induced process of autophagy in PC3 cells was determined via evaluation of the cellular expression levels of autophagosomal marker light-chain-3 (LC3)-II, using immunoblotting and counting of green fluorescent protein (GFP)-LC3-transfected autophagiccells. Apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and an MTT assay was used to evaluate cell viability. Total RNA of PC3 cells was isolated for characterization of the gene expression profile following atorvastatin treatment. Results Atorvastatin treatment of PC3 cells for 24 h increased the expression of GFP-LC3-II by >25% and expression continued for >72 h, while apoptosis was not significantly induced within this time period. Four genes associated with the autophagy machinery were also significantly upregulated. Conclusions In the presence of atorvastatin, autophagy may be unable to abrogate cell damage and may therefore contribute to cellular dysfunction, leading to autophagic/type II programmed cell death. In response to atorvastatin treatment, the expression of genes involved in autophagic mediating pathways may have a role in tumor suppression.

  20. Cell Death Pathways in Photodynamic Therapy of Cancer

    International Nuclear Information System (INIS)

    Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT

  1. Cell Death Pathways in Photodynamic Therapy of Cancer

    Directory of Open Access Journals (Sweden)

    Michael R. Hamblin

    2011-06-01

    Full Text Available Photodynamic therapy (PDT is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2 are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.

  2. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-Bromopyruvate

    OpenAIRE

    Chen, Zhao; Zhang, Hui; Lu, Weiqin; Huang, Peng

    2009-01-01

    It has long been observed that cancer cells rely more on glycolysis to generate ATP and actively use certain glycolytic metabolic intermediates for biosynthesis. Hexokinase II (HKII) is a key glycolytic enzyme that plays a role in the regulation of the mitochondria-initiated apoptotic cell death. As a potent inhibitor of hexokinase, 3-bromopyruvate (3-BrPA) is known to inhibit cancer cell energy metabolism and trigger cell death, supposedly through depletion of cellular ATP. The current study...

  3. Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism

    International Nuclear Information System (INIS)

    CD147 is a multifunctional transmembrane protein and promotes cancer progression. We found that the anti-human CD147 mouse monoclonal antibody MEM-M6/1 strongly induces necrosis-like cell death in LoVo, HT-29, WiDr, and SW620 colon cancer cells and A2058 melanoma cells, but not in WI-38 and TIG-113 normal fibroblasts. Silencing or overexpression of CD147 in LoVo cells enhanced or decreased the MEM-M6/1 induced cell death, respectively. CD147 is known to form complex with proton-linked monocarboxylate transporters (MCTs), which is critical for lactate transport and intracellular pH (pHi) homeostasis. In LoVo cells, CD147 and MCT-1 co-localized on the cell surface, and MEM-M6/1 inhibited the association of these molecules. MEM-M6/1 inhibited lactate uptake, lactate release, and reduced pHi. Further, the induction of acidification was parallel to the decrease of the glycolytic flux and intracellular ATP levels. These effects were not found in the normal fibroblasts. As cancer cells depend on glycolysis for their energy production, CD147 inhibition might induce cell death specific to cancer cells

  4. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Mok, Tony S.K. [Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Warner, Timothy D. [The William Harvey Research Institute, Queen Mary University of London, London (United Kingdom); Underwood, Malcolm J. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Chen, George G., E-mail: gchen@cuhk.edu.hk [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong)

    2009-10-15

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB{sub 2}) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB{sub 2} but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  5. Cell Death Pathways and Phthalocyanine as an Efficient Agent for Photodynamic Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Ivan Mfouo-Tynga

    2015-05-01

    Full Text Available The mechanisms of cell death can be predetermined (programmed or not and categorized into apoptotic, autophagic and necrotic pathways. The process of Hayflick limits completes the execution of death-related mechanisms. Reactive oxygen species (ROS are associated with oxidative stress and subsequent cytodamage by oxidizing and degrading cell components. ROS are also involved in immune responses, where they stabilize and activate both hypoxia-inducible factors and phagocytic effectors. ROS production and presence enhance cytodamage and photodynamic-induced cell death. Photodynamic cancer therapy (PDT uses non-toxic chemotherapeutic agents, photosensitizer (PS, to initiate a light-dependent and ROS-related cell death. Phthalocyanines (PCs are third generation and stable PSs with improved photochemical abilities. They are effective inducers of cell death in various neoplastic models. The metallated PCs localize in critical cellular organelles and are better inducers of cell death than other previous generation PSs as they favor mainly apoptotic cell death events.

  6. Triptolide induces lysosomal-mediated programmed cell death in MCF-7 breast cancer cells

    Directory of Open Access Journals (Sweden)

    Owa C

    2013-09-01

    Full Text Available Chie Owa, Michael E Messina Jr, Reginald HalabyDepartment of Biology, Montclair State University, Montclair, NJ, USABackground: Breast cancer is a major cause of death; in fact, it is the most common type, in order of the number of global deaths, of cancer in women worldwide. This research seeks to investigate how triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, induces apoptosis in MCF-7 human breast cancer cells. Accumulating evidence suggests a role for lysosomal proteases in the activation of apoptosis. However, there is also some controversy regarding the direct participation of lysosomal proteases in activation of key apoptosis-related caspases and release of mitochondrial cytochrome c. In the present study, we demonstrate that triptolide induces an atypical, lysosomal-mediated apoptotic cell death in MCF-7 cells because they lack caspase-3.Methods: MCF-7 cell death was characterized via cellular morphology, chromatin condensation, 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide colorimetric cell growth inhibition assay and the expression levels of proapoptotic proteins. Acridine orange and LysoTracker® staining were performed to visualize lysosomes. Lysosomal enzymatic activity was monitored using an acid phosphatase assay and western blotting of cathepsin B protein levels in the cytosolic fraction, which showed increased enzymatic activity in drug-treated cells.Results: These experiments suggest that triptolide-treated MCF-7 cells undergo atypical apoptosis and that, during the early stages, lysosomal enzymes leak into the cytosol, indicating lysosomal membrane permeability.Conclusion: Our results suggest that further studies are warranted to investigate triptolide's potential as an anticancer therapeutic agent.Keywords: triptolide, MCF-7 breast cancer cells, apoptosis, lysosomes, lysosomal membrane permeabilization (LMP

  7. (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization

    Science.gov (United States)

    LeGendre, Onica; Breslin, Paul AS; Foster, David A

    2015-01-01

    (-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been implicated in the health benefits associated with diets rich in EVOO. We investigated the effect of OC on human cancer cell lines in culture and found that OC induced cell death in all cancer cells examined as rapidly as 30 minutes after treatment in the absence of serum. OC treatment of non-transformed cells suppressed their proliferation but did not cause cell death. OC induced both primary necrotic and apoptotic cell death via induction of lysosomal membrane permeabilization (LMP). We provide evidence that OC promotes LMP by inhibiting acid sphingomyelinase (ASM) activity, which destabilizes the interaction between proteins required for lysosomal membrane stability. The data presented here indicate that cancer cells, which tend to have fragile lysosomal membranes compared to non-cancerous cells, are susceptible to cell death induced by lysosomotropic agents. Therefore, targeting lysosomal membrane stability represents a novel approach for the induction of cancer-specific cell death. PMID:26380379

  8. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Xuanbin Wang

    2014-01-01

    Full Text Available Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and Methods. Chinese medicines (including Chinese medicinal herbs, animal parts, and minerals were used in the study. The key words including “cancer”, “cell death”, “apoptosis”, “autophagy,” “necrosis,” and “Chinese medicine” were used in retrieval of related information from PubMed and other databases. Results. The cell death induced by Chinese medicines is described as apoptotic, autophagic, or necrotic cell death and other types with an emphasis on their mechanisms of anticancer action. The relationship among different types of cell death induced by Chinese medicines is critically reviewed and discussed. Conclusions. This review summarizes that CMs treatment could induce multiple pathways leading to cancer cell death, in which apoptosis is the dominant type. To apply these preclinical researches to clinic application will be a key issue in the future.

  9. Regulatory mechanism of radiation-induced cancer cell death by the change of cell cycle

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Soo Jin; Jeong, Min Ho; Jang, Ji Yeon [College of Medicine, Donga Univ., Pusan (Korea, Republic of)

    2003-09-01

    cycle regulatory activites. In this study, we present a unique and reproducible model in which for investigating the mechanisms of various, radiation-induced, cancer cell death patterns. Further evaluation by using this model will provide a potent target for a new strategy of radiotherapy.

  10. Role of p53 in Cell Death and Human Cancers

    International Nuclear Information System (INIS)

    p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers

  11. Role of p53 in Cell Death and Human Cancers

    OpenAIRE

    Toshinori Ozaki; Akira Nakagawara

    2011-01-01

    p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA ...

  12. Apoptotic Death of Prostate Cancer Cells by a Gonadotropin-Releasing Hormone-II Antagonist

    OpenAIRE

    Park, Sumi; Han, Ji Man; Cheon, Jun; Hwang, Jong-Ik; Seong, Jae Young

    2014-01-01

    Gonadotropin-releasing hormone-I (GnRH-I) has attracted strong attention as a hormonal therapeutic tool, particularly for androgen-dependent prostate cancer patients. However, the androgen-independency of the cancer in advanced stages has spurred researchers to look for new medical treatments. In previous reports, we developed the GnRH-II antagonist Trp-1 to inhibit proliferation and stimulate the autophagic death of various prostate cancer cells, including androgen-independent cells. We furt...

  13. Apoptosis Cell Death Effect of Scrophularia Variegata on Breast Cancer Cells via Mitochondrial Intrinsic Pathway

    Science.gov (United States)

    Azadmehr, Abbas; Hajiaghaee, Reza; Baradaran, Behzad; Haghdoost-Yazdi, Hashem

    2015-01-01

    Purpose: Scrophularia variegata M. Beib. (Scrophulariaceae) is an Iranian medicinal plant which is used for various inflammatory disorders in traditional medicine. In this study we evaluated the anti-cancer and cytotoxic effects of the Scrophularia variegata (S. variegata) ethanolic extract on the human breast cancer cell line. Methods: The cytotoxicity effect of the extract on MCF-7 cells was evaluated by MTT assay. In addition, Caspase activity, DNA ladder and Cell death were evaluated by ELISA, gel electrophoresis and Annexin V-FITC/PI staining, respectively. Results: The S. variegata extract showed significant effect cytotoxicity on MCF-7 human breast cancer cell line. Treatment with the extract induced apoptosis on the breast cancer cells by cell cycle arrest in G2/M phase. The results indicated that cytotoxicity activity was associated with an increase of apoptosis as demonstrated by DNA fragmentation as well as an increase of the amount of caspase 3 and caspase 9. In addition, the phytochemical assay showed that the extract had antioxidant capacity and also flavonoids, phenolic compounds and phenyl propanoids were presented in the extract. Conclusion: Our findings indicated that S. variegata extract induced apoptosis via mitochondrial intrinsic pathway on breast cancer by cell cycle arrest in G2/M phase and an increase of caspase 3 and caspase 9. However future studies are needed. PMID:26504768

  14. Induction of Cancer Cell Death by Isoflavone: The Role of Multiple Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Fazlul H. Sarkar

    2011-10-01

    Full Text Available Soy isoflavones have been documented as dietary nutrients broadly classified as “natural agents” which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR, p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials.

  15. Pyrvinium targets autophagy addiction to promote cancer cell death

    OpenAIRE

    Deng, Longfei; Lei, Yunlong; Liu, Rui; Li, Jingyi; Yuan, Kefei; Li, Yi; Chen, Yi; Liu, Yi; Lu, You; Edwards III, Carl K; Huang, Canhua; Wei, Yuquan

    2013-01-01

    Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that...

  16. Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Curry, Merril C.; Peters, Amelia A. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Kenny, Paraic A. [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461 (United States); Roberts-Thomson, Sarah J. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Monteith, Gregory R., E-mail: gregm@uq.edu.au [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia)

    2013-05-10

    Highlights: •Some clinical breast cancers are associated with MCU overexpression. •MCU silencing did not alter cell death initiated with the Bcl-2 inhibitor ABT-263. •MCU silencing potentiated caspase-independent cell death initiated by ionomycin. •MCU silencing promoted ionomycin-mediated cell death without changes in bulk Ca{sup 2+}. -- Abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca{sup 2+} into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levels of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca{sup 2+} levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca{sup 2+} levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.

  17. Apoptotic Cell Death Induced by Resveratrol Is Partially Mediated by the Autophagy Pathway in Human Ovarian Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Fangfang Lang

    Full Text Available Resveratrol (trans-3,4,5'-trihydroxystilbene is an active compound in food, such as red grapes, peanuts, and berries. Resveratrol exhibits an anticancer effect on various human cancer cells. However, the mechanism of resveratrol-induced anti-cancer effect at the molecular level remains to be elucidated. In this study, the mechanism underlying the anti-cancer effect of resveratrol in human ovarian cancer cells (OVCAR-3 and Caov-3 was investigated using various molecular biology techniques, such as flow cytometry, western blotting, and RNA interference, with a major focus on the potential role of autophagy in resveratrol-induced apoptotic cell death. We demonstrated that resveratrol induced reactive oxygen species (ROS generation, which triggers autophagy and subsequent apoptotic cell death. Resveratrol induced ATG5 expression and promoted LC3 cleavage. The apoptotic cell death induced by resveratrol was attenuated by both pharmacological and genetic inhibition of autophagy. The autophagy inhibitor chloroquine, which functions at the late stage of autophagy, significantly reduced resveratrol-induced cell death and caspase 3 activity in human ovarian cancer cells. We also demonstrated that targeting ATG5 by siRNA also suppressed resveratrol-induced apoptotic cell death. Thus, we concluded that a common pathway between autophagy and apoptosis exists in resveratrol-induced cell death in OVCAR-3 human ovarian cancer cells.

  18. Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.

    Science.gov (United States)

    Sun, Yiming; Liu, Zhe; Zou, Xue; Lan, Yadong; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Jiang, Chenchen; Liu, Hao

    2015-08-01

    3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores. PMID:26054380

  19. Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer

    OpenAIRE

    Sun, Yiming; Zhe LIU; Zou, Xue; Lan, Yadong; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Jiang, Chenchen; Liu, Hao

    2015-01-01

    3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration...

  20. VMP1 related autophagy and apoptosis in colorectal cancer cells: VMP1 regulates cell death

    Energy Technology Data Exchange (ETDEWEB)

    Qian, Qinyi [Department of Ultrasonograph, Changshu No. 2 People’s Hospital, Changshu (China); Zhou, Hao; Chen, Yan [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China); Shen, Chenglong [Department of General Surgery, Changshu No. 2 People’s Hospital, Changshu (China); He, Songbing; Zhao, Hua; Wang, Liang [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China); Wan, Daiwei, E-mail: 372710369@qq.com [Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou (China); Gu, Wen, E-mail: 505339704@qq.com [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou (China)

    2014-01-17

    Highlights: •This research confirmed VMP1 as a regulator of autophagy in colorectal cancer cell lines. •We proved the pro-survival role of VMP1-mediated autophagy in colorectal cancer cell lines. •We found the interaction between VMP1 and BECLIN1 also existing in colorectal cancer cell lines. -- Abstract: Vacuole membrane protein 1 (VMP1) is an autophagy-related protein and identified as a key regulator of autophagy in recent years. In pancreatic cell lines, VMP1-dependent autophagy has been linked to positive regulation of apoptosis. However, there are no published reports on the role of VMP1 in autophagy and apoptosis in colorectal cancers. Therefore, to address this gap of knowledge, we decided to interrogate regulation of autophagy and apoptosis by VMP1. We have studied the induction of autophagy by starvation and rapamycin treatment in colorectal cell lines using electron microscopy, immunofluorescence, and immunoblotting. We found that starvation-induced autophagy correlated with an increase in VMP1 expression, that VMP1 interacted with BECLIN1, and that siRNA mediated down-regulation of VMP1-reduced autophagy. Next, we examined the relationship between VMP1-dependent autophagy and apoptosis and found that VMP1 down-regulation sensitizes cells to apoptosis and that agents that induce apoptosis down-regulate VMP1. In conclusion, similar to its reported role in other cell types, VMP1 is an important regulator of autophagy in colorectal cell lines. However, in contrast to its role in pancreatic cell lines, in colorectal cancer cells, VMP1-dependent autophagy appears to be pro-survival rather than pro-cell death.

  1. VMP1 related autophagy and apoptosis in colorectal cancer cells: VMP1 regulates cell death

    International Nuclear Information System (INIS)

    Highlights: •This research confirmed VMP1 as a regulator of autophagy in colorectal cancer cell lines. •We proved the pro-survival role of VMP1-mediated autophagy in colorectal cancer cell lines. •We found the interaction between VMP1 and BECLIN1 also existing in colorectal cancer cell lines. -- Abstract: Vacuole membrane protein 1 (VMP1) is an autophagy-related protein and identified as a key regulator of autophagy in recent years. In pancreatic cell lines, VMP1-dependent autophagy has been linked to positive regulation of apoptosis. However, there are no published reports on the role of VMP1 in autophagy and apoptosis in colorectal cancers. Therefore, to address this gap of knowledge, we decided to interrogate regulation of autophagy and apoptosis by VMP1. We have studied the induction of autophagy by starvation and rapamycin treatment in colorectal cell lines using electron microscopy, immunofluorescence, and immunoblotting. We found that starvation-induced autophagy correlated with an increase in VMP1 expression, that VMP1 interacted with BECLIN1, and that siRNA mediated down-regulation of VMP1-reduced autophagy. Next, we examined the relationship between VMP1-dependent autophagy and apoptosis and found that VMP1 down-regulation sensitizes cells to apoptosis and that agents that induce apoptosis down-regulate VMP1. In conclusion, similar to its reported role in other cell types, VMP1 is an important regulator of autophagy in colorectal cell lines. However, in contrast to its role in pancreatic cell lines, in colorectal cancer cells, VMP1-dependent autophagy appears to be pro-survival rather than pro-cell death

  2. Novel self-micellizing anticancer lipid nanoparticles induce cell death of colorectal cancer cells.

    Science.gov (United States)

    Sundaramoorthy, Pasupathi; Baskaran, Rengarajan; Mishra, Siddhartha Kumar; Jeong, Keun-Yeong; Oh, Seung Hyun; Kyu Yoo, Bong; Kim, Hwan Mook

    2015-11-01

    In the present study, we developed a novel drug-like self-micellizing anticancer lipid (SMAL), and investigated its anticancer activity and effects on cell death pathways in human colorectal cancer (CRC) cell lines. Three self-assembled nanoparticles were prepared, namely, SMAL102 (lauramide derivative), SMAL104 (palmitamide derivative), and SMAL108 (stearamide derivative) by a thin-film hydration technique, and were characterized for physicochemical and biological parameters. SMAL102 were nanosized (160.23 ± 8.11 nm) with uniform spherical shape, while SMAL104 and SMAL108 did not form spherical shape but formed large size nanoparticles and irregular in shape. Importantly, SMAL102 showed a cytotoxic effect towards CRC cell lines (HCT116 and HT-29), and less toxicity to a normal colon fibroblast cell line (CCD-18Co). Conversely, SMAL104 and SMAL108 did not have an anti-proliferative effect on CRC cell lines. SMAL102 nanoparticles were actively taken up by CRC cell lines, localized in the cell membrane, and exhibited remarkable cytotoxicity in a concentration-dependent manner. The normal colon cell line showed significantly less cellular uptake and non-cytotoxicity as compared with the CRC cell lines. SMAL102 nanoparticles induced caspase-3, caspase-9, and PARP cleavage in HT-29 cells, indicating the induction of apoptosis; whereas LC3B was activated in HCT116 cells, indicating autophagy-induced cell death. Collectively, these results demonstrate that SMAL102 induced cell death via activation of apoptosis and autophagy in CRC cell lines. The present study could be a pioneer for further preclinical and clinical development of such compounds. PMID:26342325

  3. Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death

    International Nuclear Information System (INIS)

    Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells. In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed. Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer. We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect

  4. Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment.

    Science.gov (United States)

    Wu, Amy; Liao, David; Tlsty, Thea D; Sturm, James C; Austin, Robert H

    2014-08-01

    Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression. PMID:25097749

  5. Microscopic analysis of cell death by metabolic stress-induced autophagy in prostate cancer

    Science.gov (United States)

    Changou, Chun; Cheng, R. Holland; Bold, Richard; Kung, Hsing-Jien; Chuang, Frank Y. S.

    2013-02-01

    Autophagy is an intracellular recycling mechanism that helps cells to survive against environmental stress and nutritional starvation. We have recently shown that prostate cancers undergo metabolic stress and caspase-independent cell death following exposure to arginine deiminase (ADI, an enzyme that degrades arginine in tissue). The aims of our current investigation into the application of ADI as a novel cancer therapy are to identify the components mediating tumor cell death, and to determine the role of autophagy (stimulated by ADI and/or rapamycin) on cell death. Using advanced fluorescence microscopy techniques including 3D deconvolution and superresolution structured-illumination microscopy (SIM), we show that prostate tumor cells that are killed after exposure to ADI for extended periods, exhibit a morphology that is distinct from caspase-dependent apoptosis; and that autophagosomes forming as a result of ADI stimulation contain DAPI-stained nuclear material. Fluorescence imaging (as well as cryo-electron microscopy) show a breakdown of both the inner and outer nuclear membranes at the interface between the cell nucleus and aggregated autophagolysosomes. Finally, the addition of N-acetyl cysteine (or NAC, a scavenger for reactive oxygen species) effectively abolishes the appearance of autophagolysosomes containing nuclear material. We hope to continue this research to understand the processes that govern the survival or death of these tumor cells, in order to develop methods to improve the efficacy of cancer pharmacotherapy.

  6. Apoptotic death of prostate cancer cells by a gonadotropin-releasing hormone-II antagonist.

    Directory of Open Access Journals (Sweden)

    Sumi Park

    Full Text Available Gonadotropin-releasing hormone-I (GnRH-I has attracted strong attention as a hormonal therapeutic tool, particularly for androgen-dependent prostate cancer patients. However, the androgen-independency of the cancer in advanced stages has spurred researchers to look for new medical treatments. In previous reports, we developed the GnRH-II antagonist Trp-1 to inhibit proliferation and stimulate the autophagic death of various prostate cancer cells, including androgen-independent cells. We further screened many GnRH-II antagonists to identify molecules with higher efficiency. Here, we investigated the effect of SN09-2 on the growth of PC3 prostate cancer cells. SN09-2 reduced the growth of prostate cancer cells but had no effect on cells derived from other tissues. Compared with Trp-1, SN09-2 conspicuously inhibited prostate cancer cell growth, even at low concentrations. SN09-2-induced PC3 cell growth inhibition was associated with decreased membrane potential in mitochondria where the antagonist was accumulated, and increased mitochondrial and cytosolic reactive oxygen species. SN09-2 induced lactate dehydrogenase release into the media and annexin V-staining on the PC3 cell surface, suggesting that the antagonist stimulated prostate cancer cell death by activating apoptotic signaling pathways. Furthermore, cytochrome c release from mitochondria to the cytosol and caspase-3 activation occurred in a concentration- and time-dependent manner. SN09-2 also inhibited the growth of PC3 cells xenotransplanted into nude mice. These results demonstrate that SN09-2 directly induces mitochondrial dysfunction and the consequent ROS generation, leading to not only growth inhibition but also apoptosis of prostate cancer cells.

  7. Cell death triggered by alpha-emitting {sup 213}Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Schmid, Ernst [National Research Center for Environment and Health, Institute of Radiation Biology, GSF, Neuherberg (Germany); Abend, Michael [German Armed Forces, Institute of Radiobiology, Munich (Germany); Becker, Karl-Friedrich [Technische Universitaet Muenchen, Institute of Pathology, Munich (Germany); National Research Center for Environment and Health, Institute of Pathology, GSF, Neuherberg (Germany); National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany); Apostolidis, Christos; Nikula, Tuomo K. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Kremmer, Elisabeth [National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany)

    2005-03-01

    Radioimmunotherapy with {alpha}-particle-emitting nuclides, such as{sup 213}Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by {sup 213}Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of {sup 213}Bi-d9MAb targeting d9-E-cadherin and {sup 213}Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as {sup 213}Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and {sup 213}Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with {sup 213}Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of {alpha}-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific {sup 213}Bi-d9MAb compared with unspecific {sup 213}Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound {sup 213}Bi-immunoconjugates per cell exceeded 2 x 10{sup 4}, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by {sup 213}Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. {sup 213}Bi-immunoconjugates seem

  8. Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

    International Nuclear Information System (INIS)

    Radioimmunotherapy with α-particle-emitting nuclides, such as213Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213Bi-d9MAb targeting d9-E-cadherin and 213Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of α-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213Bi-d9MAb compared with unspecific 213Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213Bi-immunoconjugates per cell exceeded 2 x 104, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. 213Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells. (orig.)

  9. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

    Directory of Open Access Journals (Sweden)

    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  10. Fluvastatin mediated breast cancer cell death: a proteomic approach to identify differentially regulated proteins in MDA-MB-231 cells.

    Directory of Open Access Journals (Sweden)

    Anantha Koteswararao Kanugula

    Full Text Available Statins are increasingly being recognized as anti-cancer agents against various cancers including breast cancer. To understand the molecular pathways targeted by fluvastatin and its differential sensitivity against metastatic breast cancer cells, we analyzed protein alterations in MDA-MB-231 cells treated with fluvastatin using 2-DE in combination with LC-MS/MS. Results revealed dys-regulation of 39 protein spots corresponding to 35 different proteins. To determine the relevance of altered protein profiles with breast cancer cell death, we mapped these proteins to major pathways involved in the regulation of cell-to-cell signaling and interaction, cell cycle, Rho GDI and proteasomal pathways using IPA analysis. Highly interconnected sub networks showed that vimentin and ERK1/2 proteins play a central role in controlling the expression of altered proteins. Fluvastatin treatment caused proteolysis of vimentin, a marker of epithelial to mesenchymal transition. This effect of fluvastatin was reversed in the presence of mevalonate, a downstream product of HMG-CoA and caspase-3 inhibitor. Interestingly, fluvastatin neither caused an appreciable cell death nor did modulate vimentin expression in normal mammary epithelial cells. In conclusion, fluvastatin alters levels of cytoskeletal proteins, primarily targeting vimentin through increased caspase-3- mediated proteolysis, thereby suggesting a role for vimentin in statin-induced breast cancer cell death.

  11. YM155 potently triggers cell death in breast cancer cells through an autophagy-NF-kB network.

    Science.gov (United States)

    Véquaud, Eloïse; Séveno, Céline; Loussouarn, Delphine; Engelhart, Lucie; Campone, Mario; Juin, Philippe; Barillé-Nion, Sophie

    2015-05-30

    Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first "Survivin suppressant" but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. We herein show that YM155 exerts single agent toxicity on primary breast cancer cells grown in an ex vivo assay preserving tumor microenvironment. In vitro assays indicate that YM155 more efficiently triggers cell death in breast cancer cells (including these with stem-cell like properties) than in non tumorigenic mammary cells. YM155-induced cell death is critically dependent on autophagy and NF-kB but independent of p53 and it coïncides with DNA damage and a DNA damage response in p53-proficient cells. Our results point out a crosstalk between NF-kB and autophagy controlling YM155-induced death in breast cancer cells and argue for the potential use of YM155 as a genotoxic agent in breast cancer therapy. PMID:25974963

  12. The DNA damage-induced cell death response: a roadmap to kill cancer cells.

    Science.gov (United States)

    Matt, Sonja; Hofmann, Thomas G

    2016-08-01

    Upon massive DNA damage cells fail to undergo productive DNA repair and trigger the cell death response. Resistance to cell death is linked to cellular transformation and carcinogenesis as well as radio- and chemoresistance, making the underlying signaling pathways a promising target for therapeutic intervention. Diverse DNA damage-induced cell death pathways are operative in mammalian cells and finally culminate in the induction of programmed cell death via activation of apoptosis or necroptosis. These signaling routes affect nuclear, mitochondria- and plasma membrane-associated key molecules to activate the apoptotic or necroptotic response. In this review, we highlight the main signaling pathways, molecular players and mechanisms guiding the DNA damage-induced cell death response. PMID:26791483

  13. Conserved features of cancer cells define their sensitivity of HAMLET-induced death; c-Myc and glycolysis

    OpenAIRE

    Storm, Petter; Puthia, Manoj Kumar; Aits, Sonja; Urbano, Alexander; Northen, Trent; Powers, Scott; Bowen, Ben; Chao, Yinxia; Reindl, Wolfgang; Lee, Do Yup; Sullivan, Nancy Liu; Zhang, Jianping; Trulsson, Maria; Yang, Henry; Watson, James

    2011-01-01

    HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small hairpin RNA inhibition, proteomic ...

  14. The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

    OpenAIRE

    Razmik Mirzayans; Bonnie Andrais; Piyush Kumar; David Murray

    2016-01-01

    It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and t...

  15. Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines.

    Science.gov (United States)

    Koty, P P; Zhang, H; Levitt, M L

    1999-02-01

    Programmed cell death (PCD) is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the ratio of PCD inducers (Bax) or inhibitors (Bcl-2). An abnormally high ratio of Bcl-2 to Bax prevents PCD, thus contributing to resistance to chemotherapeutic agents, many of which are capable of inducing PCD. Non-small cell lung cancer (NSCLC) cells demonstrate resistance to these PCD-inducing agents. If Bcl-2 prevents NSCLC cells from entering the PCD pathway, then reducing the amount of endogenous Bcl-2 product may allow these cells to spontaneously enter the PCD pathway. Our purpose was to determine the effects of bcl-2 antisense treatment on the levels of programmed cell death in NSCLC cells. First, we determined whether bcl-2 and bax mRNA were expressed in three morphologically distinct NSCLC cell lines: NCI-H226 (squamous), NCI-H358 (adenocarcinoma), and NCI-H596 (adenosquamous). Cells were then exposed to synthetic antisense bcl-2 oligonucleotide treatment, after which programmed cell death was determined, as evidenced by DNA fragmentation. Bcl-2 protein expression was detected immunohistochemically. All three NSCLC cell lines expressed both bcl-2 and bax mRNA and had functional PCD pathways. Synthetic antisense bcl-2 oligonucleotide treatment resulted in decreased Bcl-2 levels, reduced cell proliferation, decreased cell viability, and increased levels of spontaneous PCD. This represents the first evidence that decreasing Bcl-2 in three morphologically distinct NSCLC cell lines allows the cells to spontaneously enter a PCD pathway. It also indicates the potential therapeutic use of antisense bcl-2 in the treatment of NSCLC. PMID:10217615

  16. Non-chemotoxic induction of cancer cell death using magnetic nanowires

    KAUST Repository

    Contreras, Maria

    2015-03-01

    In this paper, we show that magnetic nanowires with weak magnetic fields and low frequencies can induce cell death via a mechanism that does not involve heat production. We incubated colon cancer cells with two concentrations (2.4 and 12 μg/mL) of nickel nanowires that were 35 nm in diameter and exposed the cells and nanowires to an alternating magnetic field (0.5 mT and 1 Hz or 1 kHz) for 10 or 30 minutes. This low-power field exerted a force on the magnetic nanowires, causing a mechanical disturbance to the cells. Transmission electron microscopy images showed that the nanostructures were internalized into the cells within 1 hour of incubation. Cell viability studies showed that the magnetic field and the nanowires separately had minor deleterious effects on the cells; however, when combined, the magnetic field and nanowires caused the cell viability values to drop by up to 39%, depending on the strength of the magnetic field and the concentration of the nanowires. Cell membrane leakage experiments indicated membrane leakage of 20%, suggesting that cell death mechanisms induced by the nanowires and magnetic field involve some cell membrane rupture. Results suggest that magnetic nanowires can kill cancer cells. The proposed process requires simple and low-cost equipment with exposure to only very weak magnetic fields for short time periods. © 2015 Contreras et al.

  17. Immediate in vivo target-specific cancer cell death after near infrared photoimmunotherapy

    Directory of Open Access Journals (Sweden)

    Mitsunaga Makoto

    2012-08-01

    Full Text Available Abstract Background Near infrared (NIR photoimmunotherapy (PIT is a new type of cancer treatment based on a monoclonal antibody (mAb-NIR phthalocyanine dye, (IR700 conjugate. In vitro cancer-specific cell death occurs during NIR light exposure in cells previously incubated with mAb-IR700 conjugates. However, documenting rapid cell death in vivo is more difficult. Methods A luciferase-transfected breast cancer cell (epidermal growth factor receptor+, MDA-MB-468luc cells was produced and used for both in vitro and in vivo experiments for monitoring the cell killing effect of PIT. After validation of cytotoxicity with NIR exposure up to 8 J/cm2in vitro, we employed an orthotopic breast cancer model of bilateral MDA-MB-468luc tumors in female athymic mice, which subsequently received a panitumumab-IR700 conjugate in vivo. One side was used as a control, while the other was treated with NIR light of dose ranging from 50 to 150 J/cm2. Bioluminescence imaging (BLI was performed before and after PIT. Results Dose-dependent cell killing and regrowth was successfully monitored by the BLI signal in vitro. Although tumor sizes were unchanged, BLI signals decreased by >95% immediately after PIT in vivo when light intensity was high (>100 J/cm2, however, in mice receiving lower intensity NIR (50 J/cm2, tumors recurred with gradually increasing BLI signal. Conclusion PIT induced massive cell death of targeted tumor cells immediately after exposure of NIR light that was demonstrated with BLI in vivo.

  18. Immediate in vivo target-specific cancer cell death after near infrared photoimmunotherapy

    International Nuclear Information System (INIS)

    Near infrared (NIR) photoimmunotherapy (PIT) is a new type of cancer treatment based on a monoclonal antibody (mAb)-NIR phthalocyanine dye, (IR700) conjugate. In vitro cancer-specific cell death occurs during NIR light exposure in cells previously incubated with mAb-IR700 conjugates. However, documenting rapid cell death in vivo is more difficult. A luciferase-transfected breast cancer cell (epidermal growth factor receptor+, MDA-MB-468luc cells) was produced and used for both in vitro and in vivo experiments for monitoring the cell killing effect of PIT. After validation of cytotoxicity with NIR exposure up to 8 J/cm2in vitro, we employed an orthotopic breast cancer model of bilateral MDA-MB-468luc tumors in female athymic mice, which subsequently received a panitumumab-IR700 conjugate in vivo. One side was used as a control, while the other was treated with NIR light of dose ranging from 50 to 150 J/cm2. Bioluminescence imaging (BLI) was performed before and after PIT. Dose-dependent cell killing and regrowth was successfully monitored by the BLI signal in vitro. Although tumor sizes were unchanged, BLI signals decreased by >95% immediately after PIT in vivo when light intensity was high (>100 J/cm2), however, in mice receiving lower intensity NIR (50 J/cm2), tumors recurred with gradually increasing BLI signal. PIT induced massive cell death of targeted tumor cells immediately after exposure of NIR light that was demonstrated with BLI in vivo

  19. Xylitol induces cell death in lung cancer A549 cells by autophagy.

    Science.gov (United States)

    Park, Eunjoo; Park, Mi Hee; Na, Hee Sam; Chung, Jin

    2015-05-01

    Xylitol is a widely used anti-caries agent that has anti-inflammatory effects. We have evaluated the potential of xylitol in cancer treatment. It's effects on cell proliferation and cytotoxicity were measured by MTT assay and LDH assay. Cell morphology and autophagy were examined by immunostaining and immunoblotting. Xylitol inhibited cell proliferation in a dose-dependent manner in these cancer cells: A549, Caki, NCI-H23, HCT-15, HL-60, K562, and SK MEL-2. The IC50 of xylitol in human gingival fibroblast cells was higher than in cancer cells, indicating that it is more specific for cancer cells. Moreover, xylitol induced autophagy in A549 cells that was inhibited by 3-methyladenine, an autophagy inhibitor. These results indicate that xylitol has potential in therapy against lung cancer by inhibiting cell proliferation and inducing autophagy of A549 cells. PMID:25650339

  20. Down-regulation of phosphoglucomutase 3 mediates sulforaphane-induced cell death in LNCaP prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Lee Hyo-Jeong

    2010-12-01

    Full Text Available Abstract Background Sulforaphane (SFN is an isothiocyanate found in cruciferous vegetables that exerts anti-oxidant, anti-inflammatory, anti-cancer and radio-sensitizing activities. Nonetheless, the mechanism responsible for SFN-induced cell death is not fully understood. In the present study, anti-cancer mechanism of SFN was elucidated in LNCaP prostate cancer cells. Results SFN exerted cytotoxicity and increased TUNEL positive cells in a concentration-dependent manner in LNCaP cells. Proteomics study revealed that levels of nine proteins including tubulin β-2, phosphoglucomutase-3 (PGM3, melanoma-derived leucine zipper containing extra-nuclear factor, activin A type I receptor precursor, smoothelin-A, KIA0073, hypothetical protein LOC57691 and two unnamed proteins were changed over 8 folds in SFN treated LNCaP cells compared to untreated control. We have further confirmed that SFN reduced PGM3 expression with western blotting and showed that PGM3 siRNA enhanced cytotoxicity demonstrated by cell morphology and TUNEL assays in LNCaP cells. Conclusion Taken together, these findings suggest that PGM3 plays a role in mediating SFN-induced cell death in LNCaP cells, and is a potential molecular therapeutic target for prostate cancer.

  1. A unifying mechanism for cancer cell death through ion channel activation by HAMLET.

    Directory of Open Access Journals (Sweden)

    Petter Storm

    Full Text Available Ion channels and ion fluxes control many aspects of tissue homeostasis. During oncogenic transformation, critical ion channel functions may be perturbed but conserved tumor specific ion fluxes remain to be defined. Here we used the tumoricidal protein-lipid complex HAMLET as a probe to identify ion fluxes involved in tumor cell death. We show that HAMLET activates a non-selective cation current, which reached a magnitude of 2.74±0.88 nA within 1.43±0.13 min from HAMLET application. Rapid ion fluxes were essential for HAMLET-induced carcinoma cell death as inhibitors (amiloride, BaCl2, preventing the changes in free cellular Na(+ and K(+ concentrations also prevented essential steps accompanying carcinoma cell death, including changes in morphology, uptake, global transcription, and MAP kinase activation. Through global transcriptional analysis and phosphorylation arrays, a strong ion flux dependent p38 MAPK response was detected and inhibition of p38 signaling delayed HAMLET-induced death. Healthy, differentiated cells were resistant to HAMLET challenge, which was accompanied by innate immunity rather than p38-activation. The results suggest, for the first time, a unifying mechanism for the initiation of HAMLET's broad and rapid lethal effect on tumor cells. These findings are particularly significant in view of HAMLET's documented therapeutic efficacy in human studies and animal models. The results also suggest that HAMLET offers a two-tiered therapeutic approach, killing cancer cells while stimulating an innate immune response in surrounding healthy tissues.

  2. Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines.

    Science.gov (United States)

    Oveland, Eystein; Wergeland, Line; Hovland, Randi; Lorens, James B; Gjertsen, Bjørn Tore; Fladmark, Kari E

    2012-08-01

    Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 (IL-3)-dependent murine cell lines like Ba/F3, resulting in loss of IL-3 dependence. Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia (AML) cell lines, despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients. We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death, involving Bax/Bcl2 modulation. Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs, shown here using the HL-60 leukemic cell line. Flt3 expression was investigated in two cellular model systems, the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line, and proliferation was reduced in both systems. HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2. Furthermore, we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent. Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines. PMID:22422053

  3. Cytotoxic hydrogen bridged ruthenium quinaldamide complexes showing induced cancer cell death by apoptosis.

    Science.gov (United States)

    Lord, Rianne M; Allison, Simon J; Rafferty, Karen; Ghandhi, Laura; Pask, Christopher M; McGowan, Patrick C

    2016-08-16

    This report presents the first known p-cymene ruthenium quinaldamide complexes which are stabilised by a hydrogen-bridging atom, [{(p-cym)Ru(II)X(N,N)}{H(+)}{(N,N)XRu(II)(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(μ-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 ⇔ NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H(+), which are counter-balanced by a PF6 counterion. X-ray crystallographic analysis is presented for six new structures with OO distances of 2.420(4)-2.448(15) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index >1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis. PMID:27417660

  4. IKK inhibitor suppresses epithelial-mesenchymal transition and induces cell death in prostate cancer.

    Science.gov (United States)

    Ping, Hao; Yang, Feiya; Wang, Mingshuai; Niu, Yinong; Xing, Nianzeng

    2016-09-01

    IκB kinase (IKK)/nuclear factor κB (NF-κB) pathway activation is a key event in the acquisition of invasive and metastatic capacities in prostate cancer. A potent small-molecule compound, BMS-345541, was identified as a highly selective IKKα and IKKβ inhibitor to inhibit kinase activity. This study explored the effect of IKK inhibitor on epithelial-mesenchymal transition (EMT), apoptosis and metastasis in prostate cancer. Here, we demonstrate the role of IKK inhibitor reducing proliferation and inducing apoptosis in PC-3 cells. Furthermore, BMS345541 inhibited IκBα phosphorylation and nuclear level of NF-κB/p65 in PC-3 cells. We also observed downregulation of the N-cadherin, Snail, Slug and Twist protein in a dose-dependent manner. BMS‑345541 induced upregulation of the epithelial marker E-cadherin and phosphorylated NDRG1 at protein level. Moreover, BMS‑345541 reduced invasion and metastasis of PC-3 cells in vitro. In conclusion, IKK has a key role in both EMT and apoptosis of prostate cancer. IKK inhibitor can reverse EMT and induce cell death in PCa cells. IKK was identified as a potential target structure for future therapeutic intervention in PCa. PMID:27432067

  5. Cytotoxicity of obacunone and obacunone glucoside in human prostate cancer cells involves Akt-mediated programmed cell death

    International Nuclear Information System (INIS)

    Highlights: • Possible mechanism of inhibiting LNCaP cells proliferation by obacunone and obacunone glucoside is demonstrated for the first time. • Inhibition of LNCaP cells by limonoids though induction of programmed cell death, inhibition of cell signaling and inflammatory pathways. • Limonoids exhibited multi-mode inhibition of androgen expression in LNCaP cells. - Abstract: Obacunone and obacunone glucoside (OG) are naturally occurring triterpenoids commonly found in citrus and other plants of the Rutaceae family. The current study reports the mechanism of cytotoxicity of citrus-derived obacunone and OG on human androgen-dependent prostate cancer LNCaP cells. Both limonoids exhibited time- and dose-dependent inhibition of cell proliferation, with more than 60% inhibition of cell viability at 100 μM, after 24 and 48 h. Analysis of fragmentation of DNA, activity of caspase-3, and cytosolic cytochrome-c in the cells treated with limonoids provided evidence for activation of programmed cell death by limonoids. Treatment of LNCaP cells with obacunone and OG resulted in dose-dependent changes in expression of proteins responsible for the induction of programmed cell death through the intrinsic pathway and down-regulation of Akt, a key molecule in cell signaling pathways. In addition, obacunone and OG also negatively regulated an inflammation-associated transcription factor, androgen receptor, and prostate-specific antigen, and activated proteins related to the cell cycle, confirming the ability of limonoids to induce cytotoxicity through multiple pathways. The results of this study provided, for the first time, an evidence of the cytotoxicity of obacunone and OG in androgen-dependent human prostate cancer cells

  6. Heat-Modified Citrus Pectin Induces Apoptosis-Like Cell Death and Autophagy in HepG2 and A549 Cancer Cells

    OpenAIRE

    Leclere, Lionel; Fransolet, Maude; Cote, Francois; Cambier, Pierre; Arnould, Thierry; Van Cutsem, Pierre; Michiels, Carine

    2015-01-01

    Cancer is still one of the leading causes of death worldwide, and finding new treatments remains a major challenge. Previous studies showed that modified forms of pectin, a complex polysaccharide present in the primary plant cell wall, possess anticancer properties. Nevertheless, the mechanism of action of modified pectin and the pathways involved are unclear. Here, we show that citrus pectin modified by heat treatment induced cell death in HepG2 and A549 cells. The induced cell death differs...

  7. 3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system.

    Science.gov (United States)

    Valenti, Daniela; Vacca, Rosa A; de Bari, Lidia

    2015-12-01

    3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 μM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate-dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment. PMID:26530987

  8. Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1

    Directory of Open Access Journals (Sweden)

    Dong L

    2015-12-01

    Full Text Available Liwei Dong,1 Hongge Wang,1 Jiajing Niu,1 Mingwei Zou,2 Nuoting Wu,1 Debin Yu,1 Ye Wang,1 Zhihua Zou11Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Psychology, College of Liberal Arts and Social Sciences, University of Houston, Houston, TX, USA Abstract: Inhibition of the nucleotide pool sanitizing enzyme MTH1 causes extensive oxidative DNA damages and apoptosis in cancer cells and hence may be used as an anticancer strategy. As natural products have been a rich source of medicinal chemicals, in the present study, we used the MTH1-catalyzed enzymatic reaction as a high-throughput in vitro screening assay to search for natural compounds capable of inhibiting MTH1. Echinacoside, a compound derived from the medicinal plants Cistanche and Echinacea, effectively inhibited the catalytic activity of MTH1 in an in vitro assay. Treatment of various human cancer cell lines with Echinacoside resulted in a significant increase in the cellular level of oxidized guanine (8-oxoguanine, while cellular reactive oxygen species level remained unchanged, indicating that Echinacoside also inhibited the activity of cellular MTH1. Consequently, Echinacoside treatment induced an immediate and dramatic increase in DNA damage markers and upregulation of the G1/S-CDK inhibitor p21, which were followed by marked apoptotic cell death and cell cycle arrest in cancer but not in noncancer cells. Taken together, these studies identified a natural compound as an MTH1 inhibitor and suggest that natural products can be an important source of anticancer agents. Keywords: Echinacoside, MTH1, 8-oxoG, DNA damage, apoptosis, cell cycle arrest

  9. Tualang Honey Promotes Apoptotic Cell Death Induced by Tamoxifen in Breast Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Nik Soriani Yaacob

    2013-01-01

    Full Text Available Tualang honey (TH is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM, in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.

  10. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid‐specific cancer cell death through autophagy induction

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Roylance, Rebecca; Sander, Jil;

    2012-01-01

    . Live cell microscopy analysis revealed that CERT depletion induces LAMP2‐dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over‐expressed in HER2+ breast cancer and CERT protein expression acts as an independent prognostic...

  11. Non-canonical kinase signaling by the death ligand TRAIL in cancer cells : discord in the death receptor family

    NARCIS (Netherlands)

    Azijli, K.; Weyhenmeyer, B.; Peters, G. J.; de Jong, S.; Kruyt, F. A. E.

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapy is currently evaluated in clinical studies as a tumor cell selective pro-apoptotic approach. However, besides activating canonical caspase-dependent apoptosis by binding to TRAIL-specific death receptors, the TRAIL ligand

  12. Photoacoustic spectral analysis to sense programmed erythrocyte cell death (eryptosis) for monitoring cancer response to treatment

    Science.gov (United States)

    Fadhel, Muhannad N.; Kibria, Fayruz; Kolios, Michael C.

    2016-03-01

    Many types of cancer therapies target the tumor microenvironment, causing biochemical and morphological changes in tissues. In therapies using ultrasound activated microbubbles, vascular collapse is typically reported. Red blood cells (RBCs) that leak out of the vasculature become exposed to the ceramide that is released from damaged endothelial cells. Ceramide can induce programmed cell death in RBCs (eryptosis), and is characterized by cell shrinkage, membrane blebbing and scrambling. Since the effect of eryptotic cells on generated photoacoustics (PA) signals has not been reported, we investigated the potential PA may have for cancer treatment monitoring by using PA spectral analysis to sense eryptosis. To induce eryptosis, C2-ceramide was added to RBC suspensions and that were incubated for 24 hours at 37°C. A control and ceramide-induced sample was imaged in a vessel phantom using a high frequency PA system (VevoLAZR, 10 - 45 MHz bandwidth) irradiated with multiple wavelengths ranging from 680 to 900 nm. PA spectral parameters were measured and linked to changes in RBCs as it underwent eryptosis. These samples were examined using optical microscopy, a blood gas analyzer and an integrating sphere setup to measure optical properties (wavelengths 600 - 900 nm). The results of the experiment demonstrate how PA spectral analysis can be used to identify eryptosis at a depth of more than 1 cm into the phantom using ultrasound derived the y-intercept and mid bandfit (MBF) parameters at optical wavelengths of 800 - 900 nm. These parameters were correlated to the morphological and biochemical changes that eryptotic RBCs display. The results establish the potential of PA in cancer treatment monitoring through sensing treatment induced eryptosis.

  13. Programmed cell death ligand 1 (PD-L1) expression on gastric cancer and its relationship with clinicopathologic factors

    OpenAIRE

    Zhang, Lin; Qiu, Miaozhen; Jin, Ying; Ji, Jiao; Li, Baoxia; Wang, Xueping; Yan, Shumei; Xu, Ruihua; Yang, Dajun

    2015-01-01

    Background: Targeting the immune checkpoints in solid tumors becomes hot recently. Programmed cell death ligand 1 (PD-L1) is ligand for programmed death 1 (PD-1), which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of PD-L1 in tumor specimens of gastric cancer and its relationships with clinicopathological variables and survival. Methods: The expression of PD-L1 in 132 surgically resected specimens of stage II and III gastric cancer wa...

  14. Delayed luminescence to monitor programmed cell death induced by berberine on thyroid cancer cells

    Science.gov (United States)

    Scordino, Agata; Campisi, Agata; Grasso, Rosaria; Bonfanti, Roberta; Gulino, Marisa; Iauk, Liliana; Parenti, Rosalba; Musumeci, Francesco

    2014-11-01

    Correlation between apoptosis and UVA-induced ultraweak photon emission delayed luminescence (DL) from tumor thyroid cell lines was investigated. In particular, the effects of berberine, an alkaloid that has been reported to have anticancer activities, on two cancer cell lines were studied. The FTC-133 and 8305C cell lines, as representative of follicular and anaplastic thyroid human cancer, respectively, were chosen. The results show that berberine is able to arrest cell cycle and activate apoptotic pathway as shown in both cell lines by deoxyribonucleic acid fragmentation, caspase-3 cleavage, p53 and p27 protein overexpression. In parallel, changes in DL spectral components after berberine treatment support the hypothesis that DL from human cells originates mainly from mitochondria, since berberine acts especially at the mitochondrial level. The decrease of DL blue component for both cell lines could be related to the decrease of intra-mitochondrial nicotinamide adenine dinucleotide and may be a hallmark of induced apoptosis. In contrast, the response in the red spectral range is different for the two cell lines and may be ascribed to a different iron homeostasis.

  15. Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy.

    Science.gov (United States)

    Zhao, Xiao; Yang, Keni; Zhao, Ruifang; Ji, Tianjiao; Wang, Xiuchao; Yang, Xiao; Zhang, Yinlong; Cheng, Keman; Liu, Shaoli; Hao, Jihui; Ren, He; Leong, Kam W; Nie, Guangjun

    2016-09-01

    Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD. PMID:27343466

  16. Dr. Josef Steiner Cancer Research Prize Lecture: the role of physiological cell death in neoplastic transformation and in anti-cancer therapy.

    Science.gov (United States)

    Strasser, A

    1999-05-17

    Cell death is a physiological process which is required for normal development and existence of multi-cellular organisms. Physiological cell death, or apoptosis, is controlled by an evolutionarily conserved mechanism. Abnormalities in this process are implicated as a cause or contributing factor in a variety of diseases. Inhibition of apoptosis can promote neoplastic transformation, particularly in combination with dysregulated cell-cycle control, and can influence the response of tumour cells to anti-cancer therapy. Molecular biological and biochemical approaches are used to find missing cell-death regulators and to define signalling cascades, while experiments in genetically modified mice will identify the essential function of these molecules. Discoveries from cell death research should provide clues for designing therapies for a variety of diseases, including degenerative disorders, auto-immunity and cancer. PMID:10225436

  17. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of); An, Byeong Jun; Song, Ho Sueb [College of Oriental Medicine, Kyungwon University, San 65, Bokjeong-dong, Sujeong-gu, Seongnam, Gyeonggii 461-701 (Korea, Republic of); Han, Sang Bae [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of); Kim, Jang Heub [Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Song, Min Jong, E-mail: bitsugar@catholic.ac.kr [Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Hong, Jin Tae, E-mail: jinthong@chungbuk.ac.kr [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of)

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  18. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    International Nuclear Information System (INIS)

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  19. Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies

    Directory of Open Access Journals (Sweden)

    Tengfei Zhang

    2015-01-01

    Full Text Available Cancer immunotherapy strategies based on chimeric antigen receptor (CAR transduced T cells or antibodies against immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 and programmed death 1 (PD-1, achieved significant successes from bench to clinic in the past 2 years. CARs are artificial engineered receptors that can specifically target tumor cell surface antigen, activate T cell and further enhance T cell function, independent of major histocompatibility complex. CAR T cells have shown promising outcomes in cancers, especially in hematologic malignancies. CTLA-4 and PD-1 are two important immune checkpoints negatively regulating T cell activation. Clinical benefits of CTLA-4/PD-1 antibodies are significant in melanoma and other solid tumors. PD-1 is predicted to have fewer side effects and greater antitumor activity than CTLA-4. In this review, we will summarize current immunotherapies based on CAR T cells and PD-1.

  20. Synergistic chemopreventive effects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death.

    Science.gov (United States)

    Wang, Kai; Zhang, Chao; Bao, Jiaolin; Jia, Xuejing; Liang, Yeer; Wang, Xiaotong; Chen, Meiwan; Su, Huanxing; Li, Peng; Wan, Jian-Bo; He, Chengwei

    2016-01-01

    Curcumin (CUR) and berberine (BBR) are renowned natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. However, the anticancer capacity of either CUR or BBR is limited. This prompted us to investigate the chemopreventive potential of co-treatment of CUR and BBR against breast cancers. The results showed that CUR and BBR in combination synergistically inhibited the growth of both MCF-7 and MDA-MB-231 breast cancer cells than the compounds used alone. Further study confirmed that synergistic anti-breast cancer activities of co-treatment of these two compounds was through inducing more apoptosis and autophagic cell death (ACD). The co-treatment-induced apoptosis was caspase-dependent and through activating ERK pathways. Our data also demonstrated that co-treatment of CUR and BBR strongly up-regulated phosphorylation of JNK and Beclin1, and decreased phosphorylated Bcl-2. Inhibition of JNK by SP600125 markedly decreased LC3-II and Beclin1, restored phosphorylated Bcl-2, and reduced the cytotoxicity induced by the two compounds in combination. These results strongly suggested that JNK/Bcl-2/Beclin1 pathway played a key role in the induction of ACD in breast cancer cells by co-treatment of CUR and BBR. This study provides an insight into the potential application of curcumin and berberine in combination for the chemoprevention and treatment of breast cancers. PMID:27263652

  1. The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival?

    Science.gov (United States)

    Mirzayans, Razmik; Andrais, Bonnie; Kumar, Piyush; Murray, David

    2016-01-01

    It is widely stated that wild-type p53 either mediates the activation of cell cycle checkpoints to facilitate DNA repair and promote cell survival, or orchestrates apoptotic cell death following exposure to cancer therapeutic agents. This reigning paradigm has been challenged by numerous discoveries with different human cell types, including solid tumor-derived cell lines. Thus, activation of the p53 signaling pathway by ionizing radiation and other DNA-damaging agents hinders apoptosis and triggers growth arrest (e.g., through premature senescence) in some genetic backgrounds; such growth arrested cells remain viable, secrete growth-promoting factors, and give rise to progeny with stem cell-like properties. In addition, caspase 3, which is best known for its role in the execution phase of apoptosis, has been recently reported to facilitate (rather than suppress) DNA damage-induced genomic instability and carcinogenesis. This observation is consistent with an earlier report demonstrating that caspase 3 mediates secretion of the pro-survival factor prostaglandin E2, which in turn promotes enrichment of tumor repopulating cells. In this article, we review these and related discoveries and point out novel cancer therapeutic strategies. One of our objectives is to demonstrate the growing complexity of the DNA damage response beyond the conventional “repair and survive, or die” hypothesis. PMID:27187358

  2. Circulating cell death products predict clinical outcome of colorectal cancer patients

    International Nuclear Information System (INIS)

    Tumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients. We determined the CK18-Asp396 and total CK18 levels in plasma of 49 colorectal cancer patients, before and after surgical resection of the tumor, by ELISA. Correlations with patient and tumor characteristics were determined by Kruskal-Wallis H and Mann-Whitney U tests. Disease-free survival was determined using Kaplan-Meier methodology with Log Rank tests, and univariate and multivariate Cox proportional hazard analysis. Plasma CK18-Asp396 and total CK18 levels in colorectal cancer patients were related to disease stage and tumor diameter, and were predictive of disease-free survival, independent of disease-stage, with hazard ratios (HR) of patients with high levels (> median) compared to those with low levels (≤ median) of 3.58 (95% CI: 1.17–11.02) and 3.58 (95% CI: 0.97–7.71), respectively. The CK18-Asp396/CK18 ratio, which decreased with tumor progression, was also predictive of disease-free survival, with a low ratio (≤ median) associated with worse disease-free survival: HR 2.78 (95% CI: 1.06–7.19). Remarkably, the plasma CK18-Asp396 and total CK18 levels after surgical removal of the tumor were also predictive of disease-free survival, with patients with high levels having a HR of 3.78 (95% CI: 0.77–18.50) and 4.12 (95% CI: 0.84–20.34), respectively, indicating that these parameters can be used also to monitor patients after surgery. CK18-Asp396 and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients

  3. Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Sung-Keum; Kim, Jae-Hee; Choi, Ha-Na [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Choe, Tae-Boo [Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul (Korea, Republic of); Hong, Seok-Il [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Yi, Jae-Youn [Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Lee, Hyun-Gyu [Department of Microbiology and Immunology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Lee, Yun-Han, E-mail: yhlee87@yuhs.ac [Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Park, In-Chul, E-mail: parkic@kcch.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Knockdown of TWIST1 enhanced ATO- and IR-induced cell death in NSCLCs. • Intracellular ROS levels were increased in cells treated with TWIST1 siRNA. • TWIST1 siRNA induced MMP loss and mitochondrial fragmentation. • TWIST1 siRNA upregulated the fission-related proteins FIS1 and DRP1. - Abstract: TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.

  4. Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction

    International Nuclear Information System (INIS)

    Highlights: • Knockdown of TWIST1 enhanced ATO- and IR-induced cell death in NSCLCs. • Intracellular ROS levels were increased in cells treated with TWIST1 siRNA. • TWIST1 siRNA induced MMP loss and mitochondrial fragmentation. • TWIST1 siRNA upregulated the fission-related proteins FIS1 and DRP1. - Abstract: TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells

  5. Cancer Cell Growth Inhibitory Effect of Bee Venom via Increase of Death Receptor 3 Expression and Inactivation of NF-kappa B in NSCLC Cells

    Directory of Open Access Journals (Sweden)

    Kyung Eun Choi

    2014-07-01

    Full Text Available Our previous findings have demonstrated that bee venom (BV has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB activity assay. BV (1–5 μg/mL inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.

  6. A receptor tyrosine kinase inhibitor, Tyrphostin A9 induces cancer cell death through Drp1 dependent mitochondria fragmentation

    International Nuclear Information System (INIS)

    Highlights: → We screened and identified Tyrphostin A9, a receptor tyrosine kinase inhibitor as a strong mitochondria fission inducer. → Tyrphostin A9 treatment promotes mitochondria dysfunction and contributes to cytotoxicity in cancer cells. → Tyrphostin A9 induces apoptotic cell death through a Drp1-mediated pathway. → Our studies suggest that Tyrphostin A9 induces mitochondria fragmentation and apoptotic cell death via Drp1 dependently. -- Abstract: Mitochondria dynamics controls not only their morphology but also functions of mitochondria. Therefore, an imbalance of the dynamics eventually leads to mitochondria disruption and cell death. To identify specific regulators of mitochondria dynamics, we screened a bioactive chemical compound library and selected Tyrphostin A9, a tyrosine kinase inhibitor, as a potent inducer of mitochondrial fission. Tyrphostin A9 treatment resulted in the formation of fragmented mitochondria filament. In addition, cellular ATP level was decreased and the mitochondrial membrane potential was collapsed in Tyr A9-treated cells. Suppression of Drp1 activity by siRNA or over-expression of a dominant negative mutant of Drp1 inhibited both mitochondrial fragmentation and cell death induced by Tyrpohotin A9. Moreover, treatment of Tyrphostin A9 also evoked mitochondrial fragmentation in other cells including the neuroblastomas. Taken together, these results suggest that Tyrphostin A9 induces Drp1-mediated mitochondrial fission and apoptotic cell death.

  7. Gamma-secretase inhibition combined with platinum compounds enhances cell death in a large subset of colorectal cancer cells

    Directory of Open Access Journals (Sweden)

    Feller Stephan M

    2008-10-01

    Full Text Available Abstract Background Notch signalling is essential for the development and maintenance of the colonic epithelium. Its inhibition induces a differentiation phenotype in vivo and reduces adenomas in APCmin mice. Whether Notch signals are also required in colorectal cancer (CRC has remained elusive. Therefore, 64 CRC cell lines were analysed for the occurrence of proteolytically processed, active Notch. Results 63 CRC lines contained a fragment with approximately the size of the Notch1 intracellular domain (NICD, which is required for signalling. Subsequent analyses with an antibody that specifically recognises the free Val1744 residue generated by γ-secretase-mediated cleavage of Notch1 showed that a subset of CRC cells lacks this specific Val1744-NICD. Surprisingly, inhibition of Val1744-NICD signalling with different γ-secretase inhibitors (GSI did not lead to substantial effects on CRC cell line growth or survival. However, transient activation of Erk upon GSI treatment was detected. Since cisplatin relies on Erk activation for bioactivity in some cells, platinum compounds were tested together with GSI and enhanced cell killing in a subset of Val1744-NICD-positive CRC cell lines was detected. Erk inhibition ablated this combination effect. Conclusion We conclude that γ-secretase inhibition results in activation of the MAP kinases Erk1/2 and, when used in conjunction, enhances cell death induced by platinum compounds in a large subset of colorectal cancer cell lines. Furthermore the activation of Erk appears to be of particular importance in mediating the enhanced effect seen, as its inhibition abrogates the observed phenomenon. These findings do not only highlight the importance of signalling pathway crosstalk but they may also suggest a new avenue of combination therapy for some colorectal cancers.

  8. Oxidative Stress Facilitates IFN-γ-Induced Mimic Extracellular Trap Cell Death in A549 Lung Epithelial Cancer Cells.

    Science.gov (United States)

    Lin, Chiou-Feng; Chen, Chia-Ling; Chien, Shun-Yi; Tseng, Po-Chun; Wang, Yu-Chih; Tsai, Tsung-Ting

    2016-01-01

    We previously demonstrated that IFN-γ induces an autophagy-regulated mimic extracellular trap cell death (ETosis) in A549 human lung cancer cells. Regarding reactive oxygen species (ROS) are involved in ETosis, this study investigated the role of oxidative stress. After IFN-γ stimulation, a necrosis-like cell death mimic ETosis occurred accompanied by the inhibition of cell growth, aberrant nuclear staining, and nucleosome release. ROS were generated in a time-dependent manner with an increase in NADPH oxidase component protein expression. STAT1-mediated IFN regulatory factor-1 activation was essential for upregulating ROS production. By genetically silencing p47phox, IFN-γ-induced ROS and mimic ETosis were significantly attenuated. This mechanistic study indicated that ROS may mediate DNA damage followed by histone H3 citrullination. Furthermore, ROS promoted IFN-γ-induced mimic ETosis in cooperation with autophagy. These findings further demonstrate that ROS regulates IFN-γ-induced mimic ETosis in lung epithelial malignancy. PMID:27575372

  9. Induction of multiple programmed cell death pathways by IFN-beta in human non-small-cell lung cancer cell lines.

    Science.gov (United States)

    Zhang, H; Koty, P P; Mayotte, J; Levitt, M L

    1999-02-25

    Tissue transglutaminase (tTG) and keratinocyte transglutaminase (kTG), as well as the cross-linked envelopes (CLE) that they form, have been associated with squamous differentiation and programmed cell death in epithelial cells. When interferon-beta (IFN-beta) was used to stimulate differentiation and programmed cell death in the human lung cancer cell lines NCI-H596 and NCI-H226, the cells underwent a decrease in cellular density. In NCI-H596 IFN-beta caused an increase in kTG activity and DNA fragmentation in the lower density cells, which were significantly slower growing than control cells. However, in the higher density cells, which were only slightly slower growing than control cells, IFN-beta caused an increase in tTG activity and CLE competence. Dual-parameter flow cytometry demonstrated that IFN-beta-induced squamous differentiation preceded programmed cell death. Treatment of NCI-H596 cells with monodansylcadaverine, a transglutaminase inhibitor, prevented the increase in CLE competence, but did not inhibit DNA fragmentation. These results suggest that IFN-beta can induce NCI-H596 cells to enter multiple cell death pathways and that these pathways are not only differentiation related, but may also be growth driven. PMID:10047455

  10. Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

    Directory of Open Access Journals (Sweden)

    Sachiko Hirai

    Full Text Available Up-regulated sirtuin 1 (SIRT1, an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53. Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5. In the KatoIII cell line (TP53-null, DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

  11. Programmed cell death

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-12-31

    The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

  12. Fluid shear stress sensitizes cancer cells to receptor-mediated apoptosis via trimeric death receptors

    International Nuclear Information System (INIS)

    Cancer metastasis, the process of cancer cell migration from a primary to distal location, typically leads to a poor patient prognosis. Hematogenous metastasis is initiated by intravasation of circulating tumor cells (CTCs) into the bloodstream, which are then believed to adhere to the luminal surface of the endothelium and extravasate into distal locations. Apoptotic agents such as tumor necrosis factor apoptosis-inducing ligand (TRAIL), whether in soluble ligand form or expressed on the surface of natural killer cells, have shown promise in treating CTCs to reduce the probability of metastasis. The role of hemodynamic shear forces in altering the cancer cell response to apoptotic agents has not been previously investigated. Here, we report that human colon cancer COLO 205 and prostate cancer PC-3 cells exposed to a uniform fluid shear stress in a cone-and-plate viscometer become sensitized to TRAIL-induced apoptosis. Shear-induced sensitization directly correlates with the application of fluid shear stress, and TRAIL-induced apoptosis increases in a fluid shear stress force- and time-dependent manner. In contrast, TRAIL-induced necrosis is not affected by the application fluid shear stress. Interestingly, fluid shear stress does not sensitize cancer cells to apoptosis when treated with doxorubicin, which also induces apoptosis in cancer cells. Caspase inhibition experiments reveal that shear stress-induced sensitization to TRAIL occurs via caspase-dependent apoptosis. These results suggest that physiological fluid shear forces can modulate receptor-mediated apoptosis of cancer cells in the presence of apoptotic agents. (paper)

  13. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells.

    Science.gov (United States)

    Ogura, Takeharu; Tanaka, Yoshiyuki; Tamaki, Hiroki; Harada, Mamoru

    2016-06-01

    Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemoresistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases. PMID:27082738

  14. Radical Decisions in Cancer: Redox Control of Cell Growth and Death

    Energy Technology Data Exchange (ETDEWEB)

    Sainz, Rosa M., E-mail: sainzrosa@uniovi.es [Cellular Biology and Morphology Department, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain); Lombo, Felipe [University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain); Functional Biology Department, Area of Microbiology, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); Mayo, Juan C. [Cellular Biology and Morphology Department, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain)

    2012-04-25

    Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments.

  15. Radical Decisions in Cancer: Redox Control of Cell Growth and Death

    International Nuclear Information System (INIS)

    Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments

  16. IGF-I activates caspases 3/7, 8 and 9 but does not induce cell death in colorectal cancer cells

    International Nuclear Information System (INIS)

    Colorectal cancer is the third most common cancer in the western world. Chemotherapy is often ineffective to treat the advanced colorectal cancers due to the chemo-resistance. A major contributor to chemo-resistance is tumour-derived inhibition or avoidance of apoptosis. Insulin-like growth factor I (IGF-I) has been known to play a prominent role in colorectal cancer development and progression. The role of IGF-I in cancer cell apoptosis is not completely understood. Using three colorectal cancer cell lines and one muscle cell line, associations between IGF-I and activities of caspase 3/7, 8 and 9 have been examined; the role of insulin-like growth factor I receptor (IGF-IR) in the caspase activation has been investigated. The results show that exogenous IGF-I significantly increases activity of caspases 3/7, 8 and 9 in all cell lines used; blocking IGF-I receptor reduce IGF-I-induced caspase activation. Further studies demonstrate that IGF-I induced caspase activation does not result in cell death. This is the first report to show that while IGF-I activates caspases 3/7, 8 and 9 it does not cause colorectal cancer cell death. The study suggests that caspase activation is not synonymous with apoptosis and that activation of caspases may not necessarily induce cell death

  17. Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms

    Institute of Scientific and Technical Information of China (English)

    Ying-jia ZHONG; Yong QIN; Lin-chuan; LIAO Xia WANG; Fang SHI; Xue-lian ZHENG; Qiong WANG; Lan YANG; Hong SUN; Fan HE; Lin ZHANG; Yong LIN

    2011-01-01

    To investigate the anticancer effect of crocetin,a major ingredient in saffron,and its underlying mechanisms.Methods:Cervical cancer cell line HeLa,non-small cell lung cancer cell line A549 and ovarian cancer cell line SKOV3 were treated with crocetin alone or in combination with vincristine.Cell proliferation was examined using MTT assay.Cell cycle distribution and sub-G1 fraction were analyzed using flow cytometric analysis after propidium iodide staining.Apoptosis was detected using the Annexin V-FITC Apoptosis Detection Kit with flow cytometry.Cell death was measured based on the release of lactate dehydrogenase (LDH).The expression levels of p53 and p21wAF1/Cip1 as well as caspase activation were examined using Western blot analysis.Results:Treatment of the 3 types of cancer cells with crocetin (60-240 μmol/L) for 48 h significantly inhibited their proliferation in a concentration-dependent manner.Crocetin (240 μmol/L) significantly induced cell cycle arrest through p53-dependent and -independent mechanisms accompanied with p21WAF1/Cip1 induction.Crocetin (120-240 μmoVL) caused cytotoxicity in the 3 types of cancer cells by enhancing apoptosis in a time-dependent manner.In the 3 types of cancer cells,crocetin (60 μmol/L) significantly enhanced the cytotoxicity induced by vincristine (1 μmol/L).Furthermore,this synergistic effect was also detected in the vincristine-resistant breast cancer cell line MCF-7/VCR.Conclusion:Ccrocetin is a potential anticancer agent,which may be used as a chemotherapeutic drug or as a chemosensitizer for vin-cristine.

  18. A Review on Novel Breast Cancer Therapies: Photodynamic Therapy and Plant Derived Agent Induced Cell Death Mechanisms.

    Science.gov (United States)

    George, Blassan Plackal Adimuriyil; Abrahamse, Heidi

    2016-01-01

    This review article presents an extensive examination of risk factors for breast cancer, treatment strategies with special attention to photodynamic therapy and natural product based treatments. Breast cancer remains the most commonly occurring cancer in women worldwide and the detection, treatment, and prevention are prominent concerns in public health. Background information on current developments in treatment helps to update the approach towards risk assessment. Breast cancer risk is linked to many factors such as hereditary, reproductive and lifestyle factors. Minimally invasive Photodynamic therapy (PDT) can be used in the management of various cancers; it uses a light sensitive drug (a photosensitizer, PS) and a light of visible wavelength, to destroy targeted cancer cells. State of the art analyses has been carried out to investigate advancement in the search for the cure and control of cancer progression using natural products. Traditional medicinal plants have been used as lead compounds for drug discovery in modern medicine. Both PDT and plant derived drugs induce cell death via different mechanisms including apoptosis, necrosis, autophagy, cell cycle regulation and even the regulation of various cell signalling pathways. PMID:26499768

  19. Induction of cancer cell death by proton beam in tumor hypoxic region

    International Nuclear Information System (INIS)

    Proton beam has been applied to treat various tumor patients in clinical studies. However, it is still undefined whether proton radiation can inhibit the blood vessel formation and induce the cell death in vascular endothelial cells in growing organs. The aim of this study are first, to develop an optimal animal model for the observation of blood vessel development with low dose of proton beam and second, to investigate the effect of low dose proton beam on the inhibition of blood vessel formation induced by hypoxic conditions. In this study, flk1-GFP transgenic zebrafish embryos were used to directly visualize and determine the inhibition of blood vessels by low dose (1, 2, 5 Gy) of proton beam with spread out Bragg peak (SOBP). And we observed cell death by acridine orange staining at 96 hours post fertilization (hpf) stage of embryos after proton irradiation. We also compared the effects of proton beam with those of gamma-ray. An antioxidant, N-acetyl cystein (NAC) was used to investigate whether reactive oxygen species (ROS) were involved in the cell deaths induced by proton irradiation. Irradiated flk-1-GFP transgenic embryos with proton beam irradiation (35 MeV, spread out Bragg peak, SOBP) demonstrated a marked inhibition of embryonic growth and an altered fluorescent blood vessel development in the trunk region. When the cells with DNA damage in the irradiated zebrafish were stained with acridine orange, green fluorescent cell death spots were increased in trunk regions compared to non-irradiated control embryos. Proton beam also significantly increased the cell death rate in human umbilical vein endothelial cells (HUVEC), but pretreatment of N-acetyl cystein (NAC), an antioxidant, recovered the proton-induced cell death rate (p<0.01). Moreover, pretreatment of NAC abrogated the effect of proton beam on the inhibition of trunk vessel development and malformation of trunk truncation. From this study, we found that proton radiation therapy can inhibit the

  20. Selective cell death mediated by small conditional RNAs:a novel therapeutic approach to cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Che-Kai Tsao; William K Oh

    2011-01-01

    @@ Targeted molecular therapy has been an elusive goal in the treatment of neo-plastic diseases.While chemotherapy has improved the outcome of many cancers, a non-selective cytotoxic approach invariably causes damage to normal cells, resulting in side effects and limiting treatment efficacy.This is evident in the evolution of treatment for castration-resistant prostate cancer (CRPC).

  1. Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells.

    Science.gov (United States)

    Kasukabe, Takashi; Honma, Yoshio; Okabe-Kado, Junko; Higuchi, Yusuke; Kato, Nobuo; Kumakura, Shunichi

    2016-08-01

    The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and the necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer. PMID:27375275

  2. TRAIL and docosahexaenoic acid cooperate to induce HT-29 colon cancer cell death

    Czech Academy of Sciences Publication Activity Database

    Vaculová, Alena; Hofmanová, Jiřina; Anděra, Ladislav; Kozubík, Alois

    2005-01-01

    Roč. 229, č. 1 (2005), s. 43-48. ISSN 0304-3835 R&D Projects: GA ČR(CZ) GA524/04/0895; GA ČR(CZ) GA524/03/0766 Institutional research plan: CEZ:AV0Z50040507 Keywords : TRAIL * DHA * cell death Subject RIV: BO - Biophysics Impact factor: 3.049, year: 2005

  3. Fulvic acid promotes extracellular anti-cancer mediators from RAW 264.7 cells, causing to cancer cell death in vitro.

    Science.gov (United States)

    Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Kang, Chang-Hee; Lee, Seungheon; Choi, Yung Hyun; Jeong, Yong Kee; Kim, Gi-Young

    2016-07-01

    Fulvic acid (FA) is known to promote electrochemical balance as a donor or a receptor possessing many biomedical functions. Nevertheless, the effect of FA on the anti-cancer activity has not been elucidated. In the current study, we first isolated FA from humus and investigated whether FA regulates immune-stimulating functions, such as production of nitric oxide (NO), in RAW 264.7 cells. Our data showed that FA slightly enhances cell viability in a dose-dependent manner and secretion of NO from RAW 264.7 cells. It upregulated the protein and mRNA expression of inducible NO synthesis (iNOS). In addition, FA enhanced the DNA-binding activity of nuclear factor-κB (NF-κB) in RAW 264.7 cells; the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) effectively attenuated the expression of FA-stimulated iNOS, suggesting that FA stimulates NF-κB to promote iNOS and NO production. Finally, FA-stimulated culture media (FA-CM) from RAW 264.7 cells were collected and MCA-102 fibrosarcoma cells were cultured in this media. The FA-CM augmented MCA-102 fibrosarcoma cell apoptosis; however, an NO inhibitor N(G)-monomethyl-l-arginine (NMMA) slightly inhibited the FA-CM-mediated MCA-102 fibrosarcoma cell apoptosis, which was accompanied by low levels of NO. In the present study, we found that FA induces the generation of NO and iNOS in RAW 264.7 cells by inducing NF-κB activation; however, NO did not significantly stimulate MCA-102 fibrosarcoma cell apoptosis in the current study. In addition, FA-CM enhanced cell death in various human cancer cells such as Hep3B, LNCaP, and HL60. Taken together, FA most likely stimulates immune-modulating molecules such as NO and induces cancer cell apoptosis. PMID:27177083

  4. Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

    DEFF Research Database (Denmark)

    Maddika, S; Ande, SR; Panigrahi, S;

    2007-01-01

    The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic...... regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d...... highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the...

  5. Diatom-derived polyunsaturated aldehydes activate cell death in human cancer cell lines but not normal cells.

    Directory of Open Access Journals (Sweden)

    Clementina Sansone

    Full Text Available Diatoms are an important class of unicellular algae that produce bioactive polyunsaturated aldehydes (PUAs that induce abortions or malformations in the offspring of invertebrates exposed to them during gestation. Here we compare the effects of the PUAs 2-trans,4-trans-decadienal (DD, 2-trans,4-trans-octadienal (OD and 2-trans,4-trans-heptadienal (HD on the adenocarcinoma cell lines lung A549 and colon COLO 205, and the normal lung/brunch epithelial BEAS-2B cell line. Using the viability MTT/Trypan blue assays, we show that PUAs have a toxic effect on both A549 and COLO 205 tumor cells but not BEAS-2B normal cells. DD was the strongest of the three PUAs tested, at all time-intervals considered, but HD was as strong as DD after 48 h. OD was the least active of the three PUAs. The effect of the three PUAs was somewhat stronger for A549 cells. We therefore studied the death signaling pathway activated in A549 showing that cells treated with DD activated Tumor Necrosis Factor Receptor 1 (TNFR1 and Fas Associated Death Domain (FADD leading to necroptosis via caspase-3 without activating the survival pathway Receptor-Interacting Protein (RIP. The TNFR1/FADD/caspase pathway was also observed with OD, but only after 48 h. This was the only PUA that activated RIP, consistent with the finding that OD causes less damage to the cell compared to DD and HD. In contrast, cells treated with HD activated the Fas/FADD/caspase pathway. This is the first report that PUAs activate an extrinsic apoptotic machinery in contrast to other anticancer drugs that promote an intrinsic death pathway, without affecting the viability of normal cells from the same tissue type. These findings have interesting implications also from the ecological viewpoint considering that HD is one of the most common PUAs produced by diatoms.

  6. miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

    DEFF Research Database (Denmark)

    Ostenfeld, Marie Stampe; Bramsen, Jesper Bertram; Lamy, Philippe;

    2010-01-01

    Downregulation of miR-145 in a variety of cancers suggests a possible tumor suppressor function for this microRNA. Here, we show that miR-145 expression is reduced in bladder cancer and urothelial carcinoma in situ, compared with normal urothelium, using transcription profiling and in situ...... hybridization. Ectopic expression of miR-145 induced extensive apoptosis in urothelial carcinoma cell lines (T24 and SW780) as characterized by caspase activation, nuclear condensation and fragmentation, cellular shrinkage, and detachment. However, cell death also proceeded upon caspase inhibition by the...... pharmacological inhibitor zVAD-fmk and ectopic expression of anti-apoptotic Bcl-2, indicating the activation of an alternative caspase-independent death pathway. Microarray analysis of transcript levels in T24 cells, before the onset of cell death, showed destabilization of mRNAs enriched for miR-145 7mer target...

  7. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis.

    Science.gov (United States)

    Guillermet, Julie; Saint-Laurent, Nathalie; Rochaix, Philippe; Cuvillier, Olivier; Levade, Thierry; Schally, Andrew V; Pradayrol, Lucien; Buscail, Louis; Susini, Christiane; Bousquet, Corinne

    2003-01-01

    Somatostatin receptor subtype 2 (sst2) gene expression is lost in 90% of human pancreatic adenocarcinomas. We previously demonstrated that stable sst2 transfection of human pancreatic BxPC-3 cells, which do not endogenously express sst2, inhibits cell proliferation, tumorigenicity, and metastasis. These sst2 effects occur as a consequence of an autocrine sst2-dependent loop, whereby sst2 induces expression of its own ligand, somatostatin. Here we investigated whether sst2 induces apoptosis in sst2-transfected BxPC-3 cells. Expression of sst2 induced a 4.4- +/- 0.05-fold stimulation of apoptosis in BxPC-3 through the activation of tyrosine phosphatase SHP-1. sst2 also sensitized these cells to apoptosis induced by tumor necrosis factor alpha (TNFalpha), enhancing it 4.1- +/- 1.5-fold. Apoptosis in BxPC-3 cells mediated by TNF-related apoptosis-inducing ligand (TRAIL) and CD95L was likewise increased 2.3- +/- 0.5-fold and 7.4- +/- 2.5-fold, respectively. sst2-dependent activation and cell sensitization to death ligand-induced apoptosis involved activation of the executioner caspases, key factors in both death ligand- or mitochondria-mediated apoptosis. sst2 affected both pathways: first, by up-regulating expression of TRAIL and TNFalpha receptors, DR4 and TNFRI, respectively, and sensitizing the cells to death ligand-induced initiator capase-8 activation, and, second, by down-regulating expression of the antiapoptotic mitochondrial Bcl-2 protein. These results are of interest for the clinical management of chemoresistant pancreatic adenocarcinoma by using a combined gene therapy based on the cotransfer of genes for both the sst2 and a nontoxic death ligand. PMID:12490654

  8. Induction of cancer cell death by proton beam in tumor hypoxic region

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Y. M.; Hur, T. R.; Lee, K. B.; Jeong, M. H.; Park, J. W. [Kyungbook National Univ., Daegu (Korea, Republic of)

    2007-04-15

    Proton beam induced apoptosis significantly in Lewis lung carcinoma cells and hepatoma HepG2 cells in a dose- and time-dependent manner, but slightly in leukemia Molt-4 cells. Relative biological effectiveness (RBE) values for death rate relative to gamma ray were ranged from 1.3 to 2.1 in LLC or HepG2 but 0.7 in Molt-4 cells at 72h after irradiation. The typical apoptosis was observed by nuclear DNA staining with DAPI. By FACS analysis after stained with PI, sub-G1 cell fraction was significantly increased but G2/M phase was not altered by proton beam irradiation measured at 24 h after irradiation. Proton beam-irradiated tumor cells induced cleavage of PARP-1 and procaspases (-3 and -9) and increased the level of p53 and p21. decreased pro-lamin B. Acitivity of caspases was significantly increased after proton beam irradiation. Furthermore, ROS were significantly increased and N-acetyl cystein (NAC) pretreatment restored the apoptotic cell death induced in proton beam-irradiated cells. In conclusion, single treatment of low energy proton beam with SOBP induced apoptosis of solid tumor cells via increased ROS, active caspase -3,-9 and p53, p2.

  9. Induction of cancer cell death by proton beam in tumor hypoxic region

    International Nuclear Information System (INIS)

    Proton beam induced apoptosis significantly in Lewis lung carcinoma cells and hepatoma HepG2 cells in a dose- and time-dependent manner, but slightly in leukemia Molt-4 cells. Relative biological effectiveness (RBE) values for death rate relative to gamma ray were ranged from 1.3 to 2.1 in LLC or HepG2 but 0.7 in Molt-4 cells at 72h after irradiation. The typical apoptosis was observed by nuclear DNA staining with DAPI. By FACS analysis after stained with PI, sub-G1 cell fraction was significantly increased but G2/M phase was not altered by proton beam irradiation measured at 24 h after irradiation. Proton beam-irradiated tumor cells induced cleavage of PARP-1 and procaspases (-3 and -9) and increased the level of p53 and p21. decreased pro-lamin B. Acitivity of caspases was significantly increased after proton beam irradiation. Furthermore, ROS were significantly increased and N-acetyl cystein (NAC) pretreatment restored the apoptotic cell death induced in proton beam-irradiated cells. In conclusion, single treatment of low energy proton beam with SOBP induced apoptosis of solid tumor cells via increased ROS, active caspase -3,-9 and p53, p2

  10. Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ulf Geisen

    2015-07-01

    Full Text Available Pancreatic cancer is one of the most aggressive cancer entities, with an extremely poor 5-year survival rate. Therefore, novel therapeutic agents with specific modes of action are urgently needed. Marine organisms represent a promising source to identify new pharmacologically active substances. Secondary metabolites derived from marine algae are of particular interest. The present work describes cellular and molecular mechanisms induced by an HPLC-fractionated, hydrophilic extract derived from the Baltic brown seaweed Fucus vesiculosus (Fv1. Treatment with Fv1 resulted in a strong inhibition of viability in various pancreatic cancer cell lines. This extract inhibited the cell cycle of proliferating cells due to the up-regulation of cell cycle inhibitors, shown on the mRNA (microarray data and protein level. As a result, cells were dying in a caspase-independent manner. Experiments with non-dividing cells showed that proliferation is a prerequisite for the effectiveness of Fv1. Importantly, Fv1 showed low cytotoxic activity against non-malignant resting T cells and terminally differentiated cells like erythrocytes. Interestingly, accelerated killing effects were observed in combination with inhibitors of autophagy. Our in vitro data suggest that Fv1 may represent a promising new agent that deserves further development towards clinical application.

  11. TRAIL-induced apoptosis and expression of death receptor TRAIL-R1 and TRAIL-R2 in bladder cancer cells.

    Directory of Open Access Journals (Sweden)

    Zenon P Czuba

    2010-05-01

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L is a member of TNF superfamily able to induce programmed death in cancer cells with no toxicity against normal tissues. TRAIL mediate apoptosis follows binding to the two death receptors, TRAIL-R1 (DR4 and/or TRAIL-R2 (DR5. In this study we investigated the cytotoxic and apoptotic effect of TRAIL on bladder cancer cells and the expression of death receptor TRAIL-R1 and TRAIL-R2 on the surface of these cancer cells. Three human bladder transitional cancer cell (TCC lines - SW780, 647V and T24 were tested for TRAIL sensitivity. The bladder cancer cells were incubated with human soluble recombinant TRAIL. Cytotoxicity was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide and LDH (lactate dyhydrogenase assays. Apoptosis was detected by flow cytometry with annexin V-FITC/propidium iodide and by fluorescence microscopy with Hoechst 33342/annexin V-FITC/Ethidium Homodimer. The cell surface expression of TRAIL death receptors on bladder cancer were determined using flow cytometry with phycoerythrin-conjugated monoclonal anti-human TRAIL-R1 and TRAIL-R2. Our investigations confirmed that SW780 cells were sensitive to TRAIL, and two other bladder cancer cell lines, 647V and T24, were resistant to TRAIL induced apoptosis. We therefore examined the expression of TRAIL death receptors on bladder cancer cell surfaces. We showed decreased expression of TRAIL-R2 receptor in TRAIL-resistant bladder cancer cells and increased expression of this death receptor in TRAIL-sensitive SW780 cells. The expression of TRAILR1 receptor was similar in all bladder cancer cell lines. TRAIL is one of the promising candidates for cancer therapeutics. However, some cancer cells are resistant to TRAIL-mediated apoptosis. It is therefore important to overcome this resistance for the clinical use of TRAIL in cancer therapy. TRAIL death receptors are attractive therapeutic targets in

  12. STI571 reduces TRAIL-induced apoptosis in colon cancer cells: c-Abl activation by the death receptor leads to stress kinase-dependent cell death

    Directory of Open Access Journals (Sweden)

    Huang Duen-Yi

    2012-03-01

    Full Text Available Abstract Background In an effort to achieve better cancer therapies, we elucidated the combination cancer therapy of STI571 (an inhibitor of Bcr-Abl and clinically used for chronic myelogenous leukemia and TNF-related apoptosis-inducing ligand (TRAIL, a developing antitumor agent in leukemia, colon, and prostate cancer cells. Methods Colon cancer (HCT116, SW480, prostate cancer (PC3, LNCaP and leukemia (K562 cells were treated with STI571 and TRAIL. Cell viability was determined by MTT assay and sub-G1 appearance. Protein expression and kinase phosphorylation were determined by Western blotting. c-Abl and p73 activities were inhibited by target-specific small interfering (siRNA. In vitro kinase assay of c-Abl was conducted using CRK as a substrate. Results We found that STI571 exerts opposite effects on the antitumor activity of TRAIL. It enhanced cytotoxicity in TRAIL-treated K562 leukemia cells and reduced TRAIL-induced apoptosis in HCT116 and SW480 colon cancer cells, while having no effect on PC3 and LNCaP cells. In colon and prostate cancer cells, TRAIL caused c-Abl cleavage to the active form via a caspase pathway. Interestingly, JNK and p38 MAPK inhibitors effectively blocked TRAIL-induced toxicity in the colon, but not in prostate cancer cells. Next, we found that STI571 could attenuate TRAIL-induced c-Abl, JNK and p38 activation in HCT116 cells. In addition, siRNA targeting knockdown of c-Abl and p73 also reduced TRAIL-induced cytotoxicity, rendering HCT116 cells less responsive to stress kinase activation, and masking the cytoprotective effect of STI571. Conclusions All together we demonstrate a novel mediator role of p73 in activating the stress kinases p38 and JNK in the classical apoptotic pathway of TRAIL. TRAIL via caspase-dependent action can sequentially activate c-Abl, p73, and stress kinases, which contribute to apoptosis in colon cancer cells. Through the inhibition of c-Abl-mediated apoptotic p73 signaling, STI571 reduces

  13. Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3β-mediated B-cell lymphoma 2 regulation

    Science.gov (United States)

    Noh, Kyung Tae; Cha, Gil Sun; Kang, Tae Heung; Cho, Joon; Jung, In Duk; Kim, Kwang-Youn; Ahn, Soon-Cheol; You, Ji Chang; Park, Yeong-Min

    2016-01-01

    Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine protein kinase that is known to mediate cancer cell death. Here, we show that B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, is regulated by GSK-3β and that GSK-3β-mediated regulation of Bcl-2 is crucial for mitochondrial-dependent cell death in paclitaxel-stimulated cells. We demonstrate that MCF7 GSK-3β siRNA cells are more sensitive to cell death than MCF7 GFP control cells and that in the absence of GSK-3β, Bcl-2 levels are reduced, a result enhanced by paclitaxel. Paclitaxel-induced JNK (c-Jun N-terminal kinase) activation is critical for Bcl-2 modulation. In the absence of GSK-3β, Bcl-2 was unstable in an ubiquitination-dependent manner in both basal- and paclitaxel-treated cells. Furthermore, we demonstrate that GSK-3β-mediated regulation of Bcl-2 influences cytochrome C release and mitochondrial membrane potential. Taken together, our data suggest that GSK-3β-dependent regulation of Bcl-2 is crucial for mitochondria-dependent cell death in paclitaxel-mediated breast cancer therapy. [BMB Reports 2016; 49(1): 51-56] PMID:26246283

  14. Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death.

    Science.gov (United States)

    Feng, Xiaolan; Zhang, Yi; Wang, Pan; Liu, Quanhong; Wang, Xiaobing

    2014-12-01

    Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells. PMID:25363473

  15. Novel piperazine core compound induces death in human liver cancer cells: possible pharmacological properties

    Science.gov (United States)

    Samie, Nima; Muniandy, Sekaran; Kanthimathi, M. S.; Haerian, Batoul Sadat; Raja Azudin, Raja Elina

    2016-01-01

    The current study evaluates the cytotoxic mechanism of a novel piperazine derivate designated as PCC against human liver cancer cells. In this context, human liver cancer cell lines, SNU-475 and 243, human monocyte/macrophage cell line, CRL-9855, and human B lymphocyte cell line, CCL-156, were used to determine the IC50 of PCC using the standard MTT assay. PCC displayed a strong suppressive effect on SNU-475 and SNU-423 cells with an IC50 value of 6.98 ± 0.11 μg/ml and 7.76 ± 0.45 μg/ml respectively, after 24 h of treatment. Significant dipping in the mitochondrial membrane potential and elevation in the released of cytochrome c from the mitochondria indicated the induction of the intrinsic apoptosis pathway by PCC. Activation of this pathway was further evidenced by significant activation of caspase 3/7 and 9. PCC was also shown to activate the extrinsic pathways of apoptosis via activation of caspase-8 which is linked to the suppression of NF-ƙB translocation to the nucleus. Cell cycle arrest in the G1 phase was confirmed by flow cytometry and up-regulation of glutathione reductase expression was quantified by qPCR. This study suggests that PCC is a simultaneous inducer of intrinsic and extrinsic pathways of apoptosis in liver cancer cell lines. PMID:27072064

  16. Redox-Active Selenium Compounds—From Toxicity and Cell Death to Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Sougat Misra

    2015-05-01

    Full Text Available Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed.

  17. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells

    DEFF Research Database (Denmark)

    Frankel, Lisa; Christoffersen, Nanna R; Jacobsen, Anders; Lindow, Morten; Krogh, Anders; Lund, Anders Henrik

    2008-01-01

    MicroRNAs are emerging as important regulators of cancer-related processes. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally linked to cellular proliferation, apoptosis, and migration. Inhibition of mir-21 in MCF-7 breast cancer cells causes reduced cell...... growth. Using array expression analysis of MCF-7 cells depleted of miR-21, we have identified mRNA targets of mir-21 and have shown a link between miR-21 and the p53 tumor suppressor protein. We furthermore found that the tumor suppressor protein Programmed Cell Death 4 (PDCD4) is regulated by miR-21 and...... demonstrated that PDCD4 is a functionally important target for miR-21 in breast cancer cells....

  18. Roles of dCK Ser-74 in radiation-induced cell death in breast cancer cells

    International Nuclear Information System (INIS)

    Objective: To investigate the roles of dCK Ser-74 in radiation-induced cell death in breast cancer cells. Methods: Different phenotypes of dCK plasmids were transfected into MCF-7 cells by liposome transfection, including dCK-Vector, dCK-WT (wild type), dCK-S74A (non-phosphorylation) and dCK-S74E (hyper-phosphorylation). All these cells were irradiated by 0, 2, 4, 6, 8 Gy X-rays, respectively. The transcriptional and translational level of dCK were detected with real time-PCR and Western blot, respectively. Radiosensitivity was analyzed using cell counting kit (CCK-8) and colony formation assays. Monodansylcadaverine staining (MDC) and flow cytometry were used to detect autophagy and apoptosis,respectively. Results: Four phenotypes of dCK cell models were established successfully. After irradiation, the cell viabilities of MCF-7 and dCK-Vector decreased significantly as compared with mock group (t=14.469 and 9.357, P<0.05), the cell viabilities of dCK-WT, dCK-S74A and dCK-S74E showed no changes (P>0.05). The total mortalities of dCK-WT and dCK-S74E decreased significantly as compared with dCK-Vector (χ2=3.857-3.971, P<0.05), but no changes in dCK-S74A cells (P>0.05). The apoptosis rates in dCK-S74A, dCK-Vector and control group were up-regulated after irradiation (t=-4.531, -3.688 and-7.076, P<0.05), and the irradiation-induced apoptosis was reversed in dCK-WT and dCK-S74E (66% and 68% of the increase level in dCK-Vector group). The autophagy in dCK-WT and dCK-S74E increased by 22% and 26% (t=-9.051 and-8.411, P<0.01), but no changes were observed in dCK-S74A, dCK-Vector and control groups (P>0.05). Conclusions: The dCK-WT and dCK-S74E could reverse the irradiation-induced apoptosis, increase the autophagy occurrence, and decrease the total mortality, indicating that the phosphorylation of dCK at Ser-74 sites is related to the radiosensitivity of MCF-7 cells. (authors)

  19. Investigation of selective induction of breast cancer cells to death with treatment of plasma-activated medium

    Science.gov (United States)

    Hashizume, Hiroshi; Tanaka, Hiromasa; Nakamura, Kae; Kano, Hiroyuki; Ishikawa, Kenji; Kikkawa, Fumitaka; Mizuno, Masaaki; Hori, Masaru

    2015-09-01

    The applications of plasma in medicine have much attention. We previously showed that plasma-activated medium (PAM) induced glioblastoma cells to apoptosis. However, it has not been elucidated the selectivity of PAM in detail. In this study, we investigated the selective effect of PAM on the death of human breast normal and cancer cells, MCF10A and MCF7, respectively, and observed the selective death with fluorescent microscopy. For the investigation of cell viability with PAM treatment, we prepared various PAMs according to the strengths, and treated each of cells with PAMs. Week PAM treatment only decreased the viability of MCF7 cells, while strong PAM treatment significantly affected both viabilities of MCF7 and MCF10A cells. For the fluorescent observation, we prepared the mixture of MCF7 and fluorescent-probed MCF10A cells, and seeded them. After the treatment of PAMs, the images showed that only MCF7 cells damaged in the mixture with week PAM treatment. These results suggested that a specific range existed with the selective effect in the strength of PAM. This work was partly supported by a Grant-in-Aid for Scientific Research on Innovative Areas ``Plasma Medical Innovation'' Grant No. 24108002 and 24108008 from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

  20. Phthalocyanine-mediated photodynamic therapy induces cell death and a G /G1 cell cycle arrest in cervical cancer cells

    International Nuclear Information System (INIS)

    We have developed a series of novel photosensitizers which have potential for anticancer photodynamic therapy (PDT). Photosensitizers include zinc phthalocyanine tetra-sulphonic acid and a family of derivatives with amino acid substituents of varying alkyl chain length and degree of branching. Subcellular localization of these photosensitizers at the phototoxic IC5 concentration in human cervical carcinoma cells (SiHa Cells) was similar to that of the lysosomal dye Lucifer Yellow. Subsequent nuclear relocalization was observed following irradiation with 665 nm laser light. The PDT response was characterized using the Sulforhodamine B cytotoxicity assay. Flow cytometry was used for both DNA cell cycle and dual Annexin V-FITC/propidium iodide analysis. Phototoxicity of the derivatives was of the same order of magnitude as for tetrasulphonated phthalocyanine but with an overall trend of increased phototoxicity with increasing amino acid chain length. Our results demonstrate cell death, inhibition of cell growth, and G /G1 cell cycle arrest during the phthalocyanine PDT-mediated response

  1. Activation of the Retinoblastoma Tumor Suppressor Mediates Cell Cycle Inhibition and Cell Death in Specific Cervical Cancer Cell Lines

    OpenAIRE

    Bourgo, Ryan J.; Braden, Wesley A.; Wells, Susanne I.; Knudsen, Erik S.

    2009-01-01

    High-risk human papilloma virus (HPV) encodes two oncoproteins, E6 and E7, which are vital to viral replication and contribute to the development of cervical cancer. HPV16 E7 can target over 20 cellular proteins, but is best known for inactivating the retinoblastoma (RB) tumor suppressor. RB functions by restraining cells from entering S-phase of the cell cycle, thus preventing aberrant proliferation. While it is well established that HPV16 E7 facilitates the degradation of the RB protein, th...

  2. Effects of hypoxia-inducible factor-1α on radiation-induced autophagic cell death in breast cancer cells

    International Nuclear Information System (INIS)

    Objective: To study the effects of hypoxia-inducible factor-1α (HIF-1α) on radiation-induced autophagic cell death in breast cancer cells. Methods: MCF-7 cells were divided into four groups:control (normoxia,21% Oxygen),irradiation (8 Gy X-rays), hypoxia (Cobalt chloride, CoCl2) and irradiation with hypoxia (CoCl2). 150 μmol/L CoCl2 was utilized to induce hypoxic conditions. Western blot was applied to detect the expression of HIF-1α and MAPLC3. MDC and Hoechst staining were used to detect autophagy and apoptosis. Radiosensitivity was detected by cloning formation. The short hairpin interfering RNA (shRNA) retroviral transduction particles targeting HIF-1α was transfected into MCF-7 cells to establish HIF-1α knockdown cells, then the radiosensibility, autophagy and apoptosis were detected. Results: Compared with control group and irradiation group,the protein level of HIF-1 increased obviously in the normoxia, irradiation, hypoxia and irradiation with hypoxia groups, and the values were 0, 0, 1.00, 1.89, respectively. The expression levels of MAPLC3 were markedly up-regulated in irradiation, hypoxia and irradiation with hypoxia groups as compared with control, and the ratios of LC3Ⅱ/LC3Ⅰ were 1.15, 1.73, 2.38 and 3.60, respectively. The radiosensitivity of MCF-7 cells decreased in the following order:normoxia with 3MA > normoxia > hypoxia with 3MA > hypoxia. HIF-1α knockdown cell (pSUPER-HIF-1α Ri) and vector control were constructed. After treatment with CoCl2, survival fraction of MCF-7-pSUPER was significantly higher than that of control (t=3.080, 6.946, 6.658, 6.380, P<0.05), and radiosensitivity was down-regulated after irradiation,but there was no significant difference between normoxia and hypoxia in survival fraction of MCF-7-pSUPER-HIF-1α Ri. After treatment of irradiation or hypoxia, the autophagic fractions in MCF-7-pSUPER-HIF-1α Ri significantly decreased, reduced by 21.1%, 25.5%, 15.5%, respectively (t=4.635, 4.738, 6.354, P<0.05) as

  3. Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death

    OpenAIRE

    Makhov, P; Golovine, K.; Teper, E.; Kutikov, A.; Mehrazin, R.; Corcoran, A; A. Tulin; Uzzo, R G; Kolenko, V M

    2014-01-01

    Background: The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling. Methods: We examined Akt/mTOR signalling in cancer cell...

  4. Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis.

    Science.gov (United States)

    Kim, Se-Lim; Liu, Yu-Chuan; Park, Young Ran; Seo, Seung Young; Kim, Seong Hun; Kim, In Hee; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae-Ghon; Kim, Sang-Wook

    2015-03-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL-induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells. PMID:25502339

  5. Early apoptosis and cell death induced by ATX-S10Na ( Ⅱ)-mediated photodynamic therapy are Bax- and p53-dependent in human colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Makoto Mitsunaga; Akihito Tsubota; Kohichi Nariai; Yoshihisa Namiki; Makoto Sumi; Tetsuya Yoshikawa; Kiyotaka Fujise

    2007-01-01

    AIM: To investigate the roles of Bax and p53 proteins in photosensitivity of human colon cancer cells by using lysosome-localizing photosensitizer, ATX-S10Na (Ⅱ).METHODS: HCT116 human colon cancer cells and Bax-null or p53-null isogenic derivatives were irradiated with a diode laser. Early apoptosis and cell death in response to photodynamic therapy were determined by MTT assays, annexin V assays, transmission electron microscopy assays, caspase assays and western blotting.RESULTS: Induction of early apoptosis and cell death was Bax- and p53-dependent. Bax and p53 were required for caspase-dependent apoptosis. The levels of anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-XL,were decreased in Bax- and p53-independent manner.CONCLUSION: Our results indicate that early apoptosis and cell death of human colon cancer cells induced by photodynamic therapy with lysosome-localizingphotosensitizer ATX-S10Na (Ⅱ) are mediated by p53-Bax network and Iow levels of Bcl-2 and Bcl-XL proteins.Our results might help in formulating new therapeutic approaches in photedynamic therapy.

  6. Suppression of the death gene BIK is a critical factor for resistance to tamoxifen in MCF-7 breast cancer cells.

    Science.gov (United States)

    Viedma-Rodriguez, Rubí; Baiza-Gutman, Luis Arturo; García-Carrancá, Alejandro; Moreno-Fierros, Leticia; Salamanca-Gómez, Fabio; Arenas-Aranda, Diego

    2013-12-01

    Apoptosis is controlled by the BCL-2 family of proteins, which can be divided into three different subclasses based on the conservation of BCL-2 homology domains. BIK is a founding member of the BH3-only pro-apoptotic protein family. BIK is predominantly localized in the endoplasmic reticulum (ER) and induces apoptosis through the mitochondrial pathway by mobilizing calcium from the ER to the mitochondria. In this study, we determined that suppression of the death gene Bik promotes resistance to tamoxifen (TAM) in MCF-7 breast cancer cells. We utilized small interfering (siRNA) to specifically knockdown BIK in MCF-7 cells and studied their response to tamoxifen. The levels of cell apoptosis, the potential mitochondrial membrane (∆Ψ(m)), and the activation of total caspases were analyzed. Western blot analysis was used to determine the expression of some BCL-2 family proteins. Flow cytometry studies revealed an increase in apoptosis level in MCF-7 cells and a 2-fold increase in relative BIK messenger RNA (mRNA) expression at a concentration of 6.0 μM of TAM. BIK silencing, with a specific RNAi, blocked TAM-induced apoptosis in 45 ± 6.78% of cells. Moreover, it decreased mitochondrial membrane potential (Ψm) and total caspase activity, and exhibited low expression of pro-apoptotic proteins BAX, BAK, PUMA and a high expression of BCl-2 and MCL-1. The above suggests resistance to TAM, regulating the intrinsic pathway and indicate that BIK comprises an important factor in the process of apoptosis, which may exert an influence the ER pathway, which regulates mitochondrial integrity. Collectively, our results show that BIK is a central component of the programmed cell death of TAM-induced MCF-7 breast cancer cells. The silencing of BIK gene will be useful for future studies to establish the mechanisms of regulation of resistance to TAM. PMID:24100375

  7. Protection of stromal cell-derived factor 2 by heat shock protein 72 prevents oxaliplatin-induced cell death in oxaliplatin-resistant human gastric cancer cells.

    Science.gov (United States)

    Takahashi, Katsuyuki; Tanaka, Masako; Yashiro, Masakazu; Matsumoto, Masaki; Ohtsuka, Asuka; Nakayama, Keiichi I; Izumi, Yasukatsu; Nagayama, Katsuya; Miura, Katsuyuki; Iwao, Hiroshi; Shiota, Masayuki

    2016-08-01

    Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers. PMID:27157913

  8. Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia

    Science.gov (United States)

    Oh, Eun-Taex; Kim, Chan Woo; Kim, Soo Jung; Lee, Jae-Seon; Hong, Soon-Sun; Park, Heon Joo

    2016-01-01

    HIF-1 (hypoxia-inducible factor-1) regulates the expression of more than 70 genes involved in angiogenesis, tumor growth, metastasis, chemoresistance, and radioresistance. Thus, there is growing interest in using HIF-1 inhibitors as anticancer drugs. Docetaxel, a Food and Drug Administration-approved anticancer drug, is reported to enhance HIF-1α degradation. Here, we investigated the molecular mechanism underlying docetaxel-induced HIF-1α degradation and cancer cell death under hypoxic conditions. Docetaxel pretreatment enhanced the polyubiquitination and proteasome-mediated degradation of HIF-1α, and increased cancer cell death under hypoxic conditions. Docetaxel also activated the prolyl hydroxylase, PHD1, in hypoxia, and pharmacological inhibition or siRNA-mediated knockdown of PHD1 prevented docetaxel-induced HIF-1α degradation and cancer cell death. Additionally, siRNA-mediated JNK2 knockdown blocked docetaxel-induced HIF-1α degradation and cancer cell death by inhibiting PHD1 activation. A luciferase reporter assay revealed that inhibition of the JNK2/PHD1 signaling pathway significantly increased the transcriptional activity of HIF-1 in docetaxel-treated cancer cells under hypoxia. Consistent with these results, docetaxel-treated JNK2-knockdown tumors grew much faster than control tumors through inhibition of docetaxel-induced PHD1 activation and degradation of HIF-1α. Our results collectively show that, under hypoxic conditions, docetaxel induces apoptotic cell death through JNK2/PHD1 signaling-mediated HIF-1α degradation. PMID:27263528

  9. Artesunate induces necrotic cell death in schwannoma cells

    OpenAIRE

    Button, R W; Lin, F.; Ercolano, E; Vincent, J H; Hu, B.; Hanemann, C O; Luo, S

    2014-01-01

    Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely ...

  10. Green synthesis of platinum nanoparticles that induce cell death and G2/M-phase cell cycle arrest in human cervical cancer cells.

    Science.gov (United States)

    Alshatwi, Ali A; Athinarayanan, Jegan; Vaiyapuri Subbarayan, Periasamy

    2015-01-01

    Platinum-based chemotherapeutic drugs, including cisplatin, carboplatin, and oxaliplatin, have been used to manage cancer in spite of dose-dependent side effects, including nephrotoxicity, neurotoxicity and ototoxicity. These disadvantages have prompted the development of new strategies for cancer therapy that utilize functionalized nanoparticles as nanomedicines. In the present investigation, we have synthesized platinum nanoparticles using tea polyphenol (TPP) as both a reducing and surface modifying agent. The crystalline nature and morphology of the prepared TPP-functionalized platinum nanoparticles (TPP@Pt) were analyzed using X-ray diffraction (XRD) and transmission electron microscopy (TEM). The XRD results revealed that the TPP@Pt had a crystalline nature with a face-centered cubic structure. TEM imaging suggested that the TTP@Pt are flower shaped with a well-dispersed 30-60 nm-sized TPP@Pt formation. Cervical cancer cells (SiHa) were then treated with different concentrations of TPP@Pt. The effects of TPP@Pt on cell viability, nuclear morphology and cell cycle distribution were investigated. A cell viability assay revealed that the proliferation of SiHa cells was inhibited by TPP@Pt. Propidium iodide nuclear staining indicated that TPP@Pt induced nuclear fragmentation and chromatin condensation. Treatment with TPP@Pt significantly increased the percentage of cells in the G2/M phase, which indicates induced cell cycle arrest in the G2/M phase and an increased number of cells in the subG0 cell death phase. These findings highlight a potential use of TPP@Pt in cervical cancer treatment. PMID:25577212

  11. A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires

    KAUST Repository

    Martinez Banderas, Aldo

    2016-04-01

    Cancer prevails as one of the most devastating diseases being at the top of death causes for adults despite continuous development and innovation in cancer therapy. Nanotechnology may be used to achieve therapeutic dosing, establish sustained-release drug profiles, and increase the half-life of drugs. In this context, magnetic nanowires (NWs) have shown a good biocompatibility and cellular internalization with a low cytotoxic effect. In this thesis, I induced cancer cell death by combining the chemotherapeutic effect of iron NWs functionalized with Doxorubicin (DOX) with mechanical disturbance under a low frequency alternating magnetic field. Two different agents, APTES and BSA, were separately used for coating NWs permitting further functionalization with DOX. Internalization was qualitatively and quantitatively assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal reflection analysis, BSA formulations demonstrate to have a higher internalization degree and a broader distribution within the cells in comparison to APTES formulations. Both groups of functionalized NWs generated a comparable cytotoxic effect in MDA-MB-231 breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by the free DOX (~95% at the same concentration) and non-functionalized NWs formulations (~10% at the same NWs concentration). A synergistic cytotoxic effect is obtained when a low frequency magnetic field (1 mT, 10 Hz) is applied to cells treated with the two formulations that is again comparable (~70% at the highest concentration). Furthermore, the cytotoxic effect of both groups of coated NWs without the drug increased notoriously when the field is applied (~25% at the highest concentration tested). Here, a novel bimodal method for cancer cell destruction was developed by the conjugation of the magneto

  12. Amicoumacin A induces cancer cell death by targeting the eukaryotic ribosome

    Science.gov (United States)

    Prokhorova, Irina V.; Akulich, Kseniya A.; Makeeva, Desislava S.; Osterman, Ilya A.; Skvortsov, Dmitry A.; Sergiev, Petr V.; Dontsova, Olga A.; Yusupova, Gulnara; Yusupov, Marat M.; Dmitriev, Sergey E.

    2016-01-01

    Amicoumacin A is an antibiotic that was recently shown to target bacterial ribosomes. It affects translocation and provides an additional contact interface between the ribosomal RNA and mRNA. The binding site of amicoumacin A is formed by universally conserved nucleotides of rRNA. In this work, we showed that amicoumacin A inhibits translation in yeast and mammalian systems by affecting translation elongation. We determined the structure of the amicoumacin A complex with yeast ribosomes at a resolution of 3.1  Å. Toxicity measurement demonstrated that human cancer cell lines are more susceptible to the inhibition by this compound as compared to non-cancerous ones. This might be used as a starting point to develop amicoumacin A derivatives with clinical value. PMID:27296282

  13. Hepatic Carcinoma—Associated Fibroblasts Promote an Adaptative Response in Colorectal Cancer Cells That Inhibit Proliferation and Apoptosis: Nonresistant Cells Die by Nonapoptotic Cell Death

    Directory of Open Access Journals (Sweden)

    Mireia Berdiel-Acer

    2011-10-01

    Full Text Available Carcinoma-associated fibroblasts (CAFs are important contributors of microenvironment in determining the tumor’s fate. This study aimed to compare the influence of liver microenvironment and primary tumor microenvironment on the behavior of colorectal carcinoma. Conditioned medium (CM from normal colonic fibroblasts (NCFs, CAFs from primary tumor (CAF-PT or liver metastasis (CAF-LM were obtained. We performed functional assays to test the influence of each CM on colorectal cell lines. Microarray and gene set enrichment analysis (GSEA were performed in DLD1 cells cultured in matched CM. In DLD1 cells, CAF-LM CM compared with CAF-PT CM and NCF led to a more aggressive phenotype, induced the features of an epithelial-to-mesenchymal transition more efficiently, and stimulated migration and invasion to a greater extent. Sustained stimulation with CAF-LM CM evoked a transient G2/M cell cycle arrest accompanied by a reduction of apoptosis, inhibition of proliferation, and decreased viability of SW1116, SW620, SW480, DLD1, HT-29, and Caco-2 cells and provoked nonapoptotic cell death in those cells carrying KRAS mutations. Cells resistant to CAF-LM CM completely changed their morphology in an extracellular signal-regulated protein kinase-dependent process and depicted an increased stemness capacity alongside the Wnt pathway stimulation. The transcriptomic profile of DLD1 cells treated with CAF-LM CM was associated with Wnt and mitogen-activated protein kinase pathways activation in GSEA. Therefore, the liver microenvironment induces more efficiently the aggressiveness of colorectal cancer cells than other matched microenvironments do but secondarily evokes cell death. Resistant cells displayed higher stemness capacity.

  14. Dose-Dependent ATP Depletion and Cancer Cell Death following Calcium Electroporation, Relative Effect of Calcium Concentration and Electric Field Strength

    OpenAIRE

    Hansen, Emilie Louise; Sozer, Esin Bengisu; Romeo, Stefania; Frandsen, Stine Krog; Vernier, P. Thomas; Gehl, Julie

    2015-01-01

    Background Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy. Methods In three human ...

  15. Nimbolide Sensitizes Human Colon Cancer Cells to TRAIL through Reactive Oxygen Species- and ERK-dependent Up-regulation of Death Receptors, p53, and Bax*

    OpenAIRE

    Gupta, Subash C.; Reuter, Simone; Phromnoi, Kanokkarn; Park, Byoungduck; Hema, Padmanabhan S.; Nair, Mangalam; Aggarwal, Bharat B.

    2010-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G1 fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer ce...

  16. In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on Two Non-Breast Cancer Cell Types

    OpenAIRE

    Majumdar, S. K.; Valdellon, J. A.; Brown, K A

    2001-01-01

    Tamoxifen, a potent anticancer agent known to interrupt the enhanced estrogen activity of malignant mammary gland cells, was recently approved by the Food and Drug Administration (FDA) for the treatment of breast cancer. In this investigation, the toxic effects of tamoxifen were evaluated through cell multiplication, and cytological, surface ultrastructural, and biochemical studies on human cervical carcinoma cells (HeLa) and/or murine erythroleukemic (MEL) cells (BB-88). Tamoxifen treatment ...

  17. Cytotoxic macrophage-released tumour necrosis factor-alpha (TNF-α) as a killing mechanism for cancer cell death after cold plasma activation

    International Nuclear Information System (INIS)

    The present study aims at studying the anticancer role of cold plasma-activated immune cells. The direct anti-cancer activity of plasma-activated immune cells against human solid cancers has not been described so far. Hence, we assessed the effect of plasma-treated RAW264.7 macrophages on cancer cell growth after co-culture. In particular, flow cytometer analysis revealed that plasma did not induce any cell death in RAW264.7 macrophages. Interestingly, immunofluorescence and western blot analysis confirmed that TNF-α released from plasma-activated macrophages acts as a tumour cell death inducer. In support of these findings, activated macrophages down-regulated the cell growth in solid cancer cell lines and induced cell death in vitro. Together our findings suggest plasma-induced reactive species recruit cytotoxic macrophages to release TNF-α, which blocks cancer cell growth and can have the potential to contribute to reducing tumour growth in vivo in the near future. (paper)

  18. Cytotoxic macrophage-released tumour necrosis factor-alpha (TNF-α) as a killing mechanism for cancer cell death after cold plasma activation

    Science.gov (United States)

    Kaushik, Nagendra Kumar; Kaushik, Neha; Min, Booki; Choi, Ki Hong; Hong, Young June; Miller, Vandana; Fridman, Alexander; Choi, Eun Ha

    2016-03-01

    The present study aims at studying the anticancer role of cold plasma-activated immune cells. The direct anti-cancer activity of plasma-activated immune cells against human solid cancers has not been described so far. Hence, we assessed the effect of plasma-treated RAW264.7 macrophages on cancer cell growth after co-culture. In particular, flow cytometer analysis revealed that plasma did not induce any cell death in RAW264.7 macrophages. Interestingly, immunofluorescence and western blot analysis confirmed that TNF-α released from plasma-activated macrophages acts as a tumour cell death inducer. In support of these findings, activated macrophages down-regulated the cell growth in solid cancer cell lines and induced cell death in vitro. Together our findings suggest plasma-induced reactive species recruit cytotoxic macrophages to release TNF-α, which blocks cancer cell growth and can have the potential to contribute to reducing tumour growth in vivo in the near future.

  19. Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage

    OpenAIRE

    Dhillon, Harsharan; Chikara, Shireen; Reindl, Katie M.

    2014-01-01

    Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The poor response of pancreatic cancer to currently available therapies and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS)-inducing agents has emerged as an innovative and effective strategy to treat various cancers. In this study, we investigated the potential of a known ROS inducer, pipe...

  20. In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on Two Non-Breast Cancer Cell Types

    OpenAIRE

    Majumdar, S. K.; Valdellon, J. A.; Brown, K A

    2001-01-01

    Tamoxifen, a potent anticancer agent known to interrupt the enhanced estrogen activity of malignant mammary gland cells, was recently approved by the Food and Drug Administration (FDA)for the treatment of breast cancer. In this investigation, the toxic effects of tamoxifen were evaluated through cell multiplication, and cytological, surface ultrastructural, and biochemical studies on human cervical carcinoma cells (HeLa)and/or murine erythroleukemic (MEL)c ells (BB-88). Tamoxifen treatment...

  1. Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength

    DEFF Research Database (Denmark)

    Hansen, Emilie Louise; Sozer, Esin Bengisu; Romeo, Stefania;

    2015-01-01

    BACKGROUND: Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell......-dependently reduced cell survival and intracellular ATP. Increasing extracellular calcium allows the use of a lower electric field. GENERAL SIGNIFICANCE: This study supports the use of calcium electroporation for treatment of cancer and possibly lowering the applied electric field in future trials....... death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy. METHODS: In three human cell lines--H69 (small-cell lung cancer), SW780 (bladder cancer), and U937 (leukaemia), viability was...

  2. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie;

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...... upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na(+)/H(+) exchanger (SLC9A1/NHE1) strongly sensitizes ΔNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which ΔNErbB2 regulates cisplatin-induced breast...... cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin...

  3. Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance

    Directory of Open Access Journals (Sweden)

    Anna E. Maciag

    2013-01-01

    Full Text Available JS-K is a nitric oxide (NO-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action.

  4. Comparison of cell death-inducing effect of novel taxane SB-T-1216 and paclitaxel in breast cancer cells

    Czech Academy of Sciences Publication Activity Database

    Kovář, J.; Ehrlichová, M.; Šmejkalová, Barbora; Zanardi, I.; Ojima, I.; Gut, I.

    2009-01-01

    Roč. 29, č. 8 (2009), s. 2951-2960. ISSN 0250-7005 R&D Projects: GA ČR(CZ) GD204/05/H023 Grant ostatní: GA MZd(CZ) NR9426; GA ČR(CZ) GA301/09/0362 Institutional research plan: CEZ:AV0Z50520514 Keywords : Cell death * taxane SB-T-1216 * paclitaxel Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.428, year: 2009

  5. Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Hyun-Kyu An

    Full Text Available Anticancer properties and mechanisms of mimulone (MML, C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3 puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA, pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy.

  6. Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.

    Science.gov (United States)

    An, Hyun-Kyu; Kim, Kyoung-Sook; Lee, Ji-Won; Park, Mi-Hyun; Moon, Hyung-In; Park, Shin-Ji; Baik, Ji-Sue; Kim, Cheorl-Ho; Lee, Young-Choon

    2014-01-01

    Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3) puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC) staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA), pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ) suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α) and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy. PMID:25490748

  7. The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

    Directory of Open Access Journals (Sweden)

    Cuezva José M

    2011-02-01

    Full Text Available Abstract Background Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase. The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH, which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP and iodoacetate (IA, and the anti-metabolite, 5-fluorouracil (5-FU. Methods The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. Results We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Conclusions Overall, we suggest that the

  8. Snake venom toxin from vipera lebetina turanica induces apoptosis of colon cancer cells via upregulation of ROS- and JNK-mediated death receptor expression

    International Nuclear Information System (INIS)

    Abundant research suggested that the cancer cells avoid destruction by the immune system through down-regulation or mutation of death receptors. Therefore, it is very important that finding the agents that increase the death receptors of cancer cells. In this study, we demonstrated that the snake venom toxin from Vipera lebetina turanica induce the apoptosis of colon cancer cells through reactive oxygen species (ROS) and c-Jun N-terminal kinases (JNK) dependent death receptor (DR4 and DR5) expression. We used cell viability assays, DAPI/TUNEL assays, as well as western blot for detection of apoptosis related proteins and DRs to demonstrate that snake venom toxin-induced apoptosis is DR4 and DR5 dependent. We carried out transient siRNA knockdowns of DR4 and DR5 in colon cancer cells. We showed that snake venom toxin inhibited growth of colon cancer cells through induction of apoptosis. We also showed that the expression of DR4 and DR5 was increased by treatment of snake venom toxin. Moreover, knockdown of DR4 or DR5 reversed the effect of snake venom toxin. Snake venom toxin also induced JNK phosphorylation and ROS generation, however, pretreatment of JNK inhibitor and ROS scavenger reversed the inhibitory effect of snake venom toxin on cancer cell proliferation, and reduced the snake venom toxin-induced upregulation of DR4 and DR5 expression. Our results indicated that snake venom toxin could inhibit human colon cancer cell growth, and these effects may be related to ROS and JNK mediated activation of death receptor (DR4 and DR5) signals

  9. Effects of gamma-radiation on cell growth, cycle arrest, death, and superoxide dismutase expression by DU 145 human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Vucic V.

    2006-01-01

    Full Text Available Gamma-irradiation (gamma-IR is extensively used in the treatment of hormone-resistant prostate carcinoma. The objective of the present study was to investigate the effects of 60Co gamma-IR on the growth, cell cycle arrest and cell death of the human prostate cancer cell line DU 145. The viability of DU 145 cells was measured by the Trypan blue exclusion assay and the 3(4,5-dimethylthiazol-2-yl-2,5,diphenyltetrazolium bromide test. Bromodeoxyuridine incorporation was used for the determination of cell proliferation. Cell cycle arrest and cell death were analyzed by flow cytometry. Superoxide dismutase (SOD, specifically CuZnSOD and MnSOD protein expression, after 10 Gy gamma-IR, was determined by Western immunoblotting analysis. gamma-IR treatment had a significant (P < 0.001 antiproliferative and cytotoxic effect on DU 145 cells. Both effects were time and dose dependent. Also, the dose of gamma-IR which inhibited DNA synthesis and cell proliferation by 50% was 9.7 Gy. Furthermore, gamma-IR induced cell cycle arrest in the G2/M phase and the percentage of cells in the G2/M phase was increased from 15% (control to 49% (IR cells, with a nonsignificant induction of apoptosis. Treatment with 10 Gy gamma-IR for 24, 48, and 72 h stimulated CuZnSOD and MnSOD protein expression in a time-dependent manner, approximately by 3- to 3.5-fold. These data suggest that CuZnSOD and MnSOD enzymes may play an important role in the gamma-IR-induced changes in DU 145 cell growth, cell cycle arrest and cell death.

  10. LCL124, a Cationic Analog of Ceramide, Selectively Induces Pancreatic Cancer Cell Death by Accumulating in Mitochondria

    OpenAIRE

    Beckham, Thomas H; Lu, Ping; Jones, Elizabeth E.; Marrison, Tucker; Lewis, Clayton S.; Cheng, Joseph C.; Ramshesh, Venkat K.; Beeson, Gyda; Beeson, Craig C.; Richard R. Drake; Bielawska, Alicja; Bielawski, Jacek; Szulc, Zdzislaw M; Ogretmen, Besim; Norris, James S.

    2013-01-01

    Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve defects in the intrinsic/mitochondrial apoptotic pathway. The bioactive sphingolipid ceramide is a crit...

  11. Lactaptin induces p53-independent cell death associated with features of apoptosis and autophagy and delays growth of breast cancer cells in mouse xenografts.

    Directory of Open Access Journals (Sweden)

    Olga A Koval

    Full Text Available Lactaptin, the proteolytic fragment of human milk kappa-casein, induces the death of various cultured cancer cells. The mechanisms leading to cell death after lactaptin treatment have not been well characterized. In this study the in vivo and in vitro effects of a recombinant analogue of lactaptin (RL2 were examined. Following treatment with the recombinant analogue of lactaptin strong caspase -3, -7 activation was detected. As a consequence of caspase activation we observed the appearance of a sub-G1 population of cells with subdiploid DNA content. Dynamic changes in the mRNA and protein levels of apoptosis-related genes were estimated. No statistically reliable differences in p53 mRNA level or protein level were found between control and RL2-treated cells. We observed that RL2 constitutively suppressed bcl-2 mRNA expression and down regulated Bcl-2 protein expression in MDA-MB-231 cells. We demonstrated that RL2 penetrates cancer and non-transformed cells. Identification of the cellular targets of the lactaptin analogue revealed that α/β-tubulin and α-actinin-1 were RL2-bound proteins. As the alteration in cellular viability in response to protein stimulus can be realized not only by way of apoptosis but also by autophagy, we examined the implications of autophagy in RL2-dependent cell death. We also found that RL2 treatment induces LC3-processing, which is a hallmark of autophagy. The autophagy inhibitor chloroquine enhanced RL2 cytotoxicity to MDA-MB-231 cells, indicating the pro-survival effect of RL2-dependent autophagy. The antitumour potential of RL2 was investigated in vivo in mouse xenografts bearing MDA-MB-231 cells. We demonstrated that the recombinant analogue of lactaptin significantly suppressed the growth of solid tumours. Our results indicate that lactaptin could be a new molecule for the development of anticancer drugs.

  12. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death.

    Science.gov (United States)

    Raimondo, Stefania; Naselli, Flores; Fontana, Simona; Monteleone, Francesca; Lo Dico, Alessia; Saieva, Laura; Zito, Giovanni; Flugy, Anna; Manno, Mauro; Di Bella, Maria Antonietta; De Leo, Giacomo; Alessandro, Riccardo

    2015-08-14

    Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing.Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifugation, with density ranging from 1,15 to 1,19 g/ml and specific proteomic profile. By using an in vitro approach, we show that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death. Furthermore, we demonstrate that lemon nanovesicles suppress CML tumor growth in vivo by specifically reaching tumor site and by activating TRAIL-mediated apoptotic cell processes. Overall, this study suggests the possible use of plant-edible nanovesicles as a feasible approach in cancer treatment. PMID:26098775

  13. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer

    OpenAIRE

    Jin Sheng; Wenfeng Fang; Juan Yu; Nan Chen; Jianhua Zhan; Yuxiang Ma; Yunpeng Yang; Yanhuang; Hongyun Zhao; Li Zhang

    2016-01-01

    The effects of treatments to programmed death ligand-1 (PD-L1) expression is unknown. The aim of this study was to investigate the impact of neoadjuvant chemotherapy (NACT) on PD-L1 expression in non-small cell lung cancer (NSCLC) patients. PD-L1 expression was detected by immunohistochemistry (IHC) method in 32 paired tumor specimens pre and post-NACT. The positivity of PD-L1 on tumor cells (TCs) changed from 75% to 37.5% after NACT (p = 0.003). Cases with IHC score of 1, 2, 3 all underwent ...

  14. Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75

    Directory of Open Access Journals (Sweden)

    Leoh Lai

    2009-08-01

    Full Text Available Abstract Background Hormone-refractory prostate cancer (HRPC is characterized by poor response to chemotherapy and high mortality, particularly among African American men when compared to other racial/ethnic groups. It is generally accepted that docetaxel, the standard of care for chemotherapy of HRPC, primarily exerts tumor cell death by inducing mitotic catastrophe and caspase-dependent apoptosis following inhibition of microtubule depolymerization. However, there is a gap in our knowledge of mechanistic events underlying docetaxel-induced caspase-independent cell death, and the genes that antagonize this process. This knowledge is important for circumventing HRPC chemoresistance and reducing disparities in prostate cancer mortality. Results We investigated mechanistic events associated with docetaxel-induced death in HRPC cell lines using various approaches that distinguish caspase-dependent from caspase-independent cell death. Docetaxel induced both mitotic catastrophe and caspase-dependent apoptosis at various concentrations. However, caspase activity was not essential for docetaxel-induced cytotoxicity since cell death associated with lysosomal membrane permeabilization still occurred in the presence of caspase inhibitors. Partial inhibition of docetaxel-induced cytotoxicity was observed after inhibition of cathepsin B, but not inhibition of cathepsins D and L, suggesting that docetaxel induces caspase-independent, lysosomal cell death. Simultaneous inhibition of caspases and cathepsin B dramatically reduced docetaxel-induced cell death. Ectopic expression of lens epithelium-derived growth factor p75 (LEDGF/p75, a stress survival autoantigen and transcription co-activator, attenuated docetaxel-induced lysosomal destabilization and cell death. Interestingly, LEDGF/p75 overexpression did not protect cells against DTX-induced mitotic catastrophe, and against apoptosis induced by tumor necrosis factor related apoptosis inducing ligand (TRAIL

  15. Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer

    International Nuclear Information System (INIS)

    There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFβ/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival. IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant. We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors. The identification of these 2 novel mechanisms leading to induction of cell death indicates

  16. NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells.

    Science.gov (United States)

    Liu, Hui-Ying; Li, Qing-Ran; Cheng, Xue-Fang; Wang, Guang-Ji; Hao, Hai-Ping

    2016-08-01

    Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer. PMID:27608947

  17. Effects of the knockdown of death-associated protein 3 expression on cell adhesion, growth and migration in breast cancer cells.

    Science.gov (United States)

    Wazir, Umar; Sanders, Andrew J; Wazir, Ahmad M A; Ye, Lin; Jiang, Wen G; Ster, Irina C; Sharma, Anup K; Mokbel, Kefah

    2015-05-01

    The death-associated protein 3 (DAP3) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP3 expression and clinicopathological parameters of human breast cancer. In the present study, we intended to determine the role of DAP3 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sub-lines of MCF7 and MDA-MB-231, and performed growth, adhesion, invasion assays and electric cell-substrate impedance sensing (ECIS) studies of post-wound migration of the cells. In addition, we studied the mRNA expression of caspase 8 and 9, death ligand signal enhancer (DELE), IFN-β promoter stimulator 1 (IPS1), cyclin D1 and p21 in the control and knockdown sub-lines. The knockdown sub-lines of MCF7 and MDA-MB-231 had significantly increased adhesion and decreased growth when compared to the controls. Furthermore, invasion and migration were significantly increased in the MDA-MB-231DAP3kd cells vs. the controls. The expression of caspase 9 and IPS1, known components of the apoptosis pathway, were significantly reduced in the MCF7DAP3kd cells (p=0.05 and p=0.003, respectively). We conclude that DAP3 silencing contributes to breast carcinogenesis by increasing cell adhesion, migration and invasion. It is possible that this may be due to the activity of focal adhesion kinase further downstream of the anoikis pathway. Further research in this direction would be beneficial in increasing our understanding of the mechanisms underlying human breast cancer. PMID:25738636

  18. Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression.

    Science.gov (United States)

    Lee, Hye Lim; Park, Mi Hee; Hong, Ji Eun; Kim, Dae Hwan; Kim, Ji Young; Seo, Hyen Ok; Han, Sang-Bae; Yoon, Joo Hee; Lee, Won Hyoung; Song, Ho Sueb; Lee, Ji In; Lee, Ung Soo; Song, Min Jong; Hong, Jin Tae

    2016-02-01

    We previously found that snake venom toxin inhibits nuclear factor kappa B (NF-κB) activity in several cancer cells. NF-κB is implicated in cancer cell growth and chemoresistance. In our present study, we investigated whether snake venom toxin (SVT) inhibits NF-κB, thereby preventing human cervical cancer cell growth (Ca Ski and C33A). SVT (0-12 μg/ml) inhibited the growth of cervical cancer cells by the induction of apoptotic cell death. These inhibitory effects were associated with the inhibition of NF-κB activity. However, SVT dose dependently increased the expression of death receptors (DRs): DR3, DR5 and DR downstream pro-apoptotic proteins. Exploration of NF-κB inhibitor (Phenylarsine oxide, 0.1 μM) synergistically further increased SVT-induced DR3 and DR5 expressions accompanied with further inhibition of cancer cells growth. Moreover, deletion of DR3 and DR5 by small interfering RNA significantly abolished SVT-induced cell growth inhibitory effects, as well as NF-κB inactivation. Using TNF-related apoptosis-inducing ligand resistance cancer cells (A549 and MCF-7), we also found that SVT enhanced the susceptibility of chemoresistance of these cancer cells through down-regulation of NF-κB, but up-regulation of DR3 and DR5. In vivo study also showed that SVT (0.5 and 1 mg/kg) inhibited tumor growth accompanied with inactivation of NF-κB. Thus, our present study indicates that SVT could be applicable as an anticancer agent for cervical cancer, or as an adjuvant agent for chemoresistant cancer cells. PMID:25417048

  19. Investigation of epothilone B-induced cell death mechanisms in human epithelial cancer cells -in consideration of combined treatment with ionizing radiation.

    Science.gov (United States)

    Baumgart, Tonja; Kriesen, Stephan; Neels, Oliver; Hildebrandt, Guido; Manda, Katrin

    2015-07-01

    Epothilone B was shown to have promising chemo- and radiosensitizing effects on cells, but the mechanisms underlying cell death remain ambiguous. The aim of the study was to examine selected cell death pathways on the basis of FaDu and A549 cells. Western blot analyses were used for investigation of specific apoptotic markers. Immunofluorescence imaging and flow cytometry were utilized for examination of cell death mechanisms. DNA-staining was used for studying influence of epothilone B on micronucleus rate. We showed that epothilone B can initiate cell death via apoptosis and mitotic catastrophe, but induction of cell death was cell type specific. PMID:25919223

  20. Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

    Directory of Open Access Journals (Sweden)

    Marco Tomasetti

    Full Text Available BACKGROUND: The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS was found to synergistically cooperate with vitamin K3 (VK3 plus ascorbic acid (AA in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. CONCLUSIONS/SIGNIFICANCE: α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

  1. Inhibition of inducible heat shock protein-70 (hsp72 enhances bortezomib-induced cell death in human bladder cancer cells.

    Directory of Open Access Journals (Sweden)

    Wei Qi

    Full Text Available The proteasome inhibitor bortezomib (Velcade is a promising new agent for bladder cancer therapy, but inducible cytoprotective mechanisms may limit its potential efficacy. We used whole genome mRNA expression profiling to study the effects of bortezomib on stress-induced gene expression in a panel of human bladder cancer cell lines. Bortezomib induced strong upregulation of the inducible HSP70 isoforms HSPA1A and HSPA1B isoforms of Hsp72 in 253J B-V and SW780 (HSPA1A(high cells, but only induced the HSPA1B isoform in UM-UC10 and UM-UC13 (HSPA1A(low cells. Bortezomib stimulated the binding of heat shock factor-1 (HSF1 to the HSPA1A promoter in 253JB-V but not in UM-UC13 cells. Methylation-specific PCR revealed that the HSPA1A promoter was methylated in the HSPA1A(low cell lines (UM-UC10 and UM-UC13, and exposure to the chromatin demethylating agent 5-aza-2'-deoxycytidine restored HSPA1A expression. Overexpression of Hsp72 promoted bortezomib resistance in the UM-UC10 and UM-UC13 cells, whereas transient knockdown of HSPA1B further sensitized these cells to bortezomib, and exposure to the chemical HSF1 inhibitor KNK-437 promoted bortezomib sensitivity in the 253J B-V cells. Finally, shRNA-mediated stable knockdown of Hsp72 in 253J B-V promoted sensitivity to bortezomib in vitro and in tumor xenografts in vivo. Together, our results provide proof-of-concept for using Hsp72 inhibitors to promote bortezomib sensitivity in bladder cancers and suggest that selective targeting of HSPA1B could produce synthetic lethality in tumors that display HSPA1A promoter methylation.

  2. Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3

    International Nuclear Information System (INIS)

    Extravasation of circulating cancer cells is a key event of metastatic dissemination that is initiated by the adhesion of cancer cells to endothelial cells. It requires interactions between adhesion receptors on endothelial cells and their counter-receptors on cancer cells. Notably, E-selectin, a major endothelial adhesion receptor, interacts with Death receptor-3 present on metastatic colon carcinoma cells. This interaction confers metastatic properties to colon cancer cells by promoting the adhesion of cancer cells to endothelial cells and triggering the activation of the pro-migratory p38 and pro-survival ERK pathways in the cancer cells. In the present study, we investigated further the mechanisms by which the E-selectin-activated pathways downstream of DR3 confer a survival advantage to colon cancer cells. Cell survival has been ascertained by using the WST-1 assay and by evaluating the activation of the PI3 kinase/NFκB survival axis. Apoptosis has been assayed by determining DNA fragmentation by Hoechst staining and by measuring cleavage of caspases-8 and -3. DR3 isoforms have been identified by PCR. For more precise quantification, targeted PCR reactions were carried out, and the amplified products were analyzed by automated chip-based microcapillary electrophoresis on an Agilent 2100 Bioanalyzer instrument. Interaction between DR3-expressing HT29 colon carcinoma cells and E-selectin induces the activation of the PI3K/Akt pathway. Moreover, p65/RelA, the anti-apoptotic subunit of NFκB, is rapidly translocated to the nucleus in response to E-selectin. This translocation is impaired by the PI3K inhibitor LY294002. Furthermore, inhibition of the PI3K/Akt pathway increases the cleavage of caspase 8 in colon cancer cells treated with E-selectin and this effect is still further increased when both ERK and PI3K pathways are concomitantly inhibited. Intriguingly, metastatic colon cancer cell lines such as HT29 and SW620 express higher levels of a splice variant of

  3. Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3

    Directory of Open Access Journals (Sweden)

    Paquet Éric R

    2011-07-01

    Full Text Available Abstract Background Extravasation of circulating cancer cells is a key event of metastatic dissemination that is initiated by the adhesion of cancer cells to endothelial cells. It requires interactions between adhesion receptors on endothelial cells and their counter-receptors on cancer cells. Notably, E-selectin, a major endothelial adhesion receptor, interacts with Death receptor-3 present on metastatic colon carcinoma cells. This interaction confers metastatic properties to colon cancer cells by promoting the adhesion of cancer cells to endothelial cells and triggering the activation of the pro-migratory p38 and pro-survival ERK pathways in the cancer cells. In the present study, we investigated further the mechanisms by which the E-selectin-activated pathways downstream of DR3 confer a survival advantage to colon cancer cells. Methods Cell survival has been ascertained by using the WST-1 assay and by evaluating the activation of the PI3 kinase/NFκB survival axis. Apoptosis has been assayed by determining DNA fragmentation by Hoechst staining and by measuring cleavage of caspases-8 and -3. DR3 isoforms have been identified by PCR. For more precise quantification, targeted PCR reactions were carried out, and the amplified products were analyzed by automated chip-based microcapillary electrophoresis on an Agilent 2100 Bioanalyzer instrument. Results Interaction between DR3-expressing HT29 colon carcinoma cells and E-selectin induces the activation of the PI3K/Akt pathway. Moreover, p65/RelA, the anti-apoptotic subunit of NFκB, is rapidly translocated to the nucleus in response to E-selectin. This translocation is impaired by the PI3K inhibitor LY294002. Furthermore, inhibition of the PI3K/Akt pathway increases the cleavage of caspase 8 in colon cancer cells treated with E-selectin and this effect is still further increased when both ERK and PI3K pathways are concomitantly inhibited. Intriguingly, metastatic colon cancer cell lines such as HT

  4. Correlation Between PARP-1 Immunoreactivity and Cytomorphological Features of Parthanatos, a Specific Cellular Death in Breast Cancer Cells

    OpenAIRE

    Donizy, P.; Halon, A.; Surowiak, P.; Pietrzyk, G.; C. Kozyra; Matkowski, R.

    2013-01-01

    In parthanatos, a PARP-1 (poly (ADP-ribose) polymerase 1)-mediated cell death, dissipation of mitochondrial membrane potential, large-scale DNA fragmentation and chromatin condensation were observed. In contrast to apoptosis, it does not cause apoptotic bodies formation. Although PARP-1-mediated cell death presents loss of membrane integrity similar to necrosis, it does not induce cell swelling. The purpose of the study was to correlate the immunohistochemical parameters of PARP-1 reactivity ...

  5. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation

    International Nuclear Information System (INIS)

    The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is frequently deregulated in prostate cancer and associated with neoplastic transformation, malignant progression, and enhanced resistance to classical chemotherapy and radiotherapy. Thus, it is a promising target for therapeutic intervention. In the present study, the cytotoxic action of the Akt inhibitor Erufosine (ErPC3) was analyzed in prostate cancer cells and compared to the cytotoxicity of the PI3K inhibitor LY294002. Moreover, the efficacy of combined treatment with Akt inhibitors and ionizing radiation in prostate cancer cells was examined. Prostate cancer cell lines PC3, DU145, and LNCaP were treated with ErPC3 (1-100 µM), LY294002 (25-100 µM), irradiated (0-10 Gy), or subjected to combined treatments. Cell viability was determined by the WST-1 assay. Apoptosis induction was analyzed by flow cytometry after staining with propidium iodide in a hypotonic citrate buffer, and by Western blotting using antibodies against caspase-3 and its substrate PARP. Akt activity and regulation of the expression of Bcl-2 family members and key downstream effectors involved in apoptosis regulation were examined by Western blot analysis. The Akt inhibitor ErPC3 exerted anti-neoplastic effects in prostate cancer cells, however with different potency. The anti-neoplastic action of ErPC3 was associated with reduced phosphoserine 473-Akt levels and induction of apoptosis. PC3 and LNCaP prostate cancer cells were also sensitive to treatment with the PI3K inhibitor LY294002. However, the ErPC3-sensitive PC3-cells were less susceptible to LY294002 than the ErPC3-refractory LNCaP cells. Although both cell lines were largely resistant to radiation-induced apoptosis, both cell lines showed higher levels of apoptotic cell death when ErPC3 was combined with radiotherapy. Our data suggest that constitutive Akt activation and survival are controlled by different different molecular mechanisms in the two prostate cancer cell lines

  6. Effect of the knockdown of death-associated protein 1 expression on cell adhesion, growth and migration in breast cancer cells.

    Science.gov (United States)

    Wazir, Umar; Sanders, Andrew J; Wazir, Ali; Baig, Ruqia Mehmood; Jiang, Wen G; Ster, Irina C; Sharma, Anup K; Mokbel, Kefah

    2015-03-01

    Death-associated protein 1 (DAP1) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP1 expression and clinicopathological parameters of human breast cancer. In the present study, we aimed to determine the role of DAP1 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sublines of MCF7 and MDA-MB‑231, and performed growth, adhesion and invasion assays and electric cell-substrate impedance sensing (ECIS) studies of the post-wound migration of cells. In addition, we studied the mRNA expression of caspase 8 and 9, DELE, IPS1, cyclin D1 and p21 in the control and knockdown sublines. Knockdown was associated with increased adhesion and migration, significantly so in the MDA-MB-231DAP1kd cell subline (p=0.029 and p=0.001, respectively). Growth in MCF7 cells showed a significant suppression on day 3 (p=0.029), followed by an increase in growth matching the controls on day 5. While no change in the apoptotic response to serum starvation could be attributed to DAP1 knockdown, the expression of known components of the apoptosis pathway (caspase 8) and cell cycle (p21) was significantly reduced in the MCF7DAP1kd cell subline (p≤0.05), while in MDA-MB-231DAP1kd the expression of a pro-apoptotic molecule, IPS1, was suppressed (p≤0.05). DAP1 may have an important role in cell adhesion, migration and growth in the context of breast cancer and has significant associations with the apoptosis pathway. Furthermore, we believe that delayed increase in growth observed in the MCF7DAP1kd cell subline may indicate activation of a strongly pro-oncogenic pathway downstream of DAP1. PMID:25530065

  7. Sensitization of (colon) cancer cells to death receptor related therapies A report from the FP6-ONCODEATH research consortium

    Czech Academy of Sciences Publication Activity Database

    Pintzas, A.; Zhivotovsky, B.; Workman, P.; Clarke, P.A.; Linardopoulos, S.; Martinou, J.C.; Lacal, J.C.; Robine, S.; Nasioulas, G.; Anděra, Ladislav

    2012-01-01

    Roč. 13, č. 7 (2012), s. 458-466. ISSN 1538-4047 Grant ostatní: EK(XE) LSHC-CT-2006-037278 Institutional support: RVO:68378050 Keywords : cancer * death receptors * kinase inhibitors * mitochondria * targeted therapies Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.287, year: 2012

  8. Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: A proteomic approach.

    Science.gov (United States)

    Li, Qingdi Quentin; Hao, Jian-Jiang; Zhang, Zheng; Hsu, Iawen; Liu, Yi; Tao, Zhen; Lewi, Keidren; Metwalli, Adam R; Agarwal, Piyush K

    2016-06-01

    The Cancer Genome Atlas (TCGA) project recently identified the importance of mutations in chromatin remodeling genes in human carcinomas. These findings imply that epigenetic modulators might have a therapeutic role in urothelial cancers. To exploit histone deacetylases (HDACs) as targets for cancer therapy, we investigated the HDAC inhibitors (HDACIs) romidepsin, trichostatin A, and vorinostat as potential chemotherapeutic agents for bladder cancer. We demonstrate that the three HDACIs suppressed cell growth and induced cell death in the bladder cancer cell line 5637. To identify potential mechanisms associated with the anti-proliferative and cytotoxic effects of the HDACIs, we used quantitative proteomics to determine the proteins potentially involved in these processes. Our proteome studies identified a total of 6003 unique proteins. Of these, 2472 proteins were upregulated and 2049 proteins were downregulated in response to HDACI exposure compared to the untreated controls (P<0.05). Bioinformatic analysis further revealed that those differentially expressed proteins were involved in multiple biological functions and enzyme-regulated pathways, including cell cycle progression, apoptosis, autophagy, free radical generation and DNA damage repair. HDACIs also altered the acetylation status of histones and non-histone proteins, as well as the levels of chromatin modification proteins, suggesting that HDACIs exert multiple cytotoxic actions in bladder cancer cells by inhibiting HDAC activity or altering the structure of chromatin. We conclude that HDACIs are effective in the inhibition of cell proliferation and the induction of apoptosis in the 5637 bladder cancer cells through multiple cell death-associated pathways. These observations support the notion that HDACIs provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration. PMID:27082124

  9. An antitubulin agent BCFMT inhibits proliferation of cancer cells and induces cell death by inhibiting microtubule dynamics.

    Directory of Open Access Journals (Sweden)

    Ankit Rai

    Full Text Available Using cell based screening assay, we identified a novel anti-tubulin agent (Z-5-((5-(4-bromo-3-chlorophenylfuran-2-ylmethylene-2-thioxothiazolidin-4-one (BCFMT that inhibited proliferation of human cervical carcinoma (HeLa (IC(50, 7.2 ± 1.8 µM, human breast adenocarcinoma (MCF-7 (IC(50, 10.0 ± 0.5 µM, highly metastatic breast adenocarcinoma (MDA-MB-231 (IC(50, 6.0 ± 1 µM, cisplatin-resistant human ovarian carcinoma (A2780-cis (IC(50, 5.8 ± 0.3 µM and multi-drug resistant mouse mammary tumor (EMT6/AR1 (IC(50, 6.5 ± 1 µM cells. Using several complimentary strategies, BCFMT was found to inhibit cancer cell proliferation at G2/M phase of the cell cycle apparently by targeting microtubules. In addition, BCFMT strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. At its half maximal proliferation inhibitory concentration (10 µM, BCFMT reduced the rates of growing and shortening phases of microtubules in MCF-7 cells by 37 and 40%, respectively. Further, it increased the time microtubules spent in the pause (neither growing nor shortening detectably state by 135% and reduced the dynamicity (dimer exchange per unit time of microtubules by 70%. In vitro, BCFMT bound to tubulin with a dissociation constant of 8.3 ± 1.8 µM, inhibited tubulin assembly and suppressed GTPase activity of microtubules. BCFMT competitively inhibited the binding of BODIPY FL-vinblastine to tubulin with an inhibitory concentration (K(i of 5.2 ± 1.5 µM suggesting that it binds to tubulin at the vinblastine site. In cultured cells, BCFMT-treatment depolymerized interphase microtubules, perturbed the spindle organization and accumulated checkpoint proteins (BubR1 and Mad2 at the kinetochores. BCFMT-treated MCF-7 cells showed enhanced nuclear accumulation of p53 and its downstream p21, which consequently activated apoptosis in these cells. The results suggested that BCFMT inhibits proliferation of several types of cancer cells including drug

  10. Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

    OpenAIRE

    Yao, Qinghua; Fu, Ting; Wang, Lu; LAI, YUEBIAO; Wang, Yuqi; Xu, Chao; Huang, Lulu; Guo, Yong

    2015-01-01

    The present study identified that ω-3 long chain polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrate anti-proliferative effects in lung cancer A549 cells. MTS and cytotoxicity assays were conducted to confirm that ω-3 PUFAs induced cell death. Autophagy-associated gene and signaling pathways were also detected. Microtubule-associated protein light chain 3 (LC3) expression was found to be increased subsequent to treatment with DHA and...

  11. Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo.

    Science.gov (United States)

    Singh, Tripti; Prasad, Ram; Katiyar, Santosh K

    2013-01-01

    Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 µM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects of honokiol were associated with a significant reduction in the viability of NSCLC cells. Concomitant treatment of cells with a proteasome inhibitor, MG132, prevented honokiol-induced degradation of class I HDACs, suggesting that honokiol reduced the levels of HDACs in NSCLC cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of NSCLC cells. Treatment of A549 and H1299 cells with honokiol resulted in an increase in G 1 phase arrest, and a decrease in the levels of cyclin D1, D2 and cyclin dependent kinases. Further, administration of honokiol by oral gavage significantly inhibited the growth of subcutaneous A549 and H1299 tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells. PMID:23221619

  12. Coherence-controlled holographic microscopy enabled recognition of necrosis as the mechanism of cancer cells death after exposure to cytopathic turbid emulsion

    Science.gov (United States)

    Collakova, Jana; Krizova, Aneta; Kollarova, Vera; Dostal, Zbynek; Slaba, Michala; Vesely, Pavel; Chmelik, Radim

    2015-11-01

    Coherence-controlled holographic microscopy (CCHM) in low-coherence mode possesses a pronounced coherence gate effect. This offers an option to investigate the details of cellular events leading to cell death caused by cytopathic turbid emulsions. CCHM capacity was first assessed in model situations that showed clear images obtained with low coherence of illumination but not with high coherence of illumination. Then, the form of death of human cancer cells induced by treatment with biologically active phospholipids (BAPs) preparation was investigated. The observed overall retraction of cell colony was apparently caused by the release of cell-to-substratum contacts. This was followed by the accumulation of granules decorating the nuclear membrane. Then, the occurrence of nuclear membrane indentations signaled the start of damage to the integrity of the cell nucleus. In the final stage, cells shrunk and disintegrated. This indicated that BAPs cause cell death by necrosis and not apoptosis. An intriguing option of checking the fate of cancer cells caused by the anticipated cooperative effect after adding another tested substance sodium dichloroacetate to turbid emulsion is discussed on grounds of pilot experiments. Such observations should reveal the impact and mechanism of action of the interacting drugs on cell behavior and fate that would otherwise remain hidden in turbid milieu.

  13. (--)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells.

    Science.gov (United States)

    Takeda, Shuso; Matsuo, Kazumasa; Yaji, Kentaro; Okajima-Miyazaki, Shunsuke; Harada, Mari; Miyoshi, Hiroko; Okamoto, Yoshiko; Amamoto, Toshiaki; Shindo, Mitsuru; Omiecinski, Curtis J; Aramaki, Hironori

    2011-06-20

    exo-Methylene lactone group-containing compounds, such as (--)-xanthatin, are present in a large variety of biologically active natural products, including extracts of Xanthium strumarium (Cocklebur). These substances are reported to possess diverse functional activities, exhibiting anti-inflammatory, antimalarial, and anticancer potential. In this study, we synthesized six structurally related xanthanolides containing exo-methylene lactone moieties, including (--)-xanthatin and (+)-8-epi-xanthatin, and examined the effects of these chemically defined substances on the highly aggressive and farnesyltransferase inhibitor (FTI)-resistant MDA-MB-231 cancer cell line. The results obtained demonstrate that (--)-xanthatin was a highly effective inhibitor of MDA-MB-231 cell growth, inducing caspase-independent cell death, and that these effects were independent of FTase inhibition. Further, our results show that among the GADD45 isoforms, GADD45γ was selectively induced by (--)-xanthatin and that GADD45γ-primed JNK and p38 signaling pathways are, at least in part, involved in mediating the growth inhibition and potential anticancer activities of this agent. Given that GADD45γ is becoming increasingly recognized for its tumor suppressor function, the results presented here suggest the novel possibility that (--)-xanthatin may have therapeutic value as a selective inducer of GADD45γ in human cancer cells, in particular in FTI-resistant aggressive breast cancers. PMID:21568272

  14. Beclin-1-independent autophagy mediates programmed cancer cell death through interplays with endoplasmic reticulum and/or mitochondria in colbat chloride-induced hypoxia.

    Science.gov (United States)

    Sun, Lei; Liu, Ning; Liu, Shan-Shan; Xia, Wu-Yan; Liu, Meng-Yao; Li, Lin-Feng; Gao, Jian-Xin

    2015-01-01

    Autophagy has dual functions in cell survival and death. However, the effects of autophagy on cancer cell survival or death remain controversial. In this study, we show that Autophagy can mediate programmed cell death (PCD) of cancer cells in responding to cobalt chloride (CoCl2)-induced hypoxia in a Beclin-1-independent but autophagy protein 5 (ATG5)-dependent manner. Although ATG5 is not directly induced by CoCl2, its constitutive expression is essential for CoCl2-induced PCD. The ATG5-mediated autophagic PCD requires interplays with endoplasmic reticulum (ER) and/or mitochondria. In this process, ATG5 plays a central role in regulating ER stress protein CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and mitochondrial protein second mitochondria derived activator of caspases (Smac). Two pathways for autophagic PCD in cancer cells responding to hypoxia have been identified: ATG5/CHOP/Smac pathway and ATG5/Smac pathway, which are probably dependent on the context of cell lines. The former is more potent than the latter for the induction of PCD at the early stage of hypoxia, although the ultimate efficiency of both pathways is comparable. In addition, both pathways may require ATG5-mediated conversion of LC3-I into LC3-II. Therefore, we have defined two autophagy-mediated pathways for the PCD of cancer cells in hypoxia, which are dependent on ATG5, interplayed with ER and mitochondria and tightly regulated by hypoxic status. The findings provide a new evidence that autophagy may inhibit tumor cell proliferation through trigger of PCD, facilitating the development of novel anti-cancer drugs. PMID:26609472

  15. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells.

    Science.gov (United States)

    Aryal, Pramod; Kim, Kijoong; Park, Pil-Hoon; Ham, Seongho; Cho, Junghee; Song, Kyung

    2014-10-01

    Baicalein, a flavonoid and aglycon hydrolyzed from baicalin, has anticancer properties in several human carcinomas, but its molecular mechanisms of action remain unclear. Here, we show that baicalein leads to human cancer cell death by inducing autophagy rather than apoptosis, because cell death induced by baicalein was completely reversed by suppressing the expression levels of key molecules in autophagy such as Beclin 1, vacuolar protein sorting 34 (Vps34), autophagy-related (Atg)5 and Atg7, but not by pan-caspase inhibitor. Our data revealed that baicalein significantly increased the number of green fluorescence protein-cytosol-associated protein light chain 3 (GFP-LC3)-containing puncta and LC3B-II expression levels, which were further enhanced by chloroquine treatment. Furthermore, a luciferase-based reporter assay showed that the ratio of RLuc-LC3wt/RLuc-LC3G120A was greatly reduced. The data suggested that baicalein induced not only autophagosome formation, but also autophagic flux. Experiments using short interfering RNAs and pharmacological inhibitors revealed that Beclin 1, Vps34, Atg5, Atg7 and UNC-51 (Caenorhabditis elegans)-like kinase 1 (ULK1) play pivotal roles in mediating baicalein-induced autophagy. Moreover, baicalein activated AMP-activated protein kinase (AMPK)α, leading to ULK1 activation through phosphorylation at Ser555, whereas both protein and mRNA levels of mammalian target of rapamycin (mTOR) and Raptor, upstream inhibitors of ULK1 and autophagy, were markedly downregulated by baicalein. Our data suggest that the anticancer effects of baicalein are mainly due to autophagic cell death through activation of the AMPK/ULK1 pathway and inhibition of mTOR/Raptor complex 1 expression. These results provide new mechanistic insights into the anticancer functions of autophagy inducers, such as baicalein, which may be used as potential therapeutics for cancer treatment. PMID:25132405

  16. Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.

    Directory of Open Access Journals (Sweden)

    Jian-Ping Zhou

    Full Text Available Despite many evidences supporting the concept of "oncogene addiction" and many hypotheses rationalizing it, there is still a lack of detailed understanding to the precise molecular mechanism underlying oncogene addiction. In this account, we developed a mathematic model of epidermal growth factor receptor (EGFR associated signaling network, which involves EGFR-driving proliferation/pro-survival signaling pathways Ras/extracellular-signal-regulated kinase (ERK and phosphoinositol-3 kinase (PI3K/AKT, and pro-apoptotic signaling pathway apoptosis signal-regulating kinase 1 (ASK1/p38. In the setting of sustained EGFR activation, the simulation results show a persistent high level of proliferation/pro-survival effectors phospho-ERK and phospho-AKT, and a basal level of pro-apoptotic effector phospho-p38. The potential of p38 activation (apoptotic potential due to the elevated level of reactive oxygen species (ROS is largely suppressed by the negative crosstalk between PI3K/AKT and ASK1/p38 pathways. Upon acute EGFR inactivation, the survival signals decay rapidly, followed by a fast increase of the apoptotic signal due to the release of apoptotic potential. Overall, our systems biology modeling together with experimental validations reveals that inhibition of survival signals and concomitant release of apoptotic potential jointly contribute to the tumor cell death following the inhibition of addicted oncogene in EGFR addicted cancers.

  17. The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastrointestinal tract cancer: a systematic review and meta-analysis

    OpenAIRE

    Huang, Baohua; Chen, Lei; Bao, Cuixia; Sun, Chengming; Jie LI; Wang, Lipeng; Zhang, Xia

    2015-01-01

    Background Programmed cell death 1 ligand 1 (PD-L1) expression has been observed in various malignancies. However, the association between PD-L1 expression and the survival of patients with gastrointestinal tract cancer remains controversial. Besides, the rate of PD-L1 positivity on tumor cells of digestive tract cancer is not clear. Thus, we performed a meta-analysis by incorporating all available evidence to evaluate the rate of PD-L1 positivity and the overall survival (OS) according to PD...

  18. A novel protoapigenone analog RY10-4 induces breast cancer MCF-7 cell death through autophagy via the Akt/mTOR pathway

    International Nuclear Information System (INIS)

    Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells is exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, Western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggesting that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed the activation of mTOR and p70S6K via the Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design a promising antitumor agent. - Highlights: • We showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. • Autophagy induced by RY10-4 played as a promotion mechanism for cell death. • RY10-4 induced autophagy in MCF-7 cell through the Akt/mTOR pathway. • We provided new insights for the mechanism of RY10-4 induced cell death

  19. A novel protoapigenone analog RY10-4 induces breast cancer MCF-7 cell death through autophagy via the Akt/mTOR pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xuenong; Wei, Han; Liu, Ziwei; Yuan, Qianying [Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Wei, Anhua [Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Shi, Du; Yang, Xian [Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Ruan, Jinlan, E-mail: jinlan8152@163.com [Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China)

    2013-07-15

    Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells is exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, Western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggesting that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed the activation of mTOR and p70S6K via the Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design a promising antitumor agent. - Highlights: • We showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. • Autophagy induced by RY10-4 played as a promotion mechanism for cell death. • RY10-4 induced autophagy in MCF-7 cell through the Akt/mTOR pathway. • We provided new insights for the mechanism of RY10-4 induced cell death.

  20. Docosahexaenoic Acid Induces Cell Death in Human Non-Small Cell Lung Cancer Cells by Repressing mTOR via AMPK Activation and PI3K/Akt Inhibition

    Directory of Open Access Journals (Sweden)

    Nayeong Kim

    2015-01-01

    Full Text Available The anticancer properties and mechanism of action of omega-3 polyunsaturated fatty acids (ω3-PUFAs have been demonstrated in several cancers; however, the mechanism in lung cancer remains unclear. Here, we show that docosahexaenoic acid (DHA, a ω3-PUFA, induced apoptosis and autophagy in non-small cell lung cancer (NSCLC cells. DHA-induced cell death was accompanied by AMP-activated protein kinase (AMPK activation and inactivated phosphatidylinositol 3-kinase (PI3K/Akt/mammalian target of rapamycin (mTOR signaling. Knocking down AMPK and overexpressing Akt increased mTOR activity and attenuated DHA-induced cell death, suggesting that DHA induces cell death via AMPK- and Akt-regulated mTOR inactivation. This was confirmed in Fat-1 transgenic mice, which produce ω3-PUFAs. Lewis lung cancer (LLC tumor cells implanted into Fat-1 mice showed slower growth, lower phospho-Akt levels, and higher levels of apoptosis and autophagy than cells implanted into wild-type mice. Taken together, these data suggest that DHA-induced apoptosis and autophagy in NSCLC cells are associated with AMPK activation and PI3K/Akt inhibition, which in turn lead to suppression of mTOR; thus ω3-PUFAs may be utilized as potential therapeutic agents for NSCLC treatment.

  1. Proteomic analysis of novel targets associated with the enhancement of TrkA-induced SK-N-MC cancer cell death caused by NGF

    Science.gov (United States)

    Jung, Eun Joo; Chung, Ky Hyun; Bae, Dong-Won; Kim, Choong Won

    2016-01-01

    Nerve growth factor (NGF) is known to regulate both cancer cell survival and death signaling, depending on the cellular circumstances, in various cell types. In this study, we showed that NGF strongly upregulated the protein level of tropomyosin-related kinase A (TrkA) in TrkA-inducible SK-N-MC cancer cells, resulting in increases in various TrkA-dependent cellular processes, including the phosphorylation of c-Jun N-terminal kinase (JNK) and caspase-8 cleavage. In addition, NGF enhanced TrkA-induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. To investigate novel targets associated with the enhancement of TrkA-induced SK-N-MC cell death caused by NGF, we performed Coomassie Brilliant Blue staining and two-dimensional (2D) proteomic analysis in TrkA-inducible SK-N-MC cells. We identified 31 protein spots that were either greatly upregulated or downregulated by TrkA during NGF treatment using matrix-associated laser desorption/ionization time of flight/time of flight mass spectrometry, and we analyzed the effects of SP600125 and wortmannin on the spots. Interestingly, 11 protein spots, including heterogeneous nuclear ribonucleoprotein K (hnRNP K), lamin B1 and TAR DNA-binding protein (TDP43), were significantly influenced by SP600125, but not by wortmannin. Moreover, the NGF/TrkA-dependent inhibition of cell viability was significantly enhanced by knockdown of hnRNP K using small interfering RNA, demonstrating that hnRNP K is a novel target associated with the regulation of TrkA-dependent SK-N-MC cancer cell death enhanced by NGF. PMID:27229480

  2. Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy

    Czech Academy of Sciences Publication Activity Database

    Torricelli, C.; Salvadori, S.; Valacchi, G.; Souček, Karel; Slabáková, Eva; Muscettola, M.; Volpi, N.; Maioli, E.

    2012-01-01

    Roč. 2012, NOV (2012), s. 1-11 /AN 980658/. ISSN 1741-427X R&D Projects: GA ČR(CZ) GPP301/12/P407 Institutional support: RVO:68081707 Keywords : PKC-DELTA * KAPPA-B * CARCINOMA CELLS Subject RIV: BO - Biophysics Impact factor: 1.722, year: 2012

  3. Declining death rates reflect progress against cancer.

    Directory of Open Access Journals (Sweden)

    Ahmedin Jemal

    Full Text Available BACKGROUND: The success of the "war on cancer" initiated in 1971 continues to be debated, with trends in cancer mortality variably presented as evidence of progress or failure. We examined temporal trends in death rates from all-cancer and the 19 most common cancers in the United States from 1970-2006. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed trends in age-standardized death rates (per 100,000 for all cancers combined, the four most common cancers, and 15 other sites from 1970-2006 in the United States using joinpoint regression model. The age-standardized death rate for all-cancers combined in men increased from 249.3 in 1970 to 279.8 in 1990, and then decreased to 221.1 in 2006, yielding a net decline of 21% and 11% from the 1990 and 1970 rates, respectively. Similarly, the all-cancer death rate in women increased from 163.0 in 1970 to 175.3 in 1991 and then decreased to 153.7 in 2006, a net decline of 12% and 6% from the 1991 and 1970 rates, respectively. These decreases since 1990/91 translate to preventing of 561,400 cancer deaths in men and 205,700 deaths in women. The decrease in death rates from all-cancers involved all ages and racial/ethnic groups. Death rates decreased for 15 of the 19 cancer sites, including the four major cancers, with lung, colorectum and prostate cancers in men and breast and colorectum cancers in women. CONCLUSIONS/SIGNIFICANCE: Progress in reducing cancer death rates is evident whether measured against baseline rates in 1970 or in 1990. The downturn in cancer death rates since 1990 result mostly from reductions in tobacco use, increased screening allowing early detection of several cancers, and modest to large improvements in treatment for specific cancers. Continued and increased investment in cancer prevention and control, access to high quality health care, and research could accelerate this progress.

  4. The peptide derived from the Ig-like domain of human herpesvirus 8 K1 protein induces death in hematological cancer cells

    Directory of Open Access Journals (Sweden)

    Daniluk Urszula

    2012-08-01

    -3 peptide can selectively induce the death of malignant hematological cell lines by Fas- and/or TNFRI-dependent mechanisms, suggesting the K1-derived peptide or peptidomimetic may have promising therapeutic potential for the treatment of hematological cancers.

  5. Cell death proteomics database: consolidating proteomics data on cell death.

    Science.gov (United States)

    Arntzen, Magnus Ø; Bull, Vibeke H; Thiede, Bernd

    2013-05-01

    Programmed cell death is a ubiquitous process of utmost importance for the development and maintenance of multicellular organisms. More than 10 different types of programmed cell death forms have been discovered. Several proteomics analyses have been performed to gain insight in proteins involved in the different forms of programmed cell death. To consolidate these studies, we have developed the cell death proteomics (CDP) database, which comprehends data from apoptosis, autophagy, cytotoxic granule-mediated cell death, excitotoxicity, mitotic catastrophe, paraptosis, pyroptosis, and Wallerian degeneration. The CDP database is available as a web-based database to compare protein identifications and quantitative information across different experimental setups. The proteomics data of 73 publications were integrated and unified with protein annotations from UniProt-KB and gene ontology (GO). Currently, more than 6,500 records of more than 3,700 proteins are included in the CDP. Comparing apoptosis and autophagy using overrepresentation analysis of GO terms, the majority of enriched processes were found in both, but also some clear differences were perceived. Furthermore, the analysis revealed differences and similarities of the proteome between autophagosomal and overall autophagy. The CDP database represents a useful tool to consolidate data from proteome analyses of programmed cell death and is available at http://celldeathproteomics.uio.no. PMID:23537399

  6. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

    OpenAIRE

    Du, Ji-Hui; Zhang, Hou-De; Ma, Zhen-Jian; Ji, Kun-Mei

    2009-01-01

    Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective c...

  7. Decursin was Accelerated Human Lung Cancer Cell Death Caused by Proton Beam Irradiation via Blocking the p42/44 MAPK pathway

    International Nuclear Information System (INIS)

    Decursin, which is one of the extract of Angelica gigas Nakai root, has been traditionally used in Korean folk medicine as a tonic and for treatment of anemia and other common diseases. There are some reports about the pharmacological properties of decursin showing anti-bacterial and anti-amnestic effect, depression of cardiac contraction, antitumor and anti-angiogenic activity. Cell death induced by proton beam is identified as apoptosis. The study investigated that genes involved in apoptosis are checked by RT-PCR and used LET instead of SPBP of proton beam. Apoptosis is the tight regulated by multi-protein action in physiological cell death program. Proton therapy is an attractive approach for the treatment of deep-seated tumor. Recently, many researchers tried to new therapeutic strategy, combination of proton therapy and chemotherapy, in order to increase therapeutic effect. In this study, we investigate whether decursin can accelerate effect of human lung cell apoptosis in proton irradiated cancer cells

  8. Decursin was Accelerated Human Lung Cancer Cell Death Caused by Proton Beam Irradiation via Blocking the p42/44 MAPK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Myung Hwan; Ra, Se Jin; Kim, Kye Ryung [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2011-10-15

    Decursin, which is one of the extract of Angelica gigas Nakai root, has been traditionally used in Korean folk medicine as a tonic and for treatment of anemia and other common diseases. There are some reports about the pharmacological properties of decursin showing anti-bacterial and anti-amnestic effect, depression of cardiac contraction, antitumor and anti-angiogenic activity. Cell death induced by proton beam is identified as apoptosis. The study investigated that genes involved in apoptosis are checked by RT-PCR and used LET instead of SPBP of proton beam. Apoptosis is the tight regulated by multi-protein action in physiological cell death program. Proton therapy is an attractive approach for the treatment of deep-seated tumor. Recently, many researchers tried to new therapeutic strategy, combination of proton therapy and chemotherapy, in order to increase therapeutic effect. In this study, we investigate whether decursin can accelerate effect of human lung cell apoptosis in proton irradiated cancer cells

  9. M867, a novel selective inhibitor of caspase-3 enhances cell death and extends tumor growth delay in irradiated lung cancer models.

    Directory of Open Access Journals (Sweden)

    Kwang Woon Kim

    Full Text Available BACKGROUND: Lung cancer remains the leading cause of cancer death worldwide. Radioresistance of lung cancer cells results in unacceptable rate of loco-regional failure. Although radiation is known to induce apoptosis, our recent study showed that knockdown of pro-apoptotic proteins Bak and Bax resulted in an increase in autophagic cell death and lung cancer radiosensitivity in vitro. To further explore the potential of apoptosis inhibition as a way to sensitize lung cancer for therapy, we tested M867, a novel chemical and reversible caspase-3 inhibitor, in combination with ionizing radiation in vivo and in vitro. METHODS AND FINDINGS: M867 reduced clonogenic survival in H460 lung cancer cells (DER = 1.27, p = 0.007 compared to the vehicle-treated treated cells. We found that administration of M867 with ionizing radiation in an in vivo mouse hind limb lung cancer model was well tolerated, and produced a significant tumor growth delay compared to radiation alone. A dramatic decrease in tumor vasculature was observed with M867 and radiation using von Willebrand factor staining. In addition, Ki67 index showed >5-fold reduction of tumor proliferation in the combination therapy group, despite the reduced levels of apoptosis observed with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Radiosensitizing effect of M867 through inhibiting caspases was validated using caspase-3/-7 double-knockout (DKO mouse embryonic fibroblasts (MEF cell model. Consistent with our previous study, autophagy contributed to the mechanism of increased cell death, following inhibition of apoptosis. In addition, matrigel assay showed a decrease in in vitro endothelial tubule formation during the M867/radiation combination treatment. CONCLUSIONS: M867 enhances the cytotoxic effects of radiation on lung cancer and its vasculature both in vitro and in vivo. M867 has the potential to prolong tumor growth delay by inhibiting tumor proliferation

  10. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells

    DEFF Research Database (Denmark)

    Griend, Donald J Vander; Antony, Lizamma; Dalrymple, Susan L;

    2009-01-01

    There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell......-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), approximately 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b, and......-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing...

  11. Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength.

    Directory of Open Access Journals (Sweden)

    Emilie Louise Hansen

    Full Text Available Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy. Electroporation with calcium causes ATP (adenosine triphosphate depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy.In three human cell lines--H69 (small-cell lung cancer, SW780 (bladder cancer, and U937 (leukaemia, viability was determined after treatment with 1, 3, or 5 mM calcium and eight 99 μs pulses with 0.8, 1.0, 1.2, 1.4 or 1.6 kV/cm. Fitting analysis was applied to quantify the cell-killing efficacy in presence of calcium. Post-treatment intracellular ATP was measured in H69 and SW780 cells. Post-treatment intracellular ATP was observed with fluorescence confocal microscopy of quinacrine-labelled U937 cells.Both H69 and SW780 cells showed dose-dependent (calcium concentration and electric field decrease in intracellular ATP (p<0.05 and reduced viability. The 50% effective cell kill was found at 3.71 kV/cm (H69 and 3.28 kV/cm (SW780, reduced to 1.40 and 1.15 kV/cm (respectively with 1 mM calcium (lower EC50 for higher calcium concentrations. Quinacrine fluorescence intensity of calcium-electroporated U937 cells was one third lower than in controls (p<0.0001.Calcium electroporation dose-dependently reduced cell survival and intracellular ATP. Increasing extracellular calcium allows the use of a lower electric field.This study supports the use of calcium electroporation for treatment of cancer and possibly lowering the applied electric field in future trials.

  12. Lung cancer death rates fall, helping drive decrease in overall cancer death rates

    Science.gov (United States)

    The Annual Report to the Nation on the Status of Cancer, covering the period 1975–2010, showed death rates for lung cancer, which accounts for more than one in four cancer deaths, dropping at a faster pace than in previous years.

  13. Liver Cancer Stem Cells

    OpenAIRE

    Sameh Mikhail; Aiwu Ruth He

    2011-01-01

    Hepatocellular carcinoma is the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related death. Recent research supports that liver cancer is a disease of adult stem cells. From the models of experimental hepatocarcinogenesis, there may be at least three distinct cell lineages with progenitor properties susceptible to neoplastic transformation. Identification of specific cell surface markers fo...

  14. Breast Cancer Death Rates Down 34% Since 1990

    Science.gov (United States)

    ... Text Size News » Filed under: Breast Cancer Report: Breast Cancer Death Rates Down 34% Since 1990 Article date: ... American Cancer Society finds that death rates from breast cancer in the United States have dropped 34% since ...

  15. Cell Death Characterization In Tumor Constructs Using Irreversible Electroporation

    OpenAIRE

    Prokop, Katherine Jane

    2013-01-01

    Cell Death Characterization in Tumor Constructs Using Irreversible Electroporation Katherine Jane Prokop ABSTRACT Pancreatic and prostate cancer are both prevalent cancers in the United States with pancreatic being one of the most aggressive of all cancers and prostate cancer being one of the most common, ranking as the number one cancer in men. Treatment of both cancers can be quite challenging as the anatomy of the pancreas and prostate, as well as the development and diagnos...

  16. Late deaths after treatment for childhood cancer.

    OpenAIRE

    Hawkins, M M; Kingston, J. E.; Kinnier Wilson, L. M.

    1990-01-01

    An investigation of 749 deaths occurring among 4082 patients surviving at least five years after the diagnosis of childhood cancer in Britain before 1971 has been undertaken. Of the 738 with sufficient information the numbers of deaths attributable to the following causes were: recurrent tumour, 550 (74%), a second primary tumour, 61 (8%), a medical condition related to treatment of the tumour, 49 (7%), an traumatic death unrelated to the tumour or its treatment, 34 (5%), finally, any other c...

  17. Programmed cell death ligand-1 (PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer?

    Science.gov (United States)

    Mino-Kenudson, Mari

    2016-01-01

    Blockade of immune checkpoints has recently emerged as a novel therapeutic strategy in various tumors. In particular, monoclonal antibodies targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been most studied in lung cancer, and PD-1 inhibitors are now established agents in the management of non-small cell lung cancer (NSCLC). The reports on high-profile clinical trials have shown the association of PD-L1 expression by immunohistochemistry (IHC) with higher overall response rates to the PD-1/PD-L1 axis blockade suggesting that PD-L1 expression may serve as a predictive marker. Unfortunately, however, each PD-1 or PD-L1 inhibitor is coupled with a specific PD-L1 antibody, IHC protocol and scoring system for the biomarker assessment, making the head-to-head comparison of the studies difficult. Similarly, multiple clinical series that correlated PD-L1 expression with clinicopathologic and/or molecular variables and/or survival have reported conflicting results. The discrepancy could be explained by the differences in ethnicity and/or histologic types included in the studies, but it appears to be attributed in part to the differences in PD-L1 IHC methods. Thus, orchestrated efforts to standardize the PD-L1 IHC are warranted to establish the IHC as a predictive and/or prognostic biomarker in NSCLC.

  18. Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells.

    Science.gov (United States)

    Yu, Xinfeng; Li, Ruilian; Shi, Wenna; Jiang, Tao; Wang, Yufei; Li, Cong; Qu, Xianjun

    2016-02-01

    Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER(+)) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER(+) breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER(+) breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER(+) breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL. PMID:26796263

  19. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase

    DEFF Research Database (Denmark)

    Petersen, Nikolaj H T; Olsen, Ole D; Groth-Pedersen, Line;

    2013-01-01

    Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome...

  20. Expression of Peroxisome Proferator-Activated Receptor γ (PPARγ in Human Transitional Bladder Cancer and its Role in Inducing Cell Death

    Directory of Open Access Journals (Sweden)

    You-Fei Guan

    1999-10-01

    Full Text Available The present study examined the expression and role of the thiazolidinedione (TZD-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ, in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's studied (n=11. PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα, a 9-cis-retinoic acid stimulated (9-cis-RA heterodimeric partner of PPARγ, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARγ agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRα ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARγ activators, ciglitazone and 15-deoxy-Δ12,14-PGJ2 (15dPGJ2. Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21wAF1/CIP1 and p16INK4, reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARγ target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP, the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARγ is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

  1. Cancer stem cells in prostate cancer

    OpenAIRE

    Moltzahn, Felix; Thalmann, George N

    2013-01-01

    Prostate cancer (P-Ca) remains a leading cause of cancer-related death in men. Lately, increasing evidence for a hierarchically organized cancer stem cell (CSC) model emerged for different tumors entities, including P-Ca. CSCs are defined by several characteristics including self-renewal, pluripotency and tumorigenicity and are thought to be responsible for tumor recurrence, metastasis and cancer related death. In this review we discuss the recent research in the field of CSCs, its limitation...

  2. Regulated cell death in diagnostic histopathology.

    Science.gov (United States)

    Skenderi, Faruk; Vranic, Semir; Damjanov, Ivan

    2015-01-01

    Regulated cell death (RCD) is a controlled cellular process, essential for normal development, tissue integrity and homeostasis, and its dysregulation has been implicated in the pathogenesis of various conditions including developmental and immunological disorders, neurodegenerative diseases, and cancer. In this review, we briefly discuss the historical perspective and conceptual development of RCD, we overview recent classifications and some of the key players in RCD; finally we focus on current applications of RCD in diagnostic histopathology. PMID:26009238

  3. Luffa echinata Roxb. Induces Human Colon Cancer Cell (HT-29 Death by Triggering the Mitochondrial Apoptosis Pathway

    Directory of Open Access Journals (Sweden)

    Yan Yu

    2012-05-01

    Full Text Available The antiproliferative properties and cell death mechanism induced by the extract of the fruits of Luffa echinata Roxb. (LER were investigated. The methanolic extract of LER inhibited the proliferation of human colon cancer cells (HT-29 in both dose-dependent and time-dependent manners and caused a significant increase in the population of apoptotic cells. In addition, obvious shrinkage and destruction of the monolayer were observed in LER-treated cells, but not in untreated cells. Analysis of the cell cycle after treatment of HT-29 cells with various concentrations indicated that LER extracts inhibited the cellular proliferation of HT-29 cells via G2/M phase arrest of the cell cycle. The Reactive oxygen species (ROS level determination revealed that LER extracts induced apoptotic cell death via ROS generation. In addition, LER treatment led to a rapid drop in mitochondrial membrane potential (MMP as a decrease in fluorescence. The transcripts of several apoptosis-related genes were investigated by RT-PCR analysis. The caspase-3 transcripts of HT-29 cells significantly accumulated and the level of Bcl-XL mRNA was decreased after treatment with LER extract. Furthermore, the ratio of mitochondria-dependent apoptosis genes (Bax and Bcl-2 was sharply increased from 1.6 to 54.1. These experiments suggest that LER has anticancer properties via inducing the apoptosis in colon cancer cells, which provided the impetus for further studies on the therapeutic potential of LER against human colon carcinoma.

  4. Prognostic value of programmed cell death-ligand 1 expression in patients with non-small-cell lung cancer: evidence from an updated meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhong AY

    2015-12-01

    Full Text Available Anyuan Zhong,1,* Yufei Xing,1,* Xue Pan,1,* Minhua Shi,1 Huajun Xu2 1Department of Respiratory Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, 2Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The association between the expression of programmed cell death-ligand 1 (PD-L1 and survival in patients with non-small-cell lung cancer (NSCLC is controversial. Thus, we conducted a meta-analysis of all available studies to evaluate the prognostic role of PD-L1 expression in NSCLC.Materials and methods: PubMed, Embase, and Chinese (China National Knowledge Infrastructure and Wanfang databases were searched to identify all eligible studies evaluating PD-L1 expression and the survival of NSCLC patients. Hazard ratios (HRs and 95% confidence interval (CI used to assess overall survival were extracted and pooled. Subgroup, sensitivity, and publication-bias analyses were also performed.Results: Eleven articles reporting 12 studies that included a total of 1,653 patients met the inclusion criteria and were included in the meta-analysis. Higher PD-L1 expression did not correlate with prognosis in terms of overall survival in patients with NSCLC (HR =1.21, 95% CI: 0.85–1.71, P=0.29. However, a subgroup analysis showed a significant association between PD-L1 expression and poor prognosis in Chinese patients with NSCLC (HR =1.55, 95% CI: 1.04–2.29, P=0.03. The sensitivity analysis showed that the pooled results were not affected by the removal of any single study. There was also no significant publication bias.Conclusion: Our meta-analysis indicated no statistically significant difference between PD-L1 expression and prognosis for patients with NSCLC. Additional, high-quality studies with larger sample sizes are needed to determine

  5. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer.

    Science.gov (United States)

    Sheng, Jin; Fang, Wenfeng; Yu, Juan; Chen, Nan; Zhan, Jianhua; Ma, Yuxiang; Yang, Yunpeng; Yanhuang; Zhao, Hongyun; Zhang, Li

    2016-01-01

    The effects of treatments to programmed death ligand-1 (PD-L1) expression is unknown. The aim of this study was to investigate the impact of neoadjuvant chemotherapy (NACT) on PD-L1 expression in non-small cell lung cancer (NSCLC) patients. PD-L1 expression was detected by immunohistochemistry (IHC) method in 32 paired tumor specimens pre and post-NACT. The positivity of PD-L1 on tumor cells (TCs) changed from 75% to 37.5% after NACT (p = 0.003). Cases with IHC score of 1, 2, 3 all underwent apparent decrease (p = 0.007). However, no significant changes were observed on tumour-infiltrating immune cells (ICs) (p = 0.337). Subgroup and semiquantitative analyses all presented similar results. Moreover, patients with response to NACT presented significantly reduced PD-L1 expression on TCs (p = 0.004). Although it was not confirmed by the Cox proportional hazard regression model, there was an apparent difference in disease-free-survival (DFS) between negative-to-positive switch of PD-L1 status and the contrary group (median DFS: 9.6 versus 25.9, p = 0.005). Our data revealed that antecedent chemotherapy for NSCLC may results in inconsistency of PD-L1 expression. PD-L1 expression is suggested to be monitored around treatment and on serial samples, at least, on the latest tumor specimen. PMID:26822379

  6. [Cell death in malignant tumors. Relevance of cell death regulation for metastasis].

    Science.gov (United States)

    Roth, W

    2015-11-01

    Defects in the regulation of cell death are important causes for both the development and therapy resistance of malignant tumors. Several distinct, molecularly defined types of cell death are known, such as apoptosis, anoikis, and necroptosis. Moreover, the specific triggering of cell death plays an important role in the prevention of metastasis. The results of recent studies have shown that various types of cell death are pivotal at different steps of the metastasis cascade, in order to prevent cellular detachment, migration, invasion, intravasation, extravasation and the establishment of micrometastasis and macrometastasis. At the subcellular level, numerous links exist between cell death regulation and metastasis, specifically regarding signaling pathways and individual proteins with dual or multiple functions. As an example, the decoy receptor 3 protein (DcR3) functions both as an anti-apoptotic protein and as a direct promotor of invasion and migration of tumor cells. In summary, the specific triggering of cell death plays a pivotal role for the prevention of metastasis. On the other hand, the stepwise process of metastasis represents a mechanism of selection resulting in established metastases with a multiresistant phenotype which corresponds to the clinical observation that many metastasized cancers are therapy resistant. In the future, innovative diagnostic tests to individually predict the resistance pattern and possibilities to overcome resistance are urgently needed. PMID:26400565

  7. In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on Two Non-Breast Cancer Cell Types

    Directory of Open Access Journals (Sweden)

    S. K. Majumdar

    2001-01-01

    protein (EGFP in tamoxifen treated MEL BB-88 cells, a general feature of cells undergoing apoptosis. Tamoxifen treated cells demonstrated internucleosomal damages of the genomic DNA and DNA fragmentations, evidenced by an increase in free nucleosomes, and distinctive DNA smear patterns on the agarose gel.

  8. Soluble VEGF receptor 1 (sFLT1) induces non-apoptotic death in ovarian and colorectal cancer cells

    Science.gov (United States)

    Miyake, Tatsuya; Kumasawa, Keiichi; Sato, Noriko; Takiuchi, Tsuyoshi; Nakamura, Hitomi; Kimura, Tadashi

    2016-01-01

    Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1/sFLT1) is an angiogenesis inhibitor that competes with angiogenic factors such as VEGF and Placental Growth Factor (PlGF). Imbalances of VEGF and sFLT1 levels can cause pathological conditions such as tumour growth or preeclampsia. We observed direct damage caused by sFLT1 in tumour cells. We exposed several kinds of cells derived from ovarian and colorectal cancers as well as HEK293T cells to sFLT1 in two ways, transfection and exogenous application. The cell morphology and an LDH assay revealed cytotoxicity. Additional experiments were performed to clarify how sFLT1 injured cells. In this study, non-apoptotic cell damage was found to be induced by sFLT1. Moreover, sFLT1 showed an anti-tumour effect in a mouse model of ovarian cancer. Our results suggest that sFLT1 has potential as a cancer therapeutic candidate. PMID:27103202

  9. Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death.

    Science.gov (United States)

    Burns, Kelly E; Thévenin, Damien

    2015-12-15

    Even though abnormal expression of G protein-coupled receptors (GPCRs) and of their ligands is observed in many cancer cells of various origins, only a few anti-cancer compounds directly act on their signalling. One promising approach to modulate their activity consists of targeting the receptor cytoplasmic surfaces interacting with the associated G-proteins using peptides mimicking the intracellular loops of the receptor. Thus, to be fully effective, the peptide mimics must be selectively targeted to the tumour while sparing healthy tissues, translocated across the cell membrane and stay anchored to the cytoplasmic leaflet of the plasma membrane. In the present study, we introduce a novel way to selectively target and inhibit the activity of a GPCR in cancer cells under acidic conditions, such as those found in solid tumours. We find that the conjugation of a peptide fragment derived from the third intracellular loop (i3) of the protease-activated receptor 1 (PAR1) to a peptide that can selectively target tumours solely based on their acidity [pH(Low) Insertion Peptide (pHLIP)], produces a construct capable of effectively down-regulating PAR1 activity in a concentration- and pH-dependent manner and of inducing a potent cytotoxic effect in a panel of cancer cells that is proportional to the relative level of receptor expression at the cell surface. This strategy not only allows for a more selective targeting and specific intracellular delivery than current approaches, but also offers new possibilities for developing novel anti-cancer drugs targeting GPCRs. PMID:26424552

  10. Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing

    Directory of Open Access Journals (Sweden)

    Akter R

    2012-07-01

    Full Text Available Rozina Akter,1 Md. Zakir Hossain,2 Maurice G Kleve,3 Michael A Gealt31Applied Biosciences Emphasis, Department of Applied Science, 2Graduate Institute of Technology, 3Department of Biology, College of Science and of Mathematics, University Arkansas at Little Rock, Little Rock, AR, USABackground: Apoptosis can be used as a reliable marker for evaluating potential chemotherapeutic agents. Because wortmannin is a microbial steroidal metabolite, it specifically inhibits the phosphatidyl inositol 3-kinase pathway, and could be used as a promising apoptosis-based therapeutic agent in the treatment of cancer. The objective of this study was to investigate the biomolecular mechanisms involved in wortmannin-induced cell death of breast cancer-derived MCF-7 cells.Methods and results: Our experimental results demonstrate that wortmannin has strong apoptotic effects through a combination of different actions, including reduction of cell viability in a dose-dependent manner, inhibition of proliferation, and enhanced generation of intracellular reactive oxygen species.Conclusion: Our findings suggest that wortmannin induces MCF-7 cell death via a programmed pathway showing chromatin condensation, nuclear fragmentation, reactive oxygen species, and membrane blebbing, which are characteristics typical of apoptosis.Keywords: wortmannin, human breast adenocarcinoma, apoptosis, reactive oxygen species, flow cytometry

  11. The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells.

    Science.gov (United States)

    Akhtar, Nosheen; Syed, Deeba N; Khan, Mohammad Imran; Adhami, Vaqar M; Mirza, Bushra; Mukhtar, Hasan

    2016-01-26

    Epidemiologic studies indicated that diabetics treated with metformin had a lower incidence of cancer than those taking other anti-diabetes drugs. This led to a surge in the efforts for identification of safer and more effective metformin mimetic compounds. The plant Ficus microcarpa is widely used for the treatment of type 2 diabetes in traditional medicine in South Asia. We obtained extracts from this plant and identified a small molecule, plectranthoic acid (PA), with potent 5'AMP-activated kinase (AMPK) activating properties far superior than metformin. AMPK is the central hub of metabolic regulation and a well-studied therapeutic target for metabolic syndrome, type-2 diabetes and cancer. We observed that treatment of prostate cancer (PCa) cells with PA inhibited proliferation and induced G0/G1 phase cell cycle arrest that was associated with up-regulation of cyclin kinase inhibitors p21/CIP1 and p27/KIP1. PA treatment suppressed mTOR/S6K signaling and induced apoptosis in PCa cells in an AMPK-dependent manner. Interestingly, PA-induced autophagy in PCa cells was found to be independent of AMPK activation. Combination studies of PA and metformin demonstrated that metformin had an inhibitory effect on PA-induced AMPK activation and suppressed PA-mediated apoptosis. Given the anti-proliferative role of PA in cancer and its potent anti-hyperglycemic activity, we suggest that PA should be explored further as a novel activator of AMPK for its ultimate use for the prevention of cancers and treatment of type 2 diabetes. PMID:26683363

  12. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

    OpenAIRE

    Darb-Esfahani, Silvia; Kunze, Catarina Alisa; Kulbe, Hagen; Sehouli, Jalid; Wienert, Stephan; Lindner, Judith; Budczies, Jan; Bockmayr, Michael; Dietel, Manfred; Denkert, Carsten; Braicu, Ioana; Jöhrens, Korinna

    2015-01-01

    Aims Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. Methods PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measure...

  13. Sorafenib attenuates p21 in kidney cancer cells and augments cell death in combination with DNA-damaging chemotherapy

    OpenAIRE

    Inoue, Hiromi; Hwang, Sung Hee; Wecksler, Aaron T.; Hammock, Bruce D.; Robert H. Weiss

    2011-01-01

    There are few effective therapeutic options for metastatic renal cell carcinoma (RCC). Conventional chemotherapeutic agents are ineffective since these tumors are unusually resistant to DNA damage, likely due to an exuberant DNA repair response. Sorafenib, as one of the few available effective therapeutic options for metastatic RCC, has been shown to inhibit cell proliferation by inhibition of tyrosine kinases. We have recently shown that sorafenib inhibits soluble epoxide hydrolase, which ca...

  14. Activation of NAG-1 via JNK signaling revealed an isochaihulactone-triggered cell death in human LNCaP prostate cancer cells

    International Nuclear Information System (INIS)

    We explored the mechanisms of cell death induced by isochaihulactone treatment in LNCaP cells. LNCaP cells were treated with isochaihulactone and growth inhibition was assessed. Cell cycle profiles after isochaihulactone treatment were determined by flow cytometry. Expression levels of cell cycle regulatory proteins, caspase 9, caspase 3, and PARP were determined after isochaihulactone treatment. Signaling pathway was verified by inhibitors pre-treatment. Expression levels of early growth response gene 1 (EGR-1) and nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1) were determined to investigate their role in LNCaP cell death. NAG-1 expression was knocked down by si-NAG-1 siRNA transfection. Rate of cell death and proliferation were obtained by MTT assay. Isochaihulactone caused cell cycle arrest at G2/M phase in LNCaP cells, which was correlated with an increase of p53 and p21 levels and downregulation of the checkpoint proteins cdc25c, cyclin B1, and cdc2. Bcl-2 phosphorylation and caspase activation were also observed. Isochaihulactone induced phosphorylation of c-Jun-N-terminal kinase (JNK), and JNK inhibitor partially reduced isochaihulactone-induced cell death. Isochaihulactone also induced the expressions of EGR-1 and NAG-1. Expression of NAG-1 was reduced by JNK inhibitor, and knocking down of NAG-1 inhibited isochaihulactone-induced cell death. Isochaihulactone apparently induces G2/M cell cycle arrest via downregulation of cyclin B1 and cdc2, and induces cellular death by upregulation of NAG-1 via JNK activation in LNCaP cells

  15. Cdk2 silencing via a DNA/PCL electrospun scaffold suppresses proliferation and increases death of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Clément Achille

    Full Text Available RNA interference (RNAi is a promising approach for cancer treatment. Site specific and controlled delivery of RNAi could be beneficial to the patient, while at the same time reducing undesirable off-target side effects. We utilized electrospinning to generate a biodegradable scaffold capable of incorporating and delivering a bioactive plasmid encoding for short hairpin (sh RNA against the cell cycle specific protein, Cdk2. Three electrospun scaffolds were constructed, one using polycaprolactone (PCL alone (Control and PCL with plasmid DNA encoding for either Cdk2 (Cdk2i and EGFP (EGFPi, also served as a control shRNA. Scaffold fiber diameters ranged from 1 to 20 µm (DNA containing and 0.2-3 µm (Control. While the electrospun fibers remained intact for more than two weeks in physiological buffer, degradation was visible during the third week of incubation. Approximately 20-60 ng/ml (~2.5% cumulative release of intact and bioactive plasmid DNA was released over 21 days. Further, Cdk2 mRNA expression in cells plated on the Cdk2i scaffold was decreased by ~51% and 30%, in comparison with that of cells plated on Control or EGFPi scaffold, respectively. This decrease in Cdk2 mRNA by the Cdk2i scaffold translated to a ~40% decrease in the proliferation of the breast cancer cell line, MCF-7, as well as the presence of increased number of dead cells. Taken together, these results represent the first successful demonstration of the delivery of bioactive RNAi-based plasmid DNA from an electrospun polymer scaffold, specifically, in disrupting cell cycle regulation and suppressing proliferation of cancer cells.

  16. Cdk2 Silencing via a DNA/PCL Electrospun Scaffold Suppresses Proliferation and Increases Death of Breast Cancer Cells

    OpenAIRE

    Achille, Clément; Sundaresh, Sowmya; Chu, Benjamin; Hadjiargyrou, Michael

    2012-01-01

    RNA interference (RNAi) is a promising approach for cancer treatment. Site specific and controlled delivery of RNAi could be beneficial to the patient, while at the same time reducing undesirable off-target side effects. We utilized electrospinning to generate a biodegradable scaffold capable of incorporating and delivering a bioactive plasmid encoding for short hairpin (sh) RNA against the cell cycle specific protein, Cdk2. Three electrospun scaffolds were constructed, one using polycaprolac...

  17. Sensitization of radiation-induced cell death by genistein

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Rim; Kim, In Gyu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-03-15

    A number of epidemiological studies as well as biological experiments, showed that genistein, one of the isoflavone, prevents prostate cancer occurrence. In this study, we showed that genistein inhibited the cell proliferation of human promyeoltic leukemia HL-60 cells and induced G2/M phase arrest. In addition, combination of genistein treatment and {gamma}-irradiation displayed synergistic effect in apoptotic cell death of HL-60 cells. This means that the repair of genistein-induced DNA damage was hindered by {gamma}-irradiation and thus cell death was increased. In conclusion, genistein is one of the important chemicals that sensitize radiation-induced cell death.

  18. Curcumin Induces Cell Death and Restores Tamoxifen Sensitivity in the Antiestrogen-Resistant Breast Cancer Cell Lines MCF-7/LCC2 and MCF-7/LCC9

    OpenAIRE

    Min Jiang; Ou Huang; Xi Zhang; Zuoquan Xie; Aijun Shen; Hongchun Liu; Meiyu Geng; Kunwei Shen

    2013-01-01

    Curcumin, a principal component of turmeric (Curcuma longa), has potential therapeutic activities against breast cancer through multiple signaling pathways. Increasing evidence indicates that curcumin reverses chemo-resistance and sensitizes cancer cells to chemotherapy and targeted therapy in breast cancer. To date, few studies have explored its potential antiproliferation effects and resistance reversal in antiestrogen-resistant breast cancer. In this study, we therefore investigated the ef...

  19. Distinct CPT-induced deaths in lung cancer cells caused by clathrin-mediated internalization of CP micelles

    Science.gov (United States)

    Liu, Yu-Sheng; Cheng, Ru-You; Lo, Yu-Lun; Hsu, Chin; Chen, Su-Hwei; Chiu, Chien-Chih; Wang, Li-Fang

    2016-02-01

    We previously synthesized a chondroitin sulfate-graft-poly(ε-caprolactone) copolymer (H-CP) with a high content of poly(ε-caprolactone) (18.7 mol%), which self-assembled in water into a rod-like micelle to encapsulate hydrophobic camptothecin (CPT) in the core (micelle/CPT) for tumor-targeted drug delivery. As a result of the recognition of the micelle by CD44, the micelle/CPT entered CRL-5802 cells efficiently and released CPT efficaciously, resulting in higher tumor suppression than commercial CPT-11. In this study, H1299 cells were found to have a higher CD44 expression than CRL-5802 cells. However, the lower CD44-expressing CRL-5802 cells had a higher percentage of cell death and higher cellular uptake of the micelle/CPT than the higher CD44-expressing H1299 cells. Examination of the internalization pathway of the micelle/CPT in the presence of different endocytic chemical inhibitors showed that the CRL-5802 cells involved clathrin-mediated endocytosis, which was not found in the H1299 cells. Analysis of the cell cycle of the two cell lines exposed to the micelle/CPT revealed that the CRL-5802 cells arrested mainly in the S phase and the H1299 cells arrested mainly in the G2-M phase. A consistent result was also found in the evaluation of γ-H2AX expression, which was about three-fold higher in the CRL-5802 cells than in the H1299 cells. A near-infrared dye, IR780, was encapsulated into the micelle to observe the in vivo biodistribution of the micelle/IR780 in tumor-bearing mice. The CRL-5802 tumor showed a higher fluorescence intensity than the H1299 tumor at any tracing time after 1 h. Thus we tentatively concluded that CRL-5802 cells utilized the clathrin-mediated internalization pathway and arrested in the S phase on exposure to the micelle/CPT; all are possible reasons for the better therapeutic outcome in CRL-5802 cells than in H1299 cells.We previously synthesized a chondroitin sulfate-graft-poly(ε-caprolactone) copolymer (H-CP) with a high content of

  20. Effect of proton and gamma irradiation on human lung carcinoma cells: Gene expression, cell cycle, cell death, epithelial-mesenchymal transition and cancer-stem cell trait as biological end points.

    Science.gov (United States)

    Narang, Himanshi; Kumar, Amit; Bhat, Nagesh; Pandey, Badri N; Ghosh, Anu

    2015-10-01

    Proton beam therapy is a cutting edge modality over conventional gamma radiotherapy because of its physical dose deposition advantage. However, not much is known about its biological effects vis-a-vis gamma irradiation. Here we investigated the effect of proton- and gamma- irradiation on cell cycle, death, epithelial-mesenchymal transition (EMT) and "stemness" in human non-small cell lung carcinoma cells (A549). Proton beam (3MeV) was two times more cytotoxic than gamma radiation and induced higher and longer cell cycle arrest. At equivalent doses, numbers of genes responsive to proton irradiation were ten times higher than those responsive to gamma irradiation. At equitoxic doses, the proton-irradiated cells had reduced cell adhesion and migration ability as compared to the gamma-irradiated cells. It was also more effective in reducing population of Cancer Stem Cell (CSC) like cells as revealed by aldehyde dehydrogenase activity and surface phenotyping by CD44(+), a CSC marker. These results can have significant implications for proton therapy in the context of suppression of molecular and cellular processes that are fundamental to tumor expansion. PMID:26278043

  1. ANOVA like analysis of cancer death age

    Science.gov (United States)

    Areia, Aníbal; Mexia, João T.

    2016-06-01

    We use ANOVA to study the influence of year, sex, country and location on the average cancer death age. The data used was from the World Health Organization (WHO) files for 1999, 2003, 2007 and 2011. The locations considered were: kidney, leukaemia, melanoma of skin and oesophagus and the countries: Portugal, Norway, Greece and Romania.

  2. Role of polyphenols in cell death control.

    Science.gov (United States)

    Giovannini, Claudio; Masella, Roberta

    2012-05-01

    Dietary consumption of fruit, vegetables, fish, and olive oil has been demonstrated to exert beneficial effects on human health. This finding may be due to the high content of antioxidant compounds including polyphenols. Current evidence strongly supports a contribution of polyphenols to the prevention of several chronic degenerative diseases such as cancer, atherosclerosis and cardiovascular diseases, central nervous system disorders, as well as aging. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathologic processes, leading to proliferative or degenerative diseases. Polyphenols can interact with specific steps and/or proteins regulating the apoptotic process in different ways depending on their concentration, the cell system, the type or stage of the pathological process. Because of their ability to modulate cell death, polyphenols have been proposed as chemopreventive and therapeutic agents. This paper reviews and discusses the last 3-year findings related to the principal molecular mechanisms involved in the control of the balance between apoptosis and cell proliferation exerted by polyphenols. PMID:22584012

  3. The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastro­intestinal tract cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Huang B

    2015-09-01

    Full Text Available Baohua Huang,* Lei Chen,* Cuixia Bao, Chengming Sun, Jie Li, Lipeng Wang, Xia Zhang Department of Laboratory Medicine, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China *These authors contributed equally to this work Background: Programmed cell death 1 ligand 1 (PD-L1 expression has been observed in various malignancies. However, the association between PD-L1 expression and the survival of patients with gastrointestinal tract cancer remains controversial. Besides, the rate of PD-L1 positivity on tumor cells of digestive tract cancer is not clear. Thus, we performed a meta-analysis by incorporating all available evidence to evaluate the rate of PD-L1 positivity and the overall survival (OS according to PD-L1 status in patients with gastrointestinal tract cancer. Methods: Electronic databases were searched for eligible literature. Hazard ratios (HRs for OS with 95% confidence intervals (CIs according to the expression status of PD-L1 evaluated by immunohistochemistry were extracted. The outcomes were synthesized based on a random-effects model.Results: Fifteen studies (only nine reported OS that involved 2,993 gastrointestinal tract cancer patients stratified by PD-L1 status were eligible for inclusion in our study. We found the PD-L1-positive expression rate was 0.495 (95% CI 0.415–0.576 if 10% was taken as the cut-off value. When the H-score method was used to evaluate PD-L1 expression, it showed that the PD-L1 positive rate was 0.639 (95% CI 0.490–0.765 if the cut-off value was <50, which was higher than when using >50 as the cut-off point (0.449, 95% CI 0.417–0.483. Additionally, PD-L1-positive gastrointestinal tract cancer patients were associated with significantly poorer OS when compared to negative ones (HR 1.61, 95% CI 1.10–2.35, P=0.014. Subgroup analysis presented similar significant results in patients with esophageal cancer (HR 2.56, 95% CI 1.55–4.21, P<0.001. Conclusion: The positive expression rate of PD-L1

  4. Synergistic growth inhibition of cancer cells harboring the RET/PTC1 oncogene by staurosporine and rotenone involves enhanced cell death

    Indian Academy of Sciences (India)

    António Pedro Gonçalves; Arnaldo Videira; Valdemar Máximo; Paula Soares

    2011-09-01

    TPC-1 is a highly proliferative thyroid papillary carcinoma-derived cell line. These cells express the RET/PTC1 fusion protein, whose isoforms are characterized in this work. The bacterial alkaloid staurosporine and the plant extract rotenone are death-inducing drugs that have an inhibitory synergistic effect on the growth of TPC-1 cells. We show that this synergism is accompanied by an enhancement of the induction of cell death. Staurosporine alone induces cell cycle arrest in G1, whereas rotenone induces arrest in G2/M. We suggest that this additive pressure may drive cells to die, resulting in the synergistic interaction of the drug combination. These data emphasize the potential use of the staurosporine plus rotenone combination as an anticancer tool.

  5. Polycation-mediated integrated cell death processes

    DEFF Research Database (Denmark)

    Parhamifar, Ladan; Andersen, Helene; Wu, Linping;

    2014-01-01

    standard. PEIs are highly efficient transfectants, but depending on their architecture and size they induce cytotoxicity through different modes of cell death pathways. Here, we briefly review dynamic and integrated cell death processes and pathways, and discuss considerations in cell death assay design...

  6. Mitochondria: pharmacological manipulation of cell death

    OpenAIRE

    Bouchier-Hayes, Lisa; Lartigue, Lydia; Newmeyer, Donald D.

    2005-01-01

    Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.

  7. Treatment-related death in patients with small-cell lung cancer in phase III trials over the last two decades.

    Directory of Open Access Journals (Sweden)

    Nobuaki Ochi

    Full Text Available INTRODUCTION: Treatment-related death (TRD remains a serious problem in small-cell lung cancer (SCLC, despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time. METHODS: We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis. RESULTS: In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139. However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033. CONCLUSIONS: The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.

  8. Cell death in the cardiovascular system

    OpenAIRE

    Clarke, Murray; Bennett, Martin; Littlewood, Trevor

    2006-01-01

    Cell death is important for both development and tissue homeostasis in the adult. As such, it is tightly controlled and deregulation is associated with diverse pathologies; for example, regulated cell death is involved in vessel remodelling during development or following injury, but deregulated death is implicated in pathologies such as atherosclerosis, aneurysm formation, ischaemic and dilated cardiomyopathies and infarction. We describe the mechanisms of cell death and its role in the norm...

  9. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model

    Directory of Open Access Journals (Sweden)

    Ni Xiao

    2012-12-01

    abundant high molecular weight compounds, including boswellic acids, in frankincense essential oil fraactions. Human pancreatic cancer cells were sensitive to Fractions III and IV (containing higher molecular weight compounds treatment with suppressed cell viability and increased cell death. Essential oil activated the caspase-dependent apoptotic pathway, induced a rapid and transient activation of Akt and Erk1/2, and suppressed levels of cyclin D1 cdk4 expression in cultured pancreatic cancer cells. In addition, Boswellia sacra essential oil Fraction IV exhibited anti-proliferative and pro-apoptotic activities against pancreatic tumors in the heterotopic xenograft mouse model. Conclusion All fractions of frankincense essential oil from Boswellia sacra are capable of suppressing viability and inducing apoptosis of a panel of human pancreatic cancer cell lines. Potency of essential oil-suppressed tumor cell viability may be associated with the greater abundance of high molecular weight compounds in Fractions III and IV. Although chemical component(s responsible for tumor cell cytotoxicity remains undefined, crude essential oil prepared from hydrodistillation of Boswellia sacra gum resins might be a useful alternative therapeutic agent for treating patients with pancreatic adenocarcinoma, an aggressive cancer with poor prognosis.

  10. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death

    OpenAIRE

    Raimondo, S; Naselli, F; S.; Fontana; Monteleone, F.; A. Lo Dico; Saieva, L; Zito, G.; Flugy, A; Manno, M; Di Bella, M; Leo, G.; ALESSANDRO, R

    2015-01-01

    Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing. Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifuga...

  11. The γ-radiation induced CD20 expression and anti-CD20 antibodies mediated cell death on hematopoietic cancer cell

    International Nuclear Information System (INIS)

    Daudi cells were exposed to sub lethal doses of γ-radiation (0.5 Gy and 1.5 Gy; dose rate 1.8Gy/min, 60CO) and followed by incubation at 37℃. Changes in CD20 expression was measured at different time intervals. In other experiment cells with over expression of CD20 were further treated with either RTX or TST following by incubation at 37℃. Anti-CD20 mediated changes in ROS, MMP and cell death were studied after 24hrs. Exposure of cells to γ-radiation showed increase in CD20 level maximally at 20h. Cells treated with both radiation and AntiCD20 antibodies showed differential responses. Combination of radiation with either RTX or TST showed significant increase in ROS generation. 0.5Gy+TST and 1.5Gy+TST showed sudden decrease in MMP with respect to TST or radiation alone, whereas Rad+RTX was shown to increase of MMP (at 24h) which was reduced with time. Percentage of cell death was significantly high in all combination group with respect to corresponding control groups. However, 1.5Gy+TST have shown high cell death levels as compared to 1.5Gy+RTX. All combination groups have shown increased PARP cleavage with respect to control groups. The combination of anti-CD20 with radiation significantly increased cell death in CD20 over expressing cells. However in vivo studies need to be done to confirm hypothesis

  12. Death Concerns among Individuals Newly Diagnosed with Lung Cancer

    Science.gov (United States)

    Lehto, Rebecca; Therrien, Barbara

    2010-01-01

    Confronting the reality of death is an important challenge for individuals facing life-threatening illness such as lung cancer, the leading cause of cancer death. Few studies, however, document the nature of death-related concerns in individuals newly diagnosed with lung cancer. The aims of this exploratory study were to examine unsolicited…

  13. Crude aqueous extracts of Pluchea indica (L. Less. inhibit proliferation and migration of cancer cells through induction of p53-dependent cell death

    Directory of Open Access Journals (Sweden)

    Cho Jonathan J

    2012-12-01

    Full Text Available Abstract Background Pluchea indica (L. Less. (Asteraceae is a perennial shrub plant with anti-inflammatory and antioxidant medicinal properties. However, the anti-cancer properties of its aqueous extracts have not been studied. The aim of this study was to investigate the anti-proliferation, anti-migration, and pro-apoptotic properties of crude aqueous extracts of P. indica leaf and root on human malignant glioma cancer cells and human cervical cancer cells, and the underlying molecular mechanism. Methods GBM8401 human glioma cells and HeLa cervical carcinoma cells were treated with various concentrations of crude aqueous extracts of P. indica leaf and root and cancer cell proliferation and viability were measured by cell growth curves, trypan blue exclusions, and the tetrazolium reduction assay. Effects of the crude aqueous extracts on focus formation, migration, and apoptosis of cancer cells were studied as well. The molecular mechanism that contributed to the anti-cancer activities of crude aqueous extracts of P. indica root was also examined using Western blotting analysis. Results Crude aqueous extracts of P. indica leaf and root suppressed proliferation, viability, and migration of GBM8401 and HeLa cells. Treatment with crude aqueous extracts of P. indica leaf and root for 48 hours resulted in a significant 75% and 70% inhibition on proliferation and viability of GBM8401 and HeLa cancer cells, respectively. Crude aqueous extracts of P. indica root inhibited focus formation and promoted apoptosis of HeLa cells. It was found that phosphorylated-p53 and p21 were induced in GBM8401 and HeLa cells treated with crude aqueous extracts of P. indica root. Expression of phosphorylated-AKT was decreased in HeLa cells treated with crude aqueous extracts of P. indica root. Conclusion The in vitro anti-cancer effects of crude aqueous extracts of P. indica leaf and root indicate that it has sufficient potential to warrant further examination and

  14. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer

    International Nuclear Information System (INIS)

    A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3). The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy

  15. Identification of a Novel Cell Death Receptor Mediating IGFBP-3-induced Anti-tumor Effects in Breast and Prostate Cancer*

    OpenAIRE

    Ingermann, Angela R.; Yang, Yong-feng; Han, Jinfeng; Mikami, Aki; Garza, Amanda E.; Mohanraj, Lathika; Fan, Lingbo; Idowu, Michael; Ware, Joy L.; Kim, Ho-Seong; Lee, Dae-Yeol; Oh, Youngman

    2010-01-01

    Insulin-like growth factor-binding protein-3 (IGFBP-3), a major regulator of endocrine actions of IGFs, is a p53-regulated potent apoptotic factor and is significantly suppressed in a variety of cancers. Recent epidemiologic studies suggest that IGFBP-3 contributes to cancer risk protection in a variety of cancers, and a polymorphic variation of IGFBP-3 influences cancer risk, although other studies vary in their conclusions. Some antiproliferative actions of IGFBP-3 have been reported to be ...

  16. Estimation of cancer deaths in Korea for the upcoming years.

    OpenAIRE

    Bae, Jong-Myon; Jung, Kyu-Won; Won, Young-Joo

    2002-01-01

    Since the cancer has been the leading cause of deaths in Korea, estimation of the cancer deaths for the upcoming years in the population using the vital statistics is considered to be necessary. The aim of this study was to estimate the number and trends of cancer deaths in Korea. The expected numbers of cancer deaths were calculated by a time series model fitting the actual numbers of cancer deaths for each of the years 1983 through 2000 reported by Korea National Statistical Office. The opt...

  17. The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

    OpenAIRE

    Cuezva José M; Sánchez-Aragó María

    2011-01-01

    Abstract Background Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a ...

  18. Crude saponins from Platycodon grandiflorum induce apoptotic cell death in RC-58T/h/SA#4 prostate cancer cells through the activation of caspase cascades and apoptosis-inducing factor.

    Science.gov (United States)

    Lee, Ju-Hye; Oh, Eun-Kyoung; Cho, Hyun-Dong; Kim, Jae-Yong; Lee, Mi-Kyung; Seo, Kwon-Il

    2013-04-01

    Saponins are a major active component of Platycodon grandiflorum (P. grandiflorum) and are known to induce apoptosis in metastatic prostate cancer cell lines. However, thus far, no research has been conducted on the anticancer activity of saponins in RC-58T/h/SA#4 primary prostate cancer cells. In this study, we show that the treatment of prostate cancer cells with saponins extracted from P. grandiflorum (SPG) inhibits cell proliferation in a dose-dependent manner. SPG significantly induced apoptotic cell death, resulting in an increase in the sub-G1 apoptotic cell population, apoptotic DNA fragmentation and morphological changes. Pre-treatment with a caspase inhibitor modestly attenuated the SPG-induced increase in the sub-G1 cell population, suggesting that caspases play a role in SPG-induced apoptosis. Moreover, SPG-induced apoptosis was associated with changes in caspase activity, the upregulation of the apoptotic protein, Bax and the downregulation of the anti-apoptotic protein, Bcl-2. Furthermore, the caspase-independent mitochondrial apoptosis factor, apoptosis-inducing factor (AIF) was upregulated following SPG treatment. These findings indicate that SPG exerts its anticancer effects on RC-58T/h/SA#4 primary prostate cancer cells through mitochondrial caspase-dependent and -independent apoptotic pathways. PMID:23443329

  19. Quinovic acid glycosides purified fraction from Uncaria tomentosa induces cell death by apoptosis in the T24 human bladder cancer cell line.

    Science.gov (United States)

    Dietrich, Fabrícia; Kaiser, Samuel; Rockenbach, Liliana; Figueiró, Fabrício; Bergamin, Letícia Scussel; da Cunha, Fernanda Monte; Morrone, Fernanda Bueno; Ortega, George González; Battastini, Ana Maria Oliveira

    2014-05-01

    Bladder cancer is the second most prevalent malignancy in the genitourinary tract and remains a therapeutic challenge. In the search for new treatments, researchers have attempted to find compounds with low toxicity. With this goal in mind, Uncaria tomentosa is noteworthy because the bark and root of this species are widely used in traditional medicine and in adjuvant therapy for the treatment of numerous diseases. The objective of this study was to investigate the antitumor effect of one purified bioactive fraction of U.tomentosa bark on cell proliferation in two human bladder cancer cell lines, T24 and RT4. Quinovic acid glycosides purified fraction (QAPF) of U.tomentosa decreased the growth and viability of both T24 and RT4 cell lines. In T24 cells, QAPF induced apoptosis by activating caspase-3 and NF-κB. Further study showed that this fraction does not induce cell cycle arrest and does not alter PTEN and ERK levels. In conclusion, we demonstrated that QAPF of U.tomentosa has a potent inhibitory effect on the growth of human bladder cancer cell lines by inducing apoptosis through modulation of NF-κB, and we suggest that QAPF may become a potential therapeutic agent for the prevention and/or treatment of this cancer. PMID:24607820

  20. Crude extracts of marine-derived and soil fungi of the genus Neosartorya exhibit selective anticancer activity by inducing cell death in colon, breast and skin cancer cell lines

    Directory of Open Access Journals (Sweden)

    Alice Abreu Ramos

    2016-01-01

    Full Text Available Background: The crude ethyl acetate extracts of marine-derived fungi Neosartorya tsunodae KUFC 9213 (E1 and N. laciniosa KUFC 7896 (E2, and soil fungus N. fischeri KUFC 6344 (E3 were evaluated for their in vitro anticancer activities on a panel of seven human cancer cell lines. Materials and Methods: The 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay was performed, after 48 h treatments with different concentrations of extracts, to determine their concentration of the extract or Dox that inhibits cell viability by 50% for each cell line. The effects of the crude extracts on DNA damage, clonogenic potential and their ability to induce cell death were also assessed. Results: E1 was found to the void of anti-proliferative effects. E2 was shown to decrease the clonogenic potential in human colorectal carcinoma cell line (HCT116, human malignant melanoma cell line (A375, human breast adenocarcinoma cell line (MCF7, and human caucasian colon adenocarcinoma Grade II cell line (HT29 cells, whereas E3 showed such effect only in HCT116 and MCF7 cells. Both extracts were found to increase DNA damage in some cell lines. E2 was found to induce cell death in HT29, HCT116, MCF7, and A375 cells while extract E3 increased cell death in MCF7 and HCT116 cell lines. Conclusion: The results reveal that E2 and E3 possess anticancer activities in human colon carcinoma, breast adenocarcinoma, and melanoma cells, validating the interest for an identification of molecular targets involved in the anticancer activity.

  1. Morphological classification of plant cell deaths

    DEFF Research Database (Denmark)

    van Doorn, W.G.; Beers, E.P.; Dangl, J.L.;

    2011-01-01

    cell contents are removed by a combination of autophagy-like process and release of hydrolases from collapsed lytic vacuoles. Necrosis is characterised by early rupture of the plasma membrane, shrinkage of the protoplast and absence of vacuolar cell death features. Vacuolar cell death is common during...

  2. The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1α in cancer cells, induces cell death, and reduces tumor xenograft growth

    Directory of Open Access Journals (Sweden)

    Koivunen P

    2016-03-01

    Full Text Available Peppi Koivunen,1 Stuart M Fell,2,3 Wenyun Lu,4 Joshua D Rabinowitz,4 Andrew L Kung,5,6 Susanne Schlisio,2,7 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; 2Ludwig Institute for Cancer Research Ltd, Stockholm, Sweden; 3Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; 4Department of Chemistry and Integrative Genomics, Princeton University, Princeton, NJ, 5Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 6Department of Pediatrics, Columbia University Medical Center, New York, NY, USA; 7Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Abstract: The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs. HIF-1α is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1α under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs. Here, we identified a high level of normoxic HIF-1α protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity. We tested the ability of several cell-permeable 2-oxoglutarate analogs to regulate the abundance of HIF-1α protein. We identified 3-oxoglutarate as a potent regulator of HIF-1α in normoxic conditions. In contrast to 2-oxoglutarate, 3-oxoglutarate decreased the abundance of HIF-1α protein in several cancer cell lines in normoxia and diminished HIF-1α levels independent of EGLN enzymatic activity. Furthermore, we observed that 3-oxoglutarate was detrimental to cancer cell survival. We show that esterified 3-oxoglutarate, in combination with the cancer chemotherapeutic drug vincristine, induces apoptosis and inhibits tumor growth in vitro and in vivo. Our data

  3. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    OpenAIRE

    Cuesta, Elena Pedraz; Christensen, Sandra; Jensen, Anders A.; Jensen, Niels Frank; Bunch, Lennart; Rømer, Maria Unni Koefoed; Brünner, Nils; Stenvang, Jan; Pedersen, Stine Helene Falsig

    2015-01-01

    Background Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed. Methods Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluoresc...

  4. Regulation of death receptors-Relevance in cancer therapies

    International Nuclear Information System (INIS)

    Apoptosis is an essential non-inflammatory mechanism for cell removal, which occurs during both physiological and pathological conditions. Apoptosis is characteristically executed by cysteine proteases, termed caspases. The most specific way to activate the caspases machinery is through death receptors (DRs), such as the tumor necrosis factor (TNFR), Fas receptor (FasR), and TRAIL (TRAIL-R). The apoptotic signaling is tightly regulated by the balance of pro-apoptotic and anti-apoptotic proteins and an imbalance between cell death and proliferation may cause numerous diseases, including cancers. The intensive research during the past decade has delineated the basic mechanisms of apoptosis and outlined many important molecular mechanisms underlying the regulation of apoptosis. There is also a better understanding of how the regulation of apoptosis can be disturbed in human cancer cells. The interplay between DRs signaling and anticancer drugs has offered new concepts for the development of highly specific therapeutical agents. Here we review the current understanding of the different molecular mechanisms that regulate DR-mediated apoptosis and the defects in apoptotic signaling discovered in cancer cells. In light of this knowledge, new promising target-based agents for future cancer therapies have been developed

  5. Cell of origin of lung cancer

    OpenAIRE

    Hanna, Jennifer M.; Onaitis, Mark W.

    2013-01-01

    Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s) of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell o...

  6. Cell death regulates muscle fiber number.

    Science.gov (United States)

    Sarkissian, Tatevik; Arya, Richa; Gyonjyan, Seda; Taylor, Barbara; White, Kristin

    2016-07-01

    Cell death can have both cell autonomous and non-autonomous roles in normal development. Previous studies have shown that the central cell death regulators grim and reaper are required for the developmentally important elimination of stem cells and neurons in the developing central nervous system (CNS). Here we show that cell death in the nervous system is also required for normal muscle development. In the absence of grim and reaper, there is an increase in the number of fibers in the ventral abdominal muscles in the Drosophila adult. This phenotype can be partially recapitulated by inhibition of cell death specifically in the CNS, indicating a non-autonomous role for neuronal death in limiting muscle fiber number. We also show that FGFs produced in the cell death defective nervous system are required for the increase in muscle fiber number. Cell death in the muscle lineage during pupal stages also plays a role in specifying fiber number. Our work suggests that FGFs from the CNS act as a survival signal for muscle founder cells. Thus, proper muscle fiber specification requires cell death in both the nervous system and in the developing muscle itself. PMID:27131625

  7. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

    OpenAIRE

    Chang W. Song; Hyemi Lee; Dings, Ruud P. M.; Brent Williams; John Powers; Troy Dos Santos; Bo-Hwa Choi; Heon Joo Park

    2012-01-01

    The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, ...

  8. Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo

    OpenAIRE

    Singh, Tripti; Prasad, Ram; Santosh K. Katiyar

    2013-01-01

    Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 µM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone a...

  9. Genetic Variation in Cell Death Genes and Risk of Non-Hodgkin Lymphoma

    OpenAIRE

    Johanna M. Schuetz; Denise Daley; Jinko Graham; Berry, Brian R.; Gallagher, Richard P.; Connors, Joseph M; Gascoyne, Randy D.; Spinelli, John J.; Angela R Brooks-Wilson

    2012-01-01

    BACKGROUND: Non-Hodgkin lymphomas are a heterogeneous group of solid tumours that constitute the 5(th) highest cause of cancer mortality in the United States and Canada. Poor control of cell death in lymphocytes can lead to autoimmune disease or cancer, making genes involved in programmed cell death of lymphocytes logical candidate genes for lymphoma susceptibility. MATERIALS AND METHODS: We tested for genetic association with NHL and NHL subtypes, of SNPs in lymphocyte cell death genes using...

  10. Predicting death from surgery for lung cancer

    DEFF Research Database (Denmark)

    O'Dowd, Emma L; Lüchtenborg, Margreet; Baldwin, David R;

    2016-01-01

    OBJECTIVES: Current British guidelines advocate the use of risk prediction scores such as Thoracoscore to estimate mortality prior to radical surgery for non-small cell lung cancer (NSCLC). A recent publication used the National Lung Cancer Audit (NLCA) to produce a score to predict 90day mortality...... (NLCA score). The aim of this study is to validate the NLCA score, and compare its performance with Thoracoscore. MATERIALS AND METHODS: We performed an internal validation using 2858 surgical patients from NLCA and an external validation using 3191 surgical patients from the Danish Lung Cancer Registry...... procedure type, age and performance status. CONCLUSIONS: Neither score performs well enough to be advocated for individual risk stratification prior to lung cancer surgery. It may be that additional physiological parameters are required; however this is a further project. In the interim we propose the use...

  11. Modulation of cell death in age-related diseases.

    Science.gov (United States)

    Tezil, Tugsan; Basaga, Huveyda

    2014-01-01

    Aging is a stage of life of all living organisms. According to the free-radical theory, aging cells gradually become unable to maintain cellular homeostasis due to the adverse effects of reactive oxygen species (ROS). ROS can cause irreversible DNA mutations, protein and lipid damage which are increasingly accumulated in the course of time if cells could not overcome these effects by the antioxidant defence system. Accrued damaged molecules in cells may either induce cellular death or contribute to develop various pathologies. Hence, programmed cell death mechanisms, apoptosis and autophagy, play a vital role in the aging process. Although they are strictly controlled by various interconnected signalling pathways, alterations in their regulations may contribute to severe pathologies including cancer, Alzheimer's and Parkinson's diseases. In this review, we summarized our current understanding and hypotheses regarding oxidative stress and age-related dysregulation of cell death signalling pathways. PMID:24079770

  12. Apoptosis: A Review of Programmed Cell Death

    OpenAIRE

    Elmore, Susan

    2007-01-01

    The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions incl...

  13. Programmed cell death during quinoa perisperm development

    OpenAIRE

    López-Fernández, María Paula; Maldonado, Sara

    2013-01-01

    At seed maturity, quinoa (Chenopodium quinoa Willd.) perisperm consists of uniform, non-living, thin-walled cells full of starch grains. The objective of the present study was to study quinoa perisperm development and describe the programme of cell death that affects the entire tissue. A number of parameters typically measured during programmed cell death (PCD), such as cellular morphological changes in nuclei and cytoplasm, endoreduplication, DNA fragmentation, and the participation of nucle...

  14. Evaluation of the efficacy & biochemical mechanism of cell death induction by Piper longum extract selectively in in-vitro and in-vivo models of human cancer cells.

    Directory of Open Access Journals (Sweden)

    Pamela Ovadje

    Full Text Available Currently chemotherapy is limited mostly to genotoxic drugs that are associated with severe side effects due to non-selective targeting of normal tissue. Natural products play a significant role in the development of most chemotherapeutic agents, with 74.8% of all available chemotherapy being derived from natural products.To scientifically assess and validate the anticancer potential of an ethanolic extract of the fruit of the Long pepper (PLX, a plant of the piperaceae family that has been used in traditional medicine, especially Ayurveda and investigate the anticancer mechanism of action of PLX against cancer cells.Following treatment with ethanolic long pepper extract, cell viability was assessed using a water-soluble tetrazolium salt; apoptosis induction was observed following nuclear staining by Hoechst, binding of annexin V to the externalized phosphatidyl serine and phase contrast microscopy. Image-based cytometry was used to detect the effect of long pepper extract on the production of reactive oxygen species and the dissipation of the mitochondrial membrane potential following Tetramethylrhodamine or 5,5,6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine chloride staining (JC-1. Assessment of PLX in-vivo was carried out using Balb/C mice (toxicity and CD-1 nu/nu immunocompromised mice (efficacy. HPLC analysis enabled detection of some primary compounds present within our long pepper extract.Our results indicated that an ethanolic long pepper extract selectively induces caspase-independent apoptosis in cancer cells, without affecting non-cancerous cells, by targeting the mitochondria, leading to dissipation of the mitochondrial membrane potential and increase in ROS production. Release of the AIF and endonuclease G from isolated mitochondria confirms the mitochondria as a potential target of long pepper. The efficacy of PLX in in-vivo studies indicates that oral administration is able to halt the growth of colon cancer

  15. Induction of apoptotic cell death by putrescine

    DEFF Research Database (Denmark)

    Takao, Koichi; Rickhag, Karl Mattias; Hegardt, Cecilia;

    2006-01-01

    overexpression of a metabolically stable ODC in CHO cells induced a massive cell death unless the cells were grown in the presence of the ODC inhibitor alpha-difluoromethylornithine (DFMO). Cells overexpressing wild-type (unstable) ODC, on the other hand, were not dependent on the presence of DFMO for their...... growth. The induction of cell death was correlated with a dramatic increase in cellular putrescine levels. Analysis using flow cytometry revealed perturbed cell cycle kinetics, with a large accumulation of cells with sub-G1 amounts of DNA, which is a typical sign of apoptosis. Another strong indication...... polyamine homeostasis may negatively affect cell proliferation and eventually lead to cell death by apoptosis if putrescine levels become too high....

  16. Treatment-Related Death during Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Studies

    Science.gov (United States)

    Zhao, Jing; Xia, Yingfeng; Kaminski, Joseph; Hao, Zhonglin; Mott, Frank; Campbell, Jeff; Sadek, Ramses; Kong, Feng-Ming (Spring)

    2016-01-01

    Treatment related death (TRD) is the worst adverse event in chemotherapy and radiotherapy for patients with cancer, the reports for TRDs were sporadically. We aimed to study TRDs in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT), and determine whether high radiation dose and newer chemotherapy regimens were associated with the risk of TRD. Data from randomized clinical trials for locally advanced/unresectable NSCLC patients were analyzed. Eligible studies had to have at least one arm with CCRT. The primary endpoint was TRD. Pooled odds ratios (ORs) for TRDs were calculated. In this study, a total of fifty-three trials (8940 patients) were eligible. The pooled TRD rate (accounting for heterogeneity) was 1.44% for all patients. In 20 trials in which comparison of TRDs between CCRT and non-CCRT was possible, the OR (95% CI) of TRDs was 1.08 (0.70–1.66) (P = 0.71). Patients treated with third-generation chemotherapy and concurrent radiotherapy had an increase of TRDs compared to those with other regimens in CCRT (2.70% vs. 1.37%, OR = 1.50, 95% CI: 1.09–2.07, P = 0.008). No significant difference was found in TRDs between high (≥ 66 Gy) and low (< 66 Gy) radiation dose during CCRT (P = 0.605). Neither consolidation (P = 0.476) nor induction chemotherapy (P = 0.175) had significant effects with increased TRDs in this study. We concluded that CCRT is not significantly associated with the risk of TRD compared to non-CCRT. The third-generation chemotherapy regimens may be a risk factor with higher TRDs in CCRT, while high dose radiation is not significantly associated with more TRDs. This observation deserves further study. PMID:27300551

  17. Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells

    Directory of Open Access Journals (Sweden)

    Smith Charlotte M

    2013-01-01

    Full Text Available Abstract Background During metaphase clathrin stabilises the mitotic spindle kinetochore(K-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis. Results Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition. Conclusions Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.

  18. Lysosomal cell death at a glance

    DEFF Research Database (Denmark)

    Aits, Sonja; Jaattela, Marja

    2013-01-01

    Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called "lysosomal cell death". This form of...... cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream...

  19. Plant Proteases Involved in Regulated Cell Death.

    Science.gov (United States)

    Zamyatnin, A A

    2015-12-01

    Each plant genome encodes hundreds of proteolytic enzymes. These enzymes can be divided into five distinct classes: cysteine-, serine-, aspartic-, threonine-, and metalloproteinases. Despite the differences in their structural properties and activities, members of all of these classes in plants are involved in the processes of regulated cell death - a basic feature of eukaryotic organisms. Regulated cell death in plants is an indispensable mechanism supporting plant development, survival, stress responses, and defense against pathogens. This review summarizes recent advances in studies of plant proteolytic enzymes functioning in the initiation and execution of distinct types of regulated cell death. PMID:26878575

  20. Cell death by the quinoxaline dioxide DCQ in human colon cancer cells is enhanced under hypoxia and is independent of p53 and p21

    International Nuclear Information System (INIS)

    We have shown that the radio sensitizer DCQ enhances sensitivity of HCT116 human colon cancer cells to hypoxia. However, it is not known whether the p53 or p21 genes influence cellular response to DCQ. In this study, we used HCT116 that are either wildtype for p53 and p21, null for p53 or null for p21 to understand the role of these genes in DCQ toxicity. HCT116 cells were exposed to DCQ and incubated under normoxia or hypoxia and the viability, colony forming ability, DNA damage and apoptotic responses of these cells was determined, in addition to the modulation of HIF-1α and of p53, p21, caspase-2, and of the ataxia telangiectasia mutated (ATM) target PIDD-C. DCQ decreased colony forming ability and viability of all HCT116 cells to a greater extent under hypoxia than normoxia and the p21-/-cell line was most sensitive. Cells had different HIF-1α responses to hypoxia and/or drug treatment. In p53+/+, DCQ significantly inhibited the hypoxia-induced increases in HIF-1α protein, in contrast to the absence of a significant HIF-1α increase or modulation by DCQ in p21-/- cells. In p53-/- cells, 10 μM DCQ significantly reduced HIF-1α expression, especially under hypoxia, despite the constitutive expression of this protein in control cells. Higher DCQ doses induced PreG1-phase increase and apoptosis, however, lower doses caused mitotic catastrophe. In p53+/+ cells, apoptosis correlated with the increased expression of the pro-apoptotic caspase-2 and inhibition of the pro-survival protein PIDD-C. Exposure of p53+/+ cells to DCQ induced single strand breaks and triggered the activation of the nuclear kinase ATM by phosphorylation at Ser-1981 in all cell cycle phases. On the other hand, no drug toxicity to normal FHs74 Int human intestinal cell line was observed. Collectively, our findings indicate that DCQ reduces the colony survival of HCT116 and induces apoptosis even in cells that are null for p53 or p21, which makes it a molecule of clinical significance, since

  1. Phloroglucinols inhibit chemical mediators and xanthine oxidase, and protect cisplatin-induced cell death by reducing reactive oxygen species in normal human urothelial and bladder cancer cells.

    Science.gov (United States)

    Lin, Kai-Wei; Huang, A-Mei; Tu, Huang-Yao; Weng, Jing-Ru; Hour, Tzyh-Chyuan; Wei, Bai-Luh; Yang, Shyh-Chyun; Wang, Jih-Pyang; Pu, Yeong-Shiau; Lin, Chun-Nan

    2009-10-14

    Phloroglucinols, garcinielliptones HA-HE (1-5), and C (6) were studied in vitro for their inhibitory effects on chemical mediators released from mast cells, neutrophils, and macrophages. Compound 6 revealed significant inhibitory effect on release of lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Compounds 3, 4, and 6 showed significant inhibitory effects on superoxide anion generation in rat neutrophils stimulated with (fMLP)/(CB), while compounds 1 and 5 revealed inhibitory effects on tumor necrosis factor-alpha (TNF-alpha) formation in macrophages stimulated with lipopolysaccharide (LPS). Compounds 1 and 3-6 showed inhibitory effects on xanthine oxidase (XO) and could inhibit the DNA breakage caused by O2(-*). Treatment of NTUB1 with 2 to 60 microM compound 3 and 5 microM cisplatin and SV-HUC1 with 9 to 60 microM 3 and 5 microM cisplatin, respectively, resulted in an increase of viability of cells. These results indicated that compounds 1 and 3-6 showed anti-inflammatory effects and antioxidant activities. Compound 3 mediates through the suppression of XO activity and reduction of reactive oxygen species (ROS), and protection of subsequent cell death. PMID:19754119

  2. Cytotoxicity and cell cycle arrest induced by andrographolide lead to programmed cell death of MDA-MB-231 breast cancer cell line

    OpenAIRE

    Banerjee, Malabika; Chattopadhyay, Subrata; Choudhuri, Tathagata; Bera, Rammohan; Kumar, Sanjay; Chakraborty, Biswajit; Mukherjee, Samir Kumar

    2016-01-01

    Background Breast cancer is considered as an increasing major life-threatening concern among the malignancies encountered globally in females. Traditional therapy is far from satisfactory due to drug resistance and various side effects, thus a search for complementary/alternative medicines from natural sources with lesser side effects is being emphasized. Andrographis paniculata, an oriental, traditional medicinal herb commonly available in Asian countries, has a long history of treating a va...

  3. Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor α and β.

    Science.gov (United States)

    Rossi, V; Bellastella, G; De Rosa, C; Abbondanza, C; Visconti, D; Maione, L; Chieffi, P; Della Ragione, F; Prezioso, D; De Bellis, A; Bellastella, A; Sinisi, A A

    2011-05-01

    Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERβ and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERβ and lacked ERα. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6)  M RAL treatment. A dose-dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERβ or ERβ/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non-genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression. PMID:20945400

  4. U.S. congressional district cancer death rates

    Directory of Open Access Journals (Sweden)

    Pickle Linda W

    2006-06-01

    Full Text Available Abstract Background Geographic patterns of cancer death rates in the U.S. have customarily been presented by county or aggregated into state economic or health service areas. Herein, we present the geographic patterns of cancer death rates in the U.S. by congressional district. Many congressional districts do not follow state or county boundaries. However, counties are the smallest geographical units for which death rates are available. Thus, a method based on the hierarchical relationship of census geographic units was developed to estimate age-adjusted death rates for congressional districts using data obtained at county level. These rates may be useful in communicating to legislators and policy makers about the cancer burden and potential impact of cancer control in their jurisdictions. Results Mortality data were obtained from the National Center for Health Statistics (NCHS for 1990–2001 for 50 states, the District of Columbia, and all counties. We computed annual average age-adjusted death rates for all cancer sites combined, the four major cancers (lung and bronchus, prostate, female breast, and colorectal cancer and cervical cancer. Cancer death rates varied widely across congressional districts for all cancer sites combined, for the four major cancers, and for cervical cancer. When examined at the national level, broad patterns of mortality by sex, race and region were generally similar with those previously observed based on county and state economic area. Conclusion We developed a method to generate cancer death rates by congressional district using county-level mortality data. Characterizing the cancer burden by congressional district may be useful in promoting cancer control and prevention programs, and persuading legislators to enact new cancer control programs and/or strengthening existing ones. The method can be applied to state legislative districts and other analyses that involve data aggregation from different geographic

  5. The control and execution of programmed cell death

    International Nuclear Information System (INIS)

    Apoptosis or programmed cell death is a highly conserved genetically controlled response of metazoan cells to commit suicide. Non apoptotic programmed cell death seems to operate in single celled eukaryotes implying that evolution of PCD has preceded the evolution of multicellularity. PCD plays a crucial role in the regulation of cellular and tissue homeostasis and any aberrations in apoptosis leads to several diseases including cancer, neurodegenerative disorders and AIDS. The mechanisms by which apoptosis is controlled are varied. In some cells, members of bcl-2 family or p53 are crucial for regulating the apoptosis programme, whereas in other cells Fas ligand is more important. bcl-2 family members have a prime role in the regulation of cell death at all stages including development, whereas cell death during development is independent of p53. bcl-2 family members being localized on the outer mitochondrial membrane, control the mitochondrial homeostasis and cytochrome c redistribution and thereby regulate the cell death process. p53 promotes DNA damage mediated cell death after growth arrest and failed DNA repair. Caspases play a key role in the execution of cell death by mediating highly specific cleavages of crucial cellular proteins collectively manifesting the apoptotic phenotype. Protein inhibitors like crm A, p35 and IAPs could prevent/control apoptosis induced by a broad array of cell death stimuli by several mechanisms specially interfering in caspase activation or caspase activity. Among endonucleases, caspase activated DNase (CAD) plays a crucial role in DNA fragmentation, a biochemical hallmark of apoptosis. As regulation of cell death seems to be as complex as regulation of cell proliferation, multiple kinase mediated regulatory mechanisms might control the apoptotic process. Thus, in spite of intensive research over the past few years, the field of apoptosis still remains fertile to unravel among others, the molecular mechanisms of cytochrome c

  6. Real-time monitoring of in vivo acute necrotic cancer cell death induced by near infrared photoimmunotherapy using fluorescence lifetime imaging

    OpenAIRE

    Nakajima, Takahito; Sano, Kohei; Mitsunaga, Makoto; Peter L. Choyke; Kobayashi, Hisataka

    2012-01-01

    A new type of monoclonal antibody (mAb)-based, highly specific phototherapy (photoimmunotherapy; PIT) that utilizes a near infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with a mAb, has recently been described. NIR light exposure leads to immediate, target-selective necrotic cell death in vitro. Detecting immediate in vivo cell death is more difficult because it takes at least 3 days for the tumor to begin to shrink in size. In this study, fluorescence lifetime (FLT) was eva...

  7. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC ...

  8. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  9. Cell death in Pseudomonas aeruginosa biofilm development

    DEFF Research Database (Denmark)

    Webb, J.S.; Thompson, L.S.; James, S.;

    2003-01-01

    Bacteria growing in biofilms often develop multicellular, three-dimensional structures known as microcolonies. Complex differentiation within biofilms of Pseudomonas aeruginosa occurs, leading to the creation of voids inside microcolonies and to the dispersal of cells from within these voids....... However, key developmental processes regulating these events are poorly understood. A normal component of multicellular development is cell death. Here we report that a repeatable pattern of cell death and lysis occurs in biofilms of P. aeruginosa during the normal course of development. Cell death...... occurred with temporal and spatial organization within biofilms, inside microcolonies, when the biofilms were allowed to develop in continuous-culture flow cells. A subpopulation of viable cells was always observed in these regions. During the onset of biofilm killing and during biofilm development...

  10. Cell death in the developing vertebrate retina.

    Science.gov (United States)

    Vecino, Elena; Hernández, María; García, Mónica

    2004-01-01

    Programmed cell death occurs naturally, as a physiological process, during the embryonic development of multicellular organisms. In the retina, which belongs to the central nervous system, at least two phases of cell death have been reported to occur during development. An early phase takes place concomitant with the processes of neurogenesis, cell migration and cell differentiation. A later phase affecting mainly neurons occurs when connections are established and synapses are formed, resulting in selective elimination of inappropriate connections. This pattern of cell death in the developing retina is common among different vertebrates. However, the timing and magnitude of retinal cell death varies among species. In addition, a precise regulation of apoptosis during retinal development has been described. Factors such as neurotrophins, among many others, and electrical activity influence the survival of retinal cells during the course of development. In this paper, we present a summary of these different aspects of programmed cell death during retinal development, and examine how these differ among different species. PMID:15558487

  11. Cell-to-cell variability in cell death: can systems biology help us make sense of it all?

    OpenAIRE

    Xia, X; Owen, M. S.; Lee, R E C; Gaudet, S

    2014-01-01

    One of the most common observations in cell death assays is that not all cells die at the same time, or at the same treatment dose. Here, using the perspective of the systems biology of apoptosis and the context of cancer treatment, we discuss possible sources of this cell-to-cell variability as well as its implications for quantitative measurements and computational models of cell death. Many different factors, both within and outside of the apoptosis signaling networks, have been correlated...

  12. Determination of Cell Death Induced by Lovastatin on Human Colon Cell Line HT29 Using the Comet Assay

    OpenAIRE

    Jafari, Marzieh; Rezaei, Mohsen; Kalantari, Heibatullah; Hashemitabar, Mahmoud

    2013-01-01

    Background Apoptosis or programmed cell death is an essential process for elimination of damaged cells. Also, induction of apoptosis is fundamental for treating cancer. Screening for agents that induce apoptosis in tumor cells help in the development of novel agents for cancer treatment. Numerous studies suggest that the exposure of tumor cells to statins can lead to cell death via two separate processes: apoptosis or necrosis. Severe fragmentation of DNA during apoptosis can be readily measu...

  13. The Apoptosome: Heart and Soul of the Cell Death Machine

    Directory of Open Access Journals (Sweden)

    Arul M. Chinnaiyan

    1999-04-01

    Full Text Available Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death. These central components biochemically intermingle in a ternary complex recently dubbed the “apoptosome.” The C elegans protein EGL-1 and its mammalian counterparts, pro-apoptotic members of the bcl-2 family, induce cell death by disrupting apoptosome interactions. Thus, EGL-1 may represent a primordial signal integrator for the apoptosome. Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex. Recent studies suggest that cell death receptors, such as CD95, may amplify their suicide signal by activating the apoptosome. These mutual associations by core components of the suicide apparatus provide a molecular framework in which diverse death signals likely interface. Understanding the apoptosome and its cellular connections will facilitate the design of novel therapeutic strategies for cancer and other disease states in which apoptosis plays a pivotal role.

  14. Bcl-2 Knockdown Accelerates T Cell Receptor-Triggered Activation-Induced Cell Death in Jurkat T Cells

    OpenAIRE

    Lee, Yun-Jung; Won, Tae Joon; Hyung, Kyeong Eun; Lee, Mi Ji; Moon, Young-hye; Lee, Ik Hee; Go, Byung Sung; Hwang, Kwang Woo

    2014-01-01

    Cell death and survival are tightly controlled through the highly coordinated activation/inhibition of diverse signal transduction pathways to insure normal development and physiology. Imbalance between cell death and survival often leads to autoimmune diseases and cancer. Death receptors sense extracellular signals to induce caspase-mediated apoptosis. Acting upstream of CED-3 family proteases, such as caspase-3, Bcl-2 prevents apoptosis. Using short hairpin RNAs (shRNAs), we suppressed Bcl-...

  15. Real-time monitoring of cisplatin-induced cell death.

    Directory of Open Access Journals (Sweden)

    Hamed Alborzinia

    Full Text Available Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred. Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision.

  16. Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model.

    Science.gov (United States)

    Bousserouel, Souad; Le Grandois, Julie; Gossé, Francine; Werner, Dalal; Barth, Stephan W; Marchioni, Eric; Marescaux, Jacques; Raul, Francis

    2013-08-01

    Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 µg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 µg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death‑receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

  17. Inflammasomes as polyvalent cell death platforms.

    Science.gov (United States)

    de Vasconcelos, Nathalia M; Van Opdenbosch, Nina; Lamkanfi, Mohamed

    2016-06-01

    Inflammasomes are multi-protein platforms that are organized in the cytosol to cope with pathogens and cellular stress. The pattern recognition receptors NLRP1, NLRP3, NLRC4, AIM2 and Pyrin all assemble canonical platforms for caspase-1 activation, while caspase-11-dependent inflammasomes respond to intracellular Gram-negative pathogens. Inflammasomes are chiefly known for their roles in maturation and secretion of the inflammatory cytokines interleukin-(IL)1β and IL18, but they can also induce regulated cell death. Activation of caspases 1 and 11 in myeloid cells can trigger pyroptosis, a lytic and inflammatory cell death mode. Pyroptosis has been implicated in secretion of IL1β, IL18 and intracellular alarmins. Akin to these factors, it may have beneficial roles in controlling pathogen replication, but become detrimental in the context of chronic autoinflammatory diseases. Inflammasomes are increasingly implicated in induction of additional regulated cell death modes such as pyronecrosis and apoptosis. In this review, we overview recent advances in inflammasome-associated cell death research, illustrating the polyvalent roles of these macromolecular platforms in regulated cell death signaling. PMID:27048821

  18. Report to the Nation shows cancer death rates dropping

    Science.gov (United States)

    The Annual Report to the Nation on the Status of Cancer, 1975–2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the most common cancer s

  19. How Heme Oxygenase-1 Prevents Heme-Induced Cell Death

    OpenAIRE

    Lilibeth Lanceta; Mattingly, Jacob M.; Chi Li; Eaton, John W.

    2015-01-01

    Earlier observations indicate that free heme is selectively toxic to cells lacking heme oxygenase-1 (HO-1) but how this enzyme prevents heme toxicity remains unexplained. Here, using A549 (human lung cancer) and immortalized human bronchial epithelial cells incubated with exogenous heme, we find knock-down of HO-1 using siRNA does promote the accumulation of cell-associated heme and heme-induced cell death. However, it appears that the toxic effects of heme are exerted by "loose" (probably in...

  20. DIETARY PHYTOCHEMICALS INDUCE p53- AND CASPASE-INDEPENDENT CELL DEATH IN HUMAN NEUROBLASTOMA CELLS

    OpenAIRE

    Sukumari-Ramesh, Sangeetha; Bentley, J Nicole; Laird, Melissa D.; Singh, Nagendra; Vender, John R.; Dhandapani, Krishnan M.

    2011-01-01

    Neuroblastoma (NB) is the most prevalent pediatric solid tumor and a leading cause of cancer-related death in children. In the present study, a novel cytotoxic role for the dietary compounds, curcumin, andrographolide, wedelolactone, dibenzoylmethane, and tanshinone IIA was identified in human S-type NB cells, SK-N-AS and SK-N-BE(2). Mechanistically, cell death appeared apoptotic by flow cytometry; however, these effects proceeded independently from both caspase-3 and p53 activation, as asses...

  1. The regulation of apoptotic cell death

    Directory of Open Access Journals (Sweden)

    Amarante-Mendes G.P.

    1999-01-01

    Full Text Available Apoptosis is a fundamental biological phenomenon in which the death of a cell is genetically and biochemically regulated. Different molecules are involved in the regulation of the apoptotic process. Death receptors, coupled to distinct members of the caspases as well as other adapter molecules, are involved in the initiation of the stress signals (The Indictment. Members of the Bcl-2 family control at the mitochondrial level the decision between life and death (The Judgement. The effector caspases are responsible for all morphological and biochemical changes related to apoptosis including the "eat-me" signals perceived by phagocytes and neighboring cells (The Execution. Finally, apoptosis would have little biological significance without the recognition and removal of the dying cells (The Burial.

  2. Time-Lapse Imaging of Cell Death.

    Science.gov (United States)

    Wallberg, Fredrik; Tenev, Tencho; Meier, Pascal

    2016-03-01

    The best approach to distinguish between necrosis and apoptosis is time-lapse video microscopy. This technique enables a biological process to be photographed at regular intervals over a period, which may last from a few hours to several days, and can be applied to cells in culture or in vivo. We have established two time-lapse microscopy methods based on different ways of calculating cell death: semiautomated and automated. In the semiautomated approach, cell death can be visualized by staining with combinations of Alexa Fluor 647-conjugated Annexin V and Sytox Green (SG), or Annexin V(FITC) and Propidium iodide (PI). The automated method is similar except that all cells are labeled with dyes. This allows faster quantification of data. To this end Cell Tracker Green is used to label all cells at time zero in combination with PI and Alexa Fluor 647-conjugated Annexin V. Necrotic cell death is accompanied by either simultaneous labeling with Annexin V and PI or SG (double-positive), or direct PI or SG staining. Additionally, necrotic cells display characteristic morphology, such as cytoplasmic swelling. In contrast to necrosis where membrane permeabilization is an early event, cells that die by apoptosis lose their membrane permeability relatively late. Therefore, the time between Annexin V staining and PI or SG uptake (double-positive) can be used to distinguish necrosis from apoptosis. This protocol describes the analysis of cell death by time-lapse imaging of HT1080 and L929 cells stained with these dyes, but it can be readily adapted to other cell types of interest. PMID:26933245

  3. Cell death signalling mechanisms in heart failure

    OpenAIRE

    Mughal, Wajihah; Kirshenbaum, Lorrie A.

    2011-01-01

    In 2003, cardiovascular disease was the most costly disease in Canada, and it is still on the rise. The loss of properly functioning cardiomyocytes leads to cardiac impairment, which is a consequence of heart failure. Therefore, understanding the pathways of cell death (necrosis and apoptosis) has potential implications for the development of therapeutic strategies. In addition, the role of B-cell lymphoma-2 family members is discussed and the importance of mitochondria in directing cell deat...

  4. Inducible cell death in plant immunity

    DEFF Research Database (Denmark)

    Hofius, Daniel; Tsitsigiannis, Dimitrios I; Jones, Jonathan D G;

    2006-01-01

    Programmed cell death (PCD) occurs during vegetative and reproductive plant growth, as typified by autumnal leaf senescence and the terminal differentiation of the endosperm of cereals which provide our major source of food. PCD also occurs in response to environmental stress and pathogen attack......, and these inducible PCD forms are intensively studied due their experimental tractability. In general, evidence exists for plant cell death pathways which have similarities to the apoptotic, autophagic and necrotic forms described in yeast and metazoans. Recent research aiming to understand these...... pathways and their molecular components in plants are reviewed here....

  5. Squamous cell skin cancer

    Science.gov (United States)

    ... earliest form of squamous cell cancer is called Bowen disease (or squamous cell carcinoma in situ). This type ... cancer; Squamous cell carcinoma of the skin Images Bowen's disease on the hand Keratoacanthoma Keratoacanthoma Skin cancer, squamous ...

  6. Cell-nonautonomous regulation of C. elegans germ cell death by kri-1.

    Science.gov (United States)

    Ito, Shu; Greiss, Sebastian; Gartner, Anton; Derry, W Brent

    2010-02-23

    Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4/APAF-1 and ced-3/caspase are required in cells fated to die. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation, is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage. PMID:20137949

  7. Global Recession May Have Contributed to Cancer Deaths

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_159060.html Global Recession May Have Contributed to Cancer Deaths Health- ... THURSDAY, May 26, 2016 (HealthDay News) -- The 2008 global economic crisis has been linked to a sharp ...

  8. Global Recession May Have Contributed to Cancer Deaths

    Science.gov (United States)

    ... nlm.nih.gov/medlineplus/news/fullstory_159060.html Global Recession May Have Contributed to Cancer Deaths Health- ... THURSDAY, May 26, 2016 (HealthDay News) -- The 2008 global economic crisis has been linked to a sharp ...

  9. Regulated cell death and adaptive stress responses.

    Science.gov (United States)

    Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Kepp, Oliver; Kroemer, Guido

    2016-06-01

    Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis. PMID:27048813

  10. Induction of indoleamine 2,3-dioxygenase (IDO) enzymatic activity contributes to interferon-gamma induced apoptosis and death receptor 5 expression in human non-small cell lung cancer cells.

    Science.gov (United States)

    Chung, Ting Wen; Tan, Kok-Tong; Chan, Hong-Lin; Lai, Ming-Derg; Yen, Meng-Chi; Li, Yi-Ron; Lin, Sheng Hao; Lin, Chi-Chen

    2014-01-01

    Interferon-gamma (IFN-γ) has been used to treat various malignant tumors. However, the molecular mechanisms underlying the direct anti-proliferative activity of IFN-γ are poorly understood. In the present study, we examined the in vitro antitumor activity of IFN-γ on two human non-small-cell lung carcinoma (NSCLC) cell lines, H322M and H226. Our findings indicated that IFN-γ treatment caused a time-dependent reduction in cell viability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway in both cell lines. Notably, we also postulated that IFN-γ increased indoleamine 2,3-dioxygenase (IDO) expression and enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor 1-MT or tryptophan significantly reduced IFN-γ-induced apoptosis and death receptor 5 (DR5) expression, which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-γ. These results provide new mechanistic insights into interferon-γ antitumor activity and further support IFN-γ as a potential therapeutic adjuvant for the treatment of NCSLC. PMID:25292102

  11. Ayanin diacetate-induced cell death is amplified by TRAIL in human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Marrero, Maria Teresa; Estevez, Sara; Negrin, Gledy; Quintana, Jose [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain); Lopez, Mariana; Perez, Francisco J.; Triana, Jorge [Departamento de Quimica, Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigacion del Cancer, 35017 Las Palmas de Gran Canaria (Spain); Leon, Francisco [Instituto de Productos Naturales y Agrobiologia, Consejo Superior de Investigaciones Cientificas, Avda. Astrofisico F. Sanchez 3, 38206 La Laguna, Tenerife (Spain); Estevez, Francisco, E-mail: festevez@dbbf.ulpgc.es [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer Ayanin diacetate as apoptotic inducer in leukemia cells. Black-Right-Pointing-Pointer Cell death was prevented by caspase inhibitors and by the overexpression of Bcl-x{sub L}. Black-Right-Pointing-Pointer The intrinsic and the extrinsic pathways are involved in the mechanism of action. Black-Right-Pointing-Pointer Death receptors are up-regulated and TRAIL enhances apoptotic cell death. -- Abstract: Here we demonstrate that the semi-synthetic flavonoid ayanin diacetate induces cell death selectively in leukemia cells without affecting the proliferation of normal lymphocytes. Incubation of human leukemia cells with ayanin diacetate induced G{sub 2}-M phase cell cycle arrest and apoptosis which was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the overexpression of Bcl-x{sub L}. Ayanin diacetate-induced cell death was found to be associated with: (i) loss of inner mitochondrial membrane potential, (ii) the release of cytochrome c, (iii) the activation of multiple caspases, (iv) cleavage of poly(ADP-ribose) polymerase and (v) the up-regulation of death receptors for TRAIL, DR4 and DR5. Moreover, the combined treatment with ayanin diacetate and TRAIL amplified cell death, compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

  12. CSR1 induces cell death through inactivation of CPSF3.

    Science.gov (United States)

    Zhu, Z-H; Yu, Y P; Shi, Y-K; Nelson, J B; Luo, J-H

    2009-01-01

    CSR1 (cellular stress response 1), a newly characterized tumor-suppressor gene, undergoes hypermethylation in over 30% of prostate cancers. Re-expression of CSR1 inhibits cell growth and induces cell death, but the mechanism by which CSR1 suppresses tumor growth is not clear. In this study, we screened a prostate cDNA library using a yeast two-hybrid system and found that the cleavage and polyadenylation-specific factor 3 (CPSF3), an essential component for converting heteronuclear RNA to mRNA, binds with high affinity to the CSR1 C terminus. Further analyses determined that the binding motifs for CPSF3 are located between amino acids 440 and 543. The interaction between CSR1 and CPSF3 induced CPSF3 translocation from the nucleus to the cytoplasm, resulting in inhibition of polyadenylation both in vitro and in vivo. Downregulation of CPSF3 using small interfering RNA induced cell death in a manner similar to CSR1 expression. A CSR1 mutant unable to bind to CPSF3 did not alter CPSF3 subcellular distribution, did not inhibit its polyadenylation activity and did not induce cell death. In summary, CSR1 appears to induce cell death through a novel mechanism by hijacking a critical RNA processing enzyme. PMID:18806823

  13. The deaths of a cell: how language and metaphor influence the science of cell death.

    Science.gov (United States)

    Reynolds, Andrew S

    2014-12-01

    Multicellular development and tissue maintenance involve the regular elimination of damaged and healthy cells. The science of this genetically regulated cell death is particularly rich in metaphors: 'programmed cell death' or 'cell suicide' is considered an 'altruistic' act on the part of a cell for the benefit of the organism as a whole. It is also considered a form of 'social control' exerted by the body/organism over its component cells. This paper analyzes the various functions of these metaphors and critical discussion about them within the scientific community. Bodies such as the Nomenclature Committee on Cell Death (NCCD) have been charged with bringing order to the language of cell death to facilitate scientific progress. While the NCCD recommends adopting more objective biochemical terminology to describe the mechanisms of cell death, the metaphors in question retain an important function by highlighting the broader context within which cell death occurs. Scientific metaphors act as conceptual 'tools' which fulfill various roles, from highlighting a phenomenon as of particular interest, situating it in a particular context, or suggesting explanatory causal mechanisms. PMID:25085023

  14. Mechanisms of Therapeutic Resistance in Cancer (Stem) Cells with Emphasis on Thyroid Cancer Cells

    OpenAIRE

    Hombach-Klonisch, Sabine; Natarajan, Suchitra; Thanasupawat, Thatchawan; Medapati, Manoj; PATHAK, ALOK; Ghavami, Saeid; Klonisch, Thomas

    2014-01-01

    The two main reasons for death of cancer patients, tumor recurrence and metastasis, are multi-stage cellular processes that involve increased cell plasticity and coincide with elevated resistance to anti-cancer treatments. Epithelial-to-mesenchymal transition (EMT) is a key contributor to metastasis in many cancer types, including thyroid cancer and is known to confer stem cell-like properties onto cancer cells. This review provides an overview of molecular mechanisms and factors known to con...

  15. Therapeutic implications of disorders of cell death signalling: membranes, micro-environment, and eicosanoid and docosanoid metabolism

    OpenAIRE

    Davidson, J.; Rotondo, D.; Rizzo, MT; Leaver, HA

    2012-01-01

    Disruptions of cell death signalling occur in pathological processes, such as cancer and degenerative disease. Increased knowledge of cell death signalling has opened new areas of therapeutic research, and identifying key mediators of cell death has become increasingly important. Early triggering events in cell death may provide potential therapeutic targets, whereas agents affecting later signals may be more palliative in nature. A group of primary mediators are derivatives of the highly uns...

  16. The Mechanism of Safrole-Induced [Ca²⁺]i Rises and Non-Ca²⁺-Triggered Cell Death in SCM1 Human Gastric Cancer Cells.

    Science.gov (United States)

    Hung, Tzu-Yi; Chou, Chiang-Ting; Sun, Te-Kung; Liang, Wei-Zhe; Cheng, Jin-Shiung; Fang, Yi-Chien; Li, Yih-Do; Shieh, Pochuen; Ho, Chin-Man; Kuo, Chun-Chi; Lin, Jia-Rong; Kuo, Daih-Huang; Jan, Chung-Ren

    2015-10-31

    Safrole is a carcinogen found in plants. The effect of safrole on cytosolic free Ca²⁺ concentrations ([Ca²⁺](i)) and viability in SCM1 human gastric cancer cells was explored. The Ca²⁺-sensitive fluorescent dye fura-2 was applied to measure [Ca²⁺](i). Safrole at concentrations of 150-450 μM induced a [Ca²⁺](i) rise in a concentration-dependent manner. The response was reduced by 60% by removing extracellular Ca²⁺. Safrole-evoked Ca²⁺ entry was not altered by nifedipine, econazole, SKF96365, and protein kinase C activator or inhibitor. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) abolished safrole-evoked [Ca²⁺](i) rises. Conversely, treatment with safrole abolished thapsigargin or BHQ-evoked [Ca²⁺](i) rises. Inhibition of phospholipase C (PLC) with U73122 abolished safrole-induced [Ca²⁺](i) rises. At 250-550 μM, safrole decreased cell viability concentration-dependently, which was not reversed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl (BAPTA/AM). Annexin V/propidium iodide staining data suggest that safrole (350-550 μM) induced apoptosis concentration-dependently. These studies suggest that in SCM1 human gastric cancer cells, safrole induced [Ca²⁺](i) rises by inducing PLC-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ influx via non-store-operated Ca²⁺ entry pathways. Safrole-induced cell death may involve apoptosis. PMID:26387654

  17. Cell death and autophagy: Cytokines, drugs, and nutritional factors

    International Nuclear Information System (INIS)

    Cells may use multiple pathways to commit suicide. In certain contexts, dying cells generate large amounts of autophagic vacuoles and clear large proportions of their cytoplasm, before they finally die, as exemplified by the treatment of human mammary carcinoma cells with the anti-estrogen tamoxifen (TAM, ≤1 μM). Protein analysis during autophagic cell death revealed distinct proteins of the nuclear fraction including GST-π and some proteasomal subunit constituents to be affected during autophagic cell death. Depending on the functional status of caspase-3, MCF-7 cells may switch between autophagic and apoptotic features of cell death [Fazi, B., Bursch, W., Fimia, G.M., Nardacci R., Piacentini, M., Di Sano, F., Piredda, L., 2008. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 4(4), 435-441]. Furthermore, the self-destruction of MCF-7 cells was found to be completed by phagocytosis of cell residues [Petrovski, G., Zahuczky, G., Katona, K., Vereb, G., Martinet, W., Nemes, Z., Bursch, W., Fesues, L., 2007. Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Diff. 14 (6), 1117-1128]. Autophagy also constitutes a cell's strategy of defense upon cell damage by eliminating damaged bulk proteins/organelles. This biological condition may be exemplified by the treatment of MCF-7 cells with a necrogenic TAM-dose (10 μM), resulting in the lysis of almost all cells within 24 h. However, a transient (1 h) challenge of MCF-7 cells with the same dose allowed the recovery of cells involving autophagy. Enrichment of chaperones in the insoluble cytoplasmic protein fraction indicated the formation of aggresomes, a potential trigger for autophagy. In a further experimental model HL60 cells were treated with TAM, causing dose-dependent distinct responses: 1-5 μM TAM, autophagy predominant; 7-9 μM, apoptosis predominant; 15 μM, necrosis. These phenomena might be

  18. Thymoquinone causes multiple effects, including cell death, on dividing plant cells.

    Science.gov (United States)

    Hassanien, Sameh E; Ramadan, Ahmed M; Azeiz, Ahmed Z Abdel; Mohammed, Rasha A; Hassan, Sabah M; Shokry, Ahmed M; Atef, Ahmed; Kamal, Khalid B H; Rabah, Samar; Sabir, Jamal S M; Abuzinadah, Osama A; El-Domyati, Fotouh M; Martin, Gregory B; Bahieldin, Ahmed

    2013-01-01

    Thymoquinone (TQ) is a major constituent of Nigella sativa oil with reported anti-oxidative activity and anti-inflammatory activity in animal cells. It also inhibits proliferation and induces programmed cell death (apoptosis) in human skin cancer cells. The present study sought to detect the influence of TQ on dividing cells of three plant systems and on expression of Bcl2-associated athanogene-like (BAG-like) genes that might be involved during the process of cell death. BAG genes are known for the regulation of diverse physiological processes in animals, including apoptosis, tumorigenesis, stress responses, and cell division. Synthetic TQ at 0.1mg/mL greatly reduced wheat seed germination rate, whereas 0.2mg/mL completely inhibited germination. An Evans blue assay revealed moderate cell death in the meristematic zone of Glycine max roots after 1h of TQ treatment (0.2mg/mL), with severe cell death occurring in this zone after 2h of treatment. Light microscopy of TQ-treated (0.2mg/mL) onion hairy root tips for 1h revealed anti-mitotic activity and also cell death-associated changes, including nuclear membrane disruption and nuclear fragmentation. Transmission electron microscopy of TQ-treated cells (0.2mg/mL) for 1h revealed shrinkage of the plasma membrane, leakage of cell lysate, degradation of cell walls, enlargement of vacuoles and condensation of nuclei. Expression of one BAG-like gene, previously associated with cell death, was induced 20 min after TQ treatment in Glycine max root tip cells. Thus, TQ has multiple effects, including cell death, on dividing plant cells and plants may serve as a useful system to further investigate the mechanisms underlying the response of eukaryotic cells to TQ. PMID:24296078

  19. Scared witless about death--ovarian cancer narratives compared.

    Science.gov (United States)

    van Duin, Isabella A J; Kaptein, Ad A

    2013-12-01

    Fifty years ago, doctors did not tell their patients they had cancer. Improved patient-physician communication, feminization of the medical profession and increased patient empowerment may have improved matters. However, death is still a subject many doctors find difficult to deal with. We explore this issue in the context of medical humanities. In order to examine the different strategies in coping with illness and death, we compared illness perceptions in a literary text, W;t by Margaret Edson, about a woman who dies of ovarian cancer, with a personal narrative of a patient with ovarian cancer. Although there are many differences between the two patients in historical and cultural background, similarities were found in the way they cope with illness and death anxiety. Insight into illness perceptions and coping strategies of patients with cancer is important for raising awareness in clinicians, leading to improved understanding and better treatment of patients. PMID:23852816

  20. CSR1 induces cell death through inactivation of CPSF3

    OpenAIRE

    Zhu, Z-H; Yu, YP; Shi, Y-K; Nelson, JB; Luo, J-H

    2008-01-01

    CSR1 (cellular stress response 1), a newly characterized tumor-suppressor gene, undergoes hypermethylation in over 30% of prostate cancers. Re-expression of CSR1 inhibits cell growth and induces cell death, but the mechanism by which CSR1 suppresses tumor growth is not clear. In this study, we screened a prostate cDNA library using a yeast two-hybrid system and found that the cleavage and polyadenylation-specific factor 3 (CPSF3), an essential component for converting heteronuclear RNA to mRN...

  1. Extinction Models for Cancer Stem Cell Therapy

    OpenAIRE

    Sehl, Mary; Zhou, Hua; Sinsheimer, Janet ,; Lange, Kenneth

    2009-01-01

    Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tool...

  2. Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell

    OpenAIRE

    Oh, Su-Jin; Ryu, Chung-Kyu; Baek, So-Young; Lee, Hyunah

    2011-01-01

    Background EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. Methods C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of ...

  3. Mitochondria, cholesterol and cancer cell metabolism.

    Science.gov (United States)

    Ribas, Vicent; García-Ruiz, Carmen; Fernández-Checa, José C

    2016-12-01

    Given the role of mitochondria in oxygen consumption, metabolism and cell death regulation, alterations in mitochondrial function or dysregulation of cell death pathways contribute to the genesis and progression of cancer. Cancer cells exhibit an array of metabolic transformations induced by mutations leading to gain-of-function of oncogenes and loss-of-function of tumor suppressor genes that include increased glucose consumption, reduced mitochondrial respiration, increased reactive oxygen species generation and cell death resistance, all of which ensure cancer progression. Cholesterol metabolism is disturbed in cancer cells and supports uncontrolled cell growth. In particular, the accumulation of cholesterol in mitochondria emerges as a molecular component that orchestrates some of these metabolic alterations in cancer cells by impairing mitochondrial function. As a consequence, mitochondrial cholesterol loading in cancer cells may contribute, in part, to the Warburg effect stimulating aerobic glycolysis to meet the energetic demand of proliferating cells, while protecting cancer cells against mitochondrial apoptosis due to changes in mitochondrial membrane dynamics. Further understanding the complexity in the metabolic alterations of cancer cells, mediated largely through alterations in mitochondrial function, may pave the way to identify more efficient strategies for cancer treatment involving the use of small molecules targeting mitochondria, cholesterol homeostasis/trafficking and specific metabolic pathways. PMID:27455839

  4. Mitophagy switches cell death from apoptosis to necrosis in NSCLC cells treated with oncolytic measles virus.

    Science.gov (United States)

    Xia, Mao; Meng, Gang; Jiang, Aiqin; Chen, Aiping; Dahlhaus, Meike; Gonzalez, Patrick; Beltinger, Christian; Wei, Jiwu

    2014-06-15

    Although apoptotic phenomena have been observed in malignant cells infected by measles virus vaccine strain Edmonston B (MV-Edm), the precise oncolytic mechanisms are poorly defined. In this study we found that MV-Edm induced autophagy and sequestosome 1-mediated mitophagy leading to decreased cytochrome c release, which blocked the pro-apoptotic cascade in non-small cell lung cancer cells (NSCLCs). The decrease of apoptosis by mitophagy favored viral replication. Persistent viral replication sustained by autophagy ultimately resulted in necrotic cell death due to ATP depletion. Importantly, when autophagy was impaired in NSCLCs MV-Edm-induced cell death was significantly abrogated despite of increased apoptosis. Taken together, our results define a novel oncolytic mechanism by which mitophagy switches cell death from apoptosis to more efficient necrosis in NSCLCs following MV-Edm infection. This provides a foundation for future improvement of oncolytic virotherapy or antiviral therapy. PMID:25004098

  5. Mimulone-Induced Autophagy through p53-Mediated AMPK/mTOR Pathway Increases Caspase-Mediated Apoptotic Cell Death in A549 Human Lung Cancer Cells

    OpenAIRE

    An, Hyun-Kyu; Kim, Kyoung-Sook; Lee, Ji-Won; Park, Mi-Hyun; Moon, Hyung-In; Park, Shin-Ji; Baik, Ji-Sue; Kim, Cheorl-Ho; Lee, Young-Choon

    2014-01-01

    Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation ...

  6. Classification of Cancer-related Death Certificates using Machine Learning

    Directory of Open Access Journals (Sweden)

    Luke Butt

    2013-05-01

    Full Text Available BackgroundCancer monitoring and prevention relies on the critical aspect of timely notification of cancer cases. However, the abstraction and classification of cancer from the free-text of pathology reports and other relevant documents, such as death certificates, exist as complex and time-consuming activities.AimsIn this paper, approaches for the automatic detection of notifiable cancer cases as the cause of death from free-text death certificates supplied to Cancer Registries are investigated.Method A number of machine learning classifiers were studied. Features were extracted using natural language techniques and the Medtex toolkit. The numerous features encompassed stemmed words, bi-grams, and concepts from the SNOMED CT medical terminology. The baseline consisted of a keyword spotter using keywords extracted from the long description of ICD-10 cancer related codes.ResultsDeath certificates with notifiable cancer listed as the cause of death can be effectively identified with the methods studied in this paper. A Support Vector Machine (SVM classifier achieved best performance with an overall F-measure of 0.9866 when evaluated on a set of 5,000 free-text death certificates using the token stem feature set. The SNOMED CT concept plus token stem feature set reached the lowest variance (0.0032 and false negative rate (0.0297 while achieving an F-measure of 0.9864. The SVM classifier accounts for the first 18 of the top 40 evaluated runs, and entails the most robust classifier with a variance of 0.001141, half the variance of the other classifiers.ConclusionThe selection of features significantly produced the most influences on the performance of the classifiers, although the type of classifier employed also affects performance. In contrast, the feature weighting schema created a negligible effect on performance. Specifically, it is found that stemmed tokens with or without SNOMED CT concepts create the most effective feature when combined with

  7. Gallbladder Cancer Incidence and Death Rates

    Science.gov (United States)

    ... they can find better ways to prevent it. Risk factors for gallbladder cancer may include— A personal or family history of gallstones. Older age. Being female. Having an American Indian, Alaska Native, or black ...

  8. Inhibition of telomerase causes vulnerability to endoplasmic reticulum stress-induced neuronal cell death.

    Science.gov (United States)

    Hosoi, Toru; Nakatsu, Kanako; Shimamoto, Akira; Tahara, Hidetoshi; Ozawa, Koichiro

    2016-08-26

    Endoplasmic reticulum (ER) stress is implicated in several diseases, such as cancer and neurodegenerative diseases. In the present study, we investigated the possible involvement of telomerase in ER stress-induced cell death. ER stress-induced cell death was ameliorated in telomerase reverse transcriptase (TERT) over-expressing MCF7 cells (MCF7-TERT cell). Telomerase specific inhibitor, BIBR1532, reversed the inhibitory effect of TERT on ER stress-induced cell death in MCF7-TERT cells. These findings suggest that BIBR1532 may specifically inhibit telomerase activity, thereby inducing cell death in ER stress-exposed cells. TERT was expressed in the SH-SY5Y neuroblastoma cell line. To analyze the possible involvement of telomerase in ER stress-induced neuronal cell death, we treated SH-SY5Y neuroblastoma cells with BIBR1532 and analyzed ER stress-induced cell death. We found that BIBR1532 significantly enhanced the ER stress-induced neuronal cell death. These findings suggest that inhibition of telomerase activity may enhance vulnerability to neuronal cell death caused by ER stress. PMID:27443785

  9. T Cells in Gastric Cancer: Friends or Foes

    OpenAIRE

    Mario M. D'Elios; Elena Silvestri; Chiara Della Bella; Amedeo Amedei; Domenico Prisco

    2012-01-01

    Gastric cancer is the second cause of cancer-related deaths worldwide. Helicobacter pylori is the major risk factor for gastric cancer. As for any type of cancer, T cells are crucial for recognition and elimination of gastric tumor cells. Unfortunately T cells, instead of protecting from the onset of cancer, can contribute to oncogenesis. Herein we review the different types, “friend or foe”, of T-cell response in gastric cancer.

  10. TNF α and reactive oxygen species in necrotic cell death

    Institute of Scientific and Technical Information of China (English)

    Michael J Morgan; You-Sun Kim; Zheng-gang Liu

    2008-01-01

    Death receptors, including the TNF receptor-1 (TNF-RI), have been shown to be able to initiate caspase-independent cell death. This form of "necrotic cell death" appears to be dependent on the generation of reactive oxygen species. Recent data have indicated that superoxide generation is dependent on the activation of NADPH oxidases, which form a complex with the adaptor molecules RIP1 and TRADD. The mechanism of superoxide generation further establishes RIP1 as the central molecule in ROS production and cell death initiated by TNFa and other death receptors. A role for the sustained JNK activation in necrotic cell death is also suggested. The sensitization of virus-infected cells to TNFa indicates that necrotic cell death may represent an alternative cell death pathway for clearance of infected cells.

  11. Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging

    Science.gov (United States)

    Flusberg, Deborah A.; Sorger, Peter K.

    2013-06-01

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization.

  12. Rates of death from lung cancer for Canadian men.

    OpenAIRE

    Irwin, A. C.

    1986-01-01

    According to a recent study the rates of death from lung cancer for white men in the United States began to level off in the late 1970s and decreased between 1982 and 1983. The author reviewed data on death from lung cancer among Canadian men and found that there was an increase of 34% in the adjusted rates between 1971 and 1984. While there was some decrease in the rate of increase among men under the age of 55 years, the rates for men aged 55 or older continued to increase.

  13. Cell death mechanisms of plant-derived anticancer drugs: beyond apoptosis.

    Science.gov (United States)

    Gali-Muhtasib, Hala; Hmadi, Raed; Kareh, Mike; Tohme, Rita; Darwiche, Nadine

    2015-12-01

    Despite remarkable progress in the discovery and development of novel cancer therapeutics, cancer remains the second leading cause of death in the world. For many years, compounds derived from plants have been at the forefront as an important source of anticancer therapies and have played a vital role in the prevention and treatment of cancer because of their availability, and relatively low toxicity when compared with chemotherapy. More than 3000 plant species have been reported to treat cancer and about thirty plant-derived compounds have been isolated so far and have been tested in cancer clinical trials. The mechanisms of action of plant-derived anticancer drugs are numerous and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and caspase and/or p53-dependent or independent mechanisms. Alternative modes of cell death by plant-derived anticancer drugs are emerging and include mainly autophagy, necrosis-like programmed cell death, mitotic catastrophe, and senescence leading to cell death. Considering that the non-apoptotic cell death mechanisms of plant-derived anticancer drugs are less reviewed than the apoptotic ones, this paper attempts to focus on such alternative cell death pathways for some representative anticancer plant natural compounds in clinical development. In particular, emphasis will be on some promising polyphenolics such as resveratrol, curcumin, and genistein; alkaloids namely berberine, noscapine, and colchicine; terpenoids such as parthenolide, triptolide, and betulinic acid; and the organosulfur compound sulforaphane. The understanding of non-apoptotic cell death mechanisms induced by these drugs would provide insights into the possibility of exploiting novel molecular pathways and targets of plant-derived compounds for future cancer therapeutics. PMID:26362468

  14. Programmed cell death and its role in inflammation

    Institute of Scientific and Technical Information of China (English)

    Yong Yang; Ge-Ning Jiang; Peng Zhang; Jie Fan

    2015-01-01

    Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases.

  15. Programmed cell death in plants and caspase-like activities

    NARCIS (Netherlands)

    Gaussand, Gwénael Martial Daniel Jean-Marie

    2007-01-01

    The development of multicellular organisms involves an important balance between cell growth, cell division and cell death. In animals, programmed cell death (PCD) plays a key role by forming and deleting structures, controlling cell numbers and eliminating abnormal damaged cells. Caspases were foun

  16. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    Science.gov (United States)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  17. Oxidative Stress, Cell Death, and Other Damage to Alveolar Epithelial Cells Induced by Cigarette Smoke

    Directory of Open Access Journals (Sweden)

    Nagai A

    2003-09-01

    Full Text Available Abstract Cigarette smoking is a major risk factor in the development of various lung diseases, including pulmonary emphysema, pulmonary fibrosis, and lung cancer. The mechanisms of these diseases include alterations in alveolar epithelial cells, which are essential in the maintenance of normal alveolar architecture and function. Following cigarette smoking, alterations in alveolar epithelial cells induce an increase in epithelial permeability, a decrease in surfactant production, the inappropriate production of inflammatory cytokines and growth factors, and an increased risk of lung cancer. However, the most deleterious effect of cigarette smoke on alveolar epithelial cells is cell death, i.e., either apoptosis or necrosis depending on the magnitude of cigarette smoke exposure. Cell death induced by cigarette smoke exposure can largely be accounted for by an enhancement in oxidative stress. In fact, cigarette smoke contains and generates many reactive oxygen species that damage alveolar epithelial cells. Whether apoptosis and/or necrosis in alveolar epithelial cells is enhanced in healthy cigarette smokers is presently unclear. However, recent evidence indicates that the apoptosis of alveolar epithelial cells and alveolar endothelial cells is involved in the pathogenesis of pulmonary emphysema, an important cigarette smoke-induced lung disease characterized by the loss of alveolar structures. This review will discuss oxidative stress, cell death, and other damage to alveolar epithelial cells induced by cigarette smoke.

  18. Death-associated Protein Kinase Mediated Cell Death Modulated by Interaction with DANGER

    OpenAIRE

    Kang, Bingnan N.; Ahmad, Abdullah S.; Saleem, Sofiyan; Patterson, Randen L.; Hester, Lynda; Doré, Sylvain; Snyder, Solomon H.

    2010-01-01

    Death-associated protein kinase (DAPK) is a key player in multiple cell death signaling pathways. We report that DAPK is regulated by DANGER, a partial MAB-21-domain containing protein. DANGER binds directly to DAPK and inhibits DAPK catalytic activity. DANGER-deficient mouse embryonic fibroblasts and neurons exhibit greater DAPK activity and increased sensitivity to cell death stimuli than do wild-type control cells. In addition, DANGER-deficient mice manifest more severe brain damage after ...

  19. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    International Nuclear Information System (INIS)

    Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies

  20. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    Directory of Open Access Journals (Sweden)

    Maria Dolores Boyano

    2011-03-01

    Full Text Available Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies.

  1. Markers of small cell lung cancer

    OpenAIRE

    Sharma SK; Taneja Tarvinder

    2004-01-01

    Abstract Lung cancer is the number one cause of cancer death; however, no specific serum biomarker is available till date for detection of early lung cancer. Despite good initial response to chemotherapy, small-cell lung cancer (SCLC) has a poor prognosis. Therefore, it is important to identify molecular markers that might influence survival and may serve as potential therapeutic targets. The review aims to summarize the current knowledge of serum biomarkers in SCLC to improve diagnostic effi...

  2. Programmed Cell Death in Unicellular Phytoplankton.

    Science.gov (United States)

    Bidle, Kay D

    2016-07-11

    Unicellular, planktonic, prokaryotic and eukaryotic photoautotrophs (phytoplankton) have an ancient evolutionary history on Earth during which time they have played key roles in the regulation of marine food webs, biogeochemical cycles, and Earth's climate. Since they represent the basis of aquatic ecosystems, the manner in which phytoplankton die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining nutrient flow. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of abiotic (nutrient, light, osmotic) and biotic (virus infection, allelopathy) environmental stresses, have an integral grip on cell fate, and have shaped the ecological success and evolutionary trajectory of diverse phytoplankton lineages. A combination of physiological, biochemical, and genetic techniques in model algal systems has demonstrated a conserved molecular and mechanistic framework of stress surveillance, signaling, and death activation pathways, involving collective and coordinated participation of organelles, redox enzymes, metabolites, and caspase-like proteases. This mechanistic understanding has provided insight into the integration of sensing and transduction of stress signals into cellular responses, and the mechanistic interfaces between PCD, cell stress and virus infection pathways. It has also provided insight into the evolution of PCD in unicellular photoautotrophs, the impact of PCD on the fate of natural phytoplankton assemblages and its role in aquatic biogeochemical cycles. PMID:27404255

  3. Lung Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Sharon R. Pine

    2008-01-01

    Full Text Available Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation pathways are maintained within distinct cancer types, and destabilization of this machinery may participate in maintenance of cancer stem cells. Characterization of lung cancer stem cells is an area of active research and is critical for developing novel therapies. This review summarizes the current knowledge on stem cell signaling pathways and cell markers used to identify the lung cancer stem cells.

  4. Role of mitochondrial function in cell death and body metabolism.

    Science.gov (United States)

    Lee, Myung-Shik

    2016-01-01

    Mitochondria are the key players in apoptosis and necrosis. Mitochondrial DNA (mtDNA)-depleted r0 cells were resistant to diverse apoptosis inducers such as TNF-alpha, TNFSF10, staurosporine and p53. Apoptosis resistance was accompanied by the absence of mitochondrial potential loss or cytochrome c translocation. r0 cells were also resistant to necrosis induced by reactive oxygen species (ROS) donors due to upregulation of antioxidant enzymes such as manganese superoxide dismutase. Mitochondria also has a close relationship with autophagy that plays a critical role in the turnover of senescent organelles or dysfunctional proteins and may be included in 'cell death' category. It was demonstrated that autophagy deficiency in insulin target tissues such as skeletal muscle induces mitochondrial stress response, which leads to the induction of FGF21 as a 'mitokine' and affects the whole body metabolism. These results show that mitochondria are not simply the power plants of cells generating ATP, but are closely related to several types of cell death and autophagy. Mitochondria affect various pathophysiological events related to diverse disorders such as cancer, metabolic disorders and aging. PMID:27100503

  5. Cell phones and cancer

    Science.gov (United States)

    Cancer and cell phones; Do cell phones cause cancer? ... Several major studies show no link between cell phones and cancer at this time. However, since the information available is based on short-term studies, the impact of many years of ...

  6. Genetic regulation of programmed cell death in Drosophila

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Programmed cell death plays an important role in maintaining homeostasis during animal development, and has been conserved in animals as different as nematodes and humans. Recent studies of Drosophila have provided valuable information toward our understanding of genetic regulation of death. Different signals trigger the novel death regulators rpr, hid, and grim, that utilize the evolutionarily conserved iap and ark genes to modulate caspase function. Subsequent removal of dying cells also appears to be accomplished by conserved mechanisms. The similarity between Drosophila and human in cell death signaling pathways illustrate the promise of fruit flies as a model system to elucidate the mechanisms underlying regulation of programmed cell death.

  7. Targeting prostate cancer stem cells for cancer therapy

    OpenAIRE

    Wang, Guocan; Wang, Zhiwei; Sarkar, Fazlul H; Wei, Wenyi

    2012-01-01

    Prostate cancer (PCa) is the most common malignant neoplasm in men and the second most frequent cause of cancer death for males in the United States. Recently, emerging evidence suggests that prostate cancer stem cells (CSCs) may play a critical role in the development and progression of PCa. Therefore, targeting prostate CSCs for the prevention of tumor progression and treatment of PCa could become a novel strategy for better treatment of patients diagnosed with PCa. In this review article, ...

  8. Non-Small Cell Lung Cancer: Screening, Diagnosis, and Staging

    OpenAIRE

    Ferreira, J; Magalhães, M; Rocha, E; Marques, F

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide. Tobacco consumption is the primary cause of lung cancer, accounting for more than 85% 90% of all lung cancer deaths. Non-small cell lung cancer accounts for about 85% of all lung cancers. Several studies have shown that low-dose helical CT of the lung detects more nodules and lung cancers, including early-stage cancers, than does chest radiography. The National Lung Cancer Screening Trial results show that three annual roun...

  9. Lung cancer-initiating cells: a novel target for cancer therapy

    OpenAIRE

    Morrison, Brian J.; Morris, John C.; Steel, Jason C

    2013-01-01

    Lung cancer is a major public health problem causing more deaths than any other cancer. A better understanding of the biology of this disease and improvements in treatment are greatly needed. Increasing evidence supports the concept that a rare and specialized population of cancer cells, so-called cancer-initiating cells with stem cell-like characteristics, is responsible for tumor growth, maintenance, and recurrence. Cancer-initiating cells also exhibit characteristics that render them resis...

  10. A critical role for ethylene in hydrogen peroxide release during programmed cell death in tomato suspension cells

    NARCIS (Netherlands)

    Jong, de A.J.; Yakimova, E.T.; Kapchina, V.M.; Woltering, E.J.

    2002-01-01

    Camptothecin, a topo isomerase-I inhibitor used in cancer therapy, induces apoptosis in animal cells. In tomato (Lycopersicon esculentum Mill.) suspension cells, camptothecin induces cell death that is accompanied by the characteristic nuclear morphological changes such as chromatin condensation and

  11. Statins, Bcl-2 and Apoptosis: Cell Death or Cell Protection?

    OpenAIRE

    Wood, W. Gibson; Igbavboa, Urule; Muller, Walter E.; Gunter P. Eckert

    2013-01-01

    Statins have proven their effectiveness in the treatment of cardiovascular disease. This class of drugs has also attracted attention as a potential treatment for dissimilar diseases such as certain types of cancers and neurodegenerative diseases. What appears to be a contradiction is that in the case of cancer, it has been suggested that statins increase apoptosis and alter levels of Bcl-2 family members (e.g., reduce Bcl-2 and increase Bax) whereas, studies mainly using non-cancerous cells r...

  12. Regulation of programmed cell death by plasminogen activator inhibitor type 1 (PAI-1)

    DEFF Research Database (Denmark)

    Lademann, Ulrik Axel; Rømer, Maria Unni Koefoed

    2008-01-01

    numbers of reports suggest that PAI-1 also can regulate programmed cell death (PCD) in cancer cells and normal cells. A number of reports suggest that PAI-1 can inhibit PCD through its pro-adhesive/anti-proteolytic property whereas other reports suggest that PAI-1 induces PCD through its anti......-adhesive property.Furthermore,it has been suggested that PAI-1 can either induce or inhibit PCD though activation of cell signalling pathways.This review will focus on the regulation of programmed cell death by PAI-1 in both normal cells and cancer cells.......Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with poor prognosis in cancer. An explanation to the elevated levels of PAI-1 could be a protective response to the increased proteolytic activity, caused by elevated levels of urokinase- type plasminogen activator (u...

  13. Plant programmed cell death, ethylene and flower senescence

    NARCIS (Netherlands)

    Woltering, E.J.; Jong, de A.; Hoeberichts, F.A.; Iakimova, E.T.; Kapchina, V.

    2005-01-01

    Programmed cell death (PCD) applies to cell death that is part of the normal life of multicellular organisms. PCD is found throughout the animal and plant kingdoms; it is an active process in which a cell suicide pathway is activated resulting in controlled disassembly of the cell. Most cases of PCD

  14. Cancer Stem Cells

    OpenAIRE

    Katarzyna Wieczorek; Jolanta Niewiarowska

    2008-01-01

    Cancer stem cell theory gains increasingly greater significance in the world of medicine. Numerous findings of scientific research in vivo and in vitro indicate that it is the population of undifferentiated, self-renewing cells which is responsible for recurrence of cancer and metastasis. Similarly to normal stem cells, cancer stem cells (CSC) function in the environment of the other cells of the organism, called the niche, where they receive signals for differentiation and proliferation proc...

  15. Characteristics of Sudden Unexpected Cancer Deaths Investigated by Medical Examiners in Tokyo, Japan (2009)

    OpenAIRE

    ,

    2014-01-01

    Background Annually, about 400 cases of sudden unexpected death are attributed to cancer in Tokyo, Japan. These individuals may have been undiagnosed, or their medical conditions may not have been carefully evaluated before death. We examined medical consultations, cancer diagnoses, and economic status of all cancer deaths investigated by medical examiners in 2009. Methods Among cases handled by the Tokyo Medical Examiner’s Office in 2009 (N = 12 493), records for all cases of cancer death (n...

  16. Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells.

    Science.gov (United States)

    Shrotriya, Sangeeta; Deep, Gagan; Lopert, Pamela; Patel, Manisha; Agarwal, Rajesh; Agarwal, Chapla

    2015-12-01

    Head and neck squamous cell carcinoma (HNSCC) is a major killer worldwide and innovative measures are urgently warranted to lower the morbidity and mortality caused by this malignancy. Aberrant redox and metabolic status in HNSCC cells offer a unique opportunity to specifically target cancer cells. Therefore, we investigated the efficacy of grape seed extract (GSE) to target the redox and bioenergetic alterations in HNSCC cells. GSE treatment decreased the mitochondrial electron transport chain complex III activity, increased the mitochondrial superoxide levels and depleted the levels of cellular antioxidant (glutathione), thus resulting in the loss of mitochondrial membrane potential in human HNSCC Detroit 562 and FaDu cells. Polyethylene glycol-SOD addition reversed the GSE-mediated apoptosis without restoring complex III activity. Along with redox changes, GSE inhibited the extracellular acidification rate (representing glycolysis) and oxygen consumption rate (indicating oxidative phosphorylation) leading to metabolic stress in HNSCC cells. Molecular studies revealed that GSE activated AMP-activated protein kinase (AMPK), and suppressed Akt/mTOR/4E-BP1/S6K signaling in both Detroit 562 and FaDu cells. Interestingly, GSE increased the autophagic load specifically in FaDu cells, and autophagy inhibition significantly augmented the apoptosis in these cells. Consistent with in vitro results, in vivo analyses also showed that GSE feeding in nude mice activated AMPK and induced-autophagy in FaDu xenograft tumor tissues. Overall, these findings are innovative as we for the first time showed that GSE targets ETC complex III and induces oxidative and metabolic stress, thereby, causing autophagy and apoptotic death in HNSCC cells. PMID:25557495

  17. Analysis of cell death inducing compounds

    DEFF Research Database (Denmark)

    Spicker, Jeppe; Pedersen, Henrik Toft; Nielsen, Henrik Bjørn;

    2007-01-01

    Biomarkers for early detection of toxicity hold the promise of improving the failure rates in drug development. In the present study, gene expression levels were measured using full-genome RAE230 version 2 Affymetrix GeneChips on rat liver tissue 48 h after administration of six different compounds......), ornithine aminotransferase (OAT) and Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase) (Cyp2C29). RT-PCR for these three genes was performed and four additional compounds were included for validation. The quantitative RT-PCR analysis confirmed the findings based on the microarray data and using the...... three genes a classification rate of 55 of 57 samples was achieved for the classification of not toxic versus toxic. The single most promising biomarker (OAT) alone resulted in a surprisingly 100% correctly classified samples. OAT has not previously been linked to toxicity and cell death in the...

  18. The anti-cell death FNK protein protects cells from death induced by freezing and thawing

    International Nuclear Information System (INIS)

    The FNK protein, constructed from anti-apoptotic Bcl-xL with enhanced activity, was fused with the protein transduction domain (PTD) of the HIV/Tat protein to mediate the delivery of FNK into cells. The fusion protein PTD-FNK was introduced into chondrocytes in isolated articular cartilage-bone sections, cultured neurons, and isolated bone marrow mononuclear cells to evaluate its ability to prevent cell death induced by freezing and thawing. PTD-FNK protected the cells from freeze-thaw damage in a concentration-dependent manner. Addition of PTD-FNK with conventional cryoprotectants (dimethyl sulfoxide and hydroxyethyl starch) increased surviving cell numbers around 2-fold compared with controls treated only with the cryoprotectants. Notably, PTD-FNK allowed CD34+ cells among bone marrow mononuclear cells to survive more efficiently (12-fold more than the control cells) from two successive freeze-thaw cycles. Thus, PTD-FNK prevented cell death induced by freezing and thawing, suggesting that it provides for the successful cryopreservation of biological materials

  19. DNA Methylation and Apoptosis Resistance in Cancer Cells

    OpenAIRE

    Pierre-François Cartron; François Marie Vallette; Eric Hervouet; Mathilde Cheray

    2013-01-01

    Apoptosis is a cell death programme primordial to cellular homeostasis efficiency. This normal cell suicide program is the result of the activation of a cascade of events in response to death stimuli. Apoptosis occurs in normal cells to maintain a balance between cell proliferation and cell death. A deregulation of this balance due to modifications in the apoptosic pathway leads to different human diseases including cancers. Apoptosis resistance is one of the most important hallmarks of cance...

  20. Lung Cancer Stem Cells

    OpenAIRE

    Pine, Sharon R.; Blair Marshall; Lyuba Varticovski

    2008-01-01

    Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation p...

  1. Programmed cell death: a way of life for plants.

    OpenAIRE

    Greenberg, J T

    1996-01-01

    Cell death in higher plants has been widely observed in predictable patterns throughout development and in response to pathogenic infection. Genetic, biochemical, and morphological evidence suggests that these cell deaths occur as active processes and can be defined formally as examples of programmed cell death (PCD). Intriguingly, plants have at least two types of PCD, an observation that is also true of PCD in animals [Schwartz, L. M., Smith, W.W., Jones, M. E. E. & Osborne, B. A. (1993) Pr...

  2. Comedo-ductal carcinoma in situ: A paradoxical role for programmed cell death

    OpenAIRE

    Shekhar, Malathy P. V.; Tait, Larry; Pauley, Robert J.; Wu, Gen Sheng; Santner, Steven J.; Nangia-Makker, Pratima; Shekhar, Varun; Nassar, Hind; Visscher, Daniel W.; Heppner, Gloria H.; Miller, Fred R.

    2008-01-01

    Comedo-DCIS is a histologic subtype of preinvasive breast neoplasia that is characterized by prominent apoptotic cell death and has greater malignant potential than other DCIS subtypes. We investigated the mechanisms of apoptosis in comedo-DCIS and its role in conversion of comedo-DCIS to invasive cancer. Clinical comedo-DCIS excisions and the MCF10DCIS.com human breast cancer model which produces lesions resembling comedo-DCIS were analyzed. Apoptotic luminal and myoepithelial cells were ide...

  3. Testing a Multigene Signature of Prostate Cancer Death in the Swedish Watchful Waiting Cohort

    OpenAIRE

    Mucci, Lorelei A.; Pawitan, Yudi; DEMICHELIS, Francesca; Fall, Katja; Stark, Jennifer R.; Adami, Hans-Olov; Andersson, Swen-Olof; Andrén, Ove; Eisenstein, Anna; Holmberg, Lars; Huang, Wei; Kantoff, Philip W.; Kim, Robert; Perner, Sven; Stampfer, Meir J

    2008-01-01

    While prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the m...

  4. Senescence and programmed cell death : substance or semantics?

    NARCIS (Netherlands)

    Doorn, van W.G.; Woltering, E.J.

    2004-01-01

    The terms senescence and programmed cell death (PCD) have led to some confusion. Senescence as visibly observed in, for example, leaf yellowing and petal wilting, has often been taken to be synonymous with the programmed death of the constituent cells. PCD also obviously refers to cells, which show

  5. Cell death sensitization of leukemia cells by opioid receptor activation

    Science.gov (United States)

    Friesen, Claudia; Roscher, Mareike; Hormann, Inis; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf A.; Debatin, Klaus-Michael; Miltner, Erich

    2013-01-01

    Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID:23633472

  6. Breast cancer stem cells

    OpenAIRE

    Owens, Thomas W.; Naylor, Matthew J.

    2013-01-01

    Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumors are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs). Understanding how CSCs form and how they contribute to th...

  7. Anti cancer effects of curcumin: cycle of life and death

    Directory of Open Access Journals (Sweden)

    Das Tanya

    2008-10-01

    Full Text Available Abstract Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane, a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

  8. Incidence of cardiac deaths after irradiation for breast cancer

    International Nuclear Information System (INIS)

    The authors ascertained the cause of death of 1489 women who underwent mastectomy for breast cancer from 1959 through 1972. Postmastectomy irradiation, using parasternal portals which treated some heart, was given to 916 of these patients. The usual dose of raction was 45 Gray (4500 rad) in three weeks, a dose previously considered safe. Analysis by lifetable and Cox proportional hazard methods showed an excess of cardiac deaths in the irradiated women (logrank P = .02) even after controlling for age, hospital, calendar year, number of axillary lymph nodes involved, abnormal electrocardiogram, and prior history of heart disease. The excess deaths only occurred more than ten years after irradiation and only in women under age 70 at the time of mastectomy. Limiting analysis to patients age 40 and 69 years at the time of mastectomy, the authors observed that the hazard ratio for cardiac death was 2.24 (90% confidence interval 1.40 to 3.61) for right sided irradiation and 1.95 (90% confidence interval 1.87 to 4.66) for left sided irradiation. They conclude that irradiation of the heart, in doses previously considered safe, predisposes to cardiac death more than ten years later

  9. α-Synuclein and neuronal cell death

    Directory of Open Access Journals (Sweden)

    Cookson Mark R

    2009-02-01

    Full Text Available Abstract α-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is α-synuclein found in Lewy bodies characteristic of Parkinson disease, but also mutations in the gene for α-synuclein can cause an inherited form of Parkinson disease and expression of normal α-synuclein can increase the risk of developing Parkinson disease in sporadic, or non-familial, cases. Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies. Therefore, it is predicted that α-synuclein, especially in its mutant forms or under conditions where its expression levels are increased, is a toxic protein in the sense that it is associated with an increased rate of neuronal cell death. This review will discuss the experimental contexts in which α-synuclein has been demonstrated to be toxic. I will also outline what is known about the mechanisms by which α-synuclein triggers neuronal damage, and identify some of the current gaps in our knowledge about this subject. Finally, the therapeutic implications of toxicity of α-synuclein will be discussed.

  10. Autophagy in response to photodynamic therapy: cell survival vs. cell death

    Science.gov (United States)

    Oleinick, Nancy L.; Xue, Liang-yan; Chiu, Song-mao; Joseph, Sheeba

    2009-02-01

    Autophagy (or more properly, macroautophagy) is a pathway whereby damaged organelles or other cell components are encased in a double membrane, the autophagosome, which fuses with lysosomes for digestion by lysosomal hydrolases. This process can promote cell survival by removing damaged organelles, but when damage is extensive, it can also be a mechanism of cell death. Similar to the Kessel and Agostinis laboratories, we have reported the vigorous induction of autophagy by PDT; this was found in human breast cancer MCF-7 cells whether or not they were able to efficiently induce apoptosis. One way to evaluate the role of autophagy in PDT-treated cells is to silence one of the essential genes in the pathway. Kessel and Reiners silenced the Atg7 gene of murine leukemia L1210 cells using inhibitory RNA and found sensitization to PDT-induced cell death at a low dose of PDT, implying that autophagy is protective when PDT damage is modest. We have examined the role of autophagy in an epithelium-derived cancer cell by comparing parental and Atg7-silenced MCF-7 cells to varying doses of PDT with the phthalocyanine photosensitizer Pc 4. In contrast to L1210 cells, autophagy-deficient MCF-7 cells were more resistant to the lethal effects of PDT, as judged by clonogenic assays. A possible explanation for the difference in outcome for L1210 vs. MCF-7 cells is the greatly reduced ability of the latter to undergo apoptosis, a deficiency that may convert autophagy into a cell-death process even at low PDT doses. Experiments to investigate the mechanism(s) responsible are in process.

  11. Ras and Rheb Signaling in Survival and Cell Death

    International Nuclear Information System (INIS)

    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

  12. Stages of Renal Cell Cancer

    Science.gov (United States)

    ... cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney. Renal cell ... diagnosed, tests are done to find out if cancer cells have spread within the kidney or to other ...

  13. Attributing death to cancer: cause-specific survival estimation.

    Directory of Open Access Journals (Sweden)

    Mathew A

    2002-10-01

    Full Text Available Cancer survival estimation is an important part of assessing the overall strength of cancer care in a region. Generally, the death of a patient is taken as the end point in estimation of overall survival. When calculating the overall survival, the cause of death is not taken into account. With increasing demand for better survival of cancer patients it is important for clinicians and researchers to know about survival statistics due to disease of interest, i.e. net survival. It is also important to choose the best method for estimating net survival. Increase in the use of computer programmes has made it possible to carry out statistical analysis without guidance from a bio-statistician. This is of prime importance in third- world countries as there are a few trained bio-statisticians to guide clinicians and researchers. The present communication describes current methods used to estimate net survival such as cause-specific survival and relative survival. The limitation of estimation of cause-specific survival particularly in India and the usefulness of relative survival are discussed. The various sources for estimating cancer survival are also discussed. As survival-estimates are to be projected on to the population at large, it becomes important to measure the variation of the estimates, and thus confidence intervals are used. Rothman′s confidence interval gives the most satisfactory result for survival estimate.

  14. Effect of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality

    Science.gov (United States)

    Zhang, Sui-Liang; Chen, Ting-Song; Ma, Chen-Yun; Meng, Yong-Bin; Zhang, Yu-Fei; Chen, Yi-Wei; Zhou, Yu-Hao

    2016-01-01

    Abstract Background: Observational studies have suggested that vitamin B supplementation is associated with cancer risk, but this association remains controversial. A pooled data-based meta-analysis was conducted to summarize the evidence from randomized controlled trials (RCTs) investigating the effects of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality. Methods: PubMed, EmBase, and the Cochrane Library databases were searched to identify trials to fit our analysis through August 2015. Relative risk (RR) was used to measure the effect of vitamin B supplementation on the risk of cancer incidence, death due to cancer, and total mortality using a random-effect model. Cumulative meta-analysis, sensitivity analysis, subgroup analysis, heterogeneity tests, and tests for publication bias were also conducted. Results: Eighteen RCTs reporting the data on 74,498 individuals were included in the meta-analysis. Sixteen of these trials included 4103 cases of cancer; in 6 trials, 731 cancer-related deaths occurred; and in 15 trials, 7046 deaths occurred. Vitamin B supplementation had little or no effect on the incidence of cancer (RR: 1.04; 95% confidence interval [CI]: 0.98–1.10; P = 0.216), death due to cancer (RR, 1.05; 95% CI: 0.90–1.22; P = 0.521), and total mortality (RR, 1.00; 95% CI: 0.94–1.06; P = 0.952). Upon performing a cumulative meta-analysis for cancer incidence, death due to cancer, and total mortality, the nonsignificance of the effect of vitamin B persisted. With respect to specific types of cancer, vitamin B supplementation significantly reduced the risk of skin melanoma (RR, 0.47; 95% CI: 0.23–0.94; P = 0.032). Conclusion: Vitamin B supplementation does not have an effect on cancer incidence, death due to cancer, or total mortality. It is associated with a lower risk of skin melanoma, but has no effect on other cancers. PMID:27495015

  15. Interaction of CSR1 with XIAP reverses inhibition of caspases and accelerates cell death.

    Science.gov (United States)

    Zheng, Zhong-Liang; Tan, Lang-Zhu; Yu, Yan P; Michalopoulos, George; Luo, Jian-Hua

    2012-08-01

    Cellular Stress Response 1 (CSR1) is a tumor suppressor gene that is located at 8p21, a region that is frequently deleted in prostate cancer as well as a variety of human malignancies. Previous studies have indicated that the expression of CSR1 induces cell death. In this study, we found that CSR1 interacts with X-linked Inhibitor of Apoptosis Protein (XIAP), using yeast two-hybrid screening analyses. XIAP overexpression has been found in many human cancers, and forced expression of XIAP blocks apoptosis. Both in vitro and in vivo analyses indicated that the C-terminus of CSR1 binds XIAP with high affinity. Through a series of in vitro recombinant protein-binding analyses, the XIAP-binding motif in CSR1 was determined to include amino acids 513 to 572. Targeted knock-down of XIAP enhanced CSR1-induced cell death, while overexpression of XIAP antagonized CSR1 activity. The binding of CSR1 with XIAP enhanced caspase-9 and caspase-3 protease activities, and CSR1-induced cell death was dramatically reduced on expression of a mutant CSR1 that does not bind XIAP. However, a XIAP mutant that does not interact with caspase-9 had no impact on CSR1-induced cell death. These results suggest that cell death is induced when CSR1 binds XIAP, preventing the interaction of XIAP with caspases. Thus, this study may have elucidated a novel mechanism by which tumor suppressors induce cell death. PMID:22683311

  16. Gastric Cancer Stem Cells

    OpenAIRE

    Takaishi, Shigeo; Okumura, Tomoyuki; Timothy C Wang

    2008-01-01

    Cancer stem cells are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. Accumulating evidence in recent years strongly indicate the existence of cancer stem cells in solid tumors of a wide variety of organs. In this review, we will discuss the possible existence of a gastric cancer stem cell. Our recent data suggest that a subpopulation with a defined marker shows spheroid colony format...

  17. Cancer stem cell metabolism

    OpenAIRE

    Peiris-Pagès, Maria; Martinez-Outschoorn, Ubaldo E.; Pestell, Richard G.; Sotgia, Federica; Lisanti, Michael P

    2016-01-01

    Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Deter...

  18. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pattani, Varun P., E-mail: varun.pattani@utexas.edu; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W. [The University of Texas at Austin, Department of Biomedical Engineering (United States)

    2015-01-15

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm{sup 2} laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  19. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    International Nuclear Information System (INIS)

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm2 laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue

  20. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells

    International Nuclear Information System (INIS)

    Ganglioside GD2 is expressed on plasma membranes of various types of malignant cells. One of the most promising approaches for cancer immunotherapy is the treatment with monoclonal antibodies recognizing tumor-associated markers such as ganglioside GD2. It is considered that major mechanisms of anticancer activity of anti-GD2 antibodies are complement-dependent cytotoxicity and/or antibody-mediated cellular cytotoxicity. At the same time, several studies suggested that anti-GD2 antibodies are capable of direct induction of cell death of number of tumor cell lines, but it has not been investigated in details. In this study we investigated the functional role of ganglioside GD2 in the induction of cell death of multiple tumor cell lines by using GD2-specific monoclonal antibodies. Expression of GD2 on different tumor cell lines was analyzed by flow cytometry using anti-GD2 antibodies. By using HPTLC followed by densitometric analysis we measured the amount of ganglioside GD2 in total ganglioside fractions isolated from tumor cell lines. An MTT assay was performed to assess viability of GD2-positive and -negative tumor cell lines treated with anti-GD2 mAbs. Cross-reactivity of anti-GD2 mAbs with other gangliosides or other surface molecules was investigated by ELISA and flow cytometry. Inhibition of GD2 expression was achieved by using of inhibitor for ganglioside synthesis PDMP and/or siRNA for GM2/GD2 and GD3 synthases. Anti-GD2 mAbs effectively induced non-classical cell death that combined features of both apoptosis and necrosis in GD2-positive tumor cells and did not affect GD2-negative tumors. Anti-GD2 mAbs directly induced cell death, which included alteration of mitochondrial membrane potential, induction of apoptotic volume decrease and cell membrane permeability. This cytotoxic effect was mediated exclusively by specific binding of anti-GD2 antibodies with ganglioside GD2 but not with other molecules. Moreover, the level of GD2 expression correlated with

  1. Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease | Division of Cancer Prevention

    Science.gov (United States)

    New results from the NCI-sponsored Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care. |

  2. Actin as deathly switch? How auxin can suppress cell-death related defence.

    Directory of Open Access Journals (Sweden)

    Xiaoli Chang

    Full Text Available Plant innate immunity is composed of two layers--a basal immunity, and a specific effector-triggered immunity, which is often accompanied by hypersensitive cell death. Initiation of cell death depends on a complex network of signalling pathways. The phytohormone auxin as central regulator of plant growth and development represents an important component for the modulation of plant defence. In our previous work, we showed that cell death is heralded by detachment of actin from the membrane. Both, actin response and cell death, are triggered by the bacterial elicitor harpin in grapevine cells. In this study we investigated, whether harpin-triggered actin bundling is necessary for harpin-triggered cell death. Since actin organisation is dependent upon auxin, we used different auxins to suppress actin bundling. Extracellular alkalinisation and transcription of defence genes as the basal immunity were examined as well as cell death. Furthermore, organisation of actin was observed in response to pharmacological manipulation of reactive oxygen species and phospholipase D. We find that induction of defence genes is independent of auxin. However, auxin can suppress harpin-induced cell death and also counteract actin bundling. We integrate our findings into a model, where harpin interferes with an auxin dependent pathway that sustains dynamic cortical actin through the activity of phospholipase D. The antagonism between growth and defence is explained by mutual competition for signal molecules such as superoxide and phosphatidic acid. Perturbations of the auxin-actin pathway might be used to detect disturbed integrity of the plasma membrane and channel defence signalling towards programmed cell death.

  3. Cell of origin of lung cancer

    Directory of Open Access Journals (Sweden)

    Jennifer M Hanna

    2013-01-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell of origin, and cancer stem cells has been hampered by the heterogeneity of the disease, the lack of good in vivo transplantation models to assess stem cell behavior, and an overall incomplete understanding of the epithelial stem cell hierarchy. As such, a systematic computerized literature search of the MEDLINE database was used to identify articles discussing current knowledge about normal lung and lung cancer stem cells or progenitor cells. In this review, we discuss what is currently known about the role of cancer-initiating cells and normal stem cells in the development of lung tumors.

  4. Coniferyl aldehyde attenuates radiation enteropathy by inhibiting cell death and promoting endothelial cell function.

    Directory of Open Access Journals (Sweden)

    Ye-Ji Jeong

    Full Text Available Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA, an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function.

  5. Programmed cell death and cell extrusion in rat duodenum

    DEFF Research Database (Denmark)

    Schauser, Kirsten; Larsson, Lars-Inge

    2005-01-01

    techniques detecting the events associated with PCD in order to better understand its role in the turnover of the intestinal epithelium, including modified double- and triple-staining techniques for simultaneously detecting multiple markers of PCD in individual cells. Only a partial correlation between TUNEL......The small intestinal epithelium is continously renewed through a balance between cell division and cell loss. How this balance is achieved is uncertain. Thus, it is unknown to what extent programmed cell death (PCD) contributes to intestinal epithelial cell loss. We have used a battery of...... positivity for DNA fragmentation, c-jun phosphorylation on serine-63, positivity for activated caspase-3 and apoptotic morphology was observed. Our results show that DNA fragmentation does not invariable correlate to activation of caspase-3. Moreover, many cells were found to activate caspase-3 early in the...

  6. Analysis of cell death inducing compounds.

    Science.gov (United States)

    Spicker, Jeppe S; Pedersen, Henrik Toft; Nielsen, Henrik Bjørn; Brunak, Søren

    2007-11-01

    Biomarkers for early detection of toxicity hold the promise of improving the failure rates in drug development. In the present study, gene expression levels were measured using full-genome RAE230 version 2 Affymetrix GeneChips on rat liver tissue 48 h after administration of six different compounds, three toxins (ANIT, DMN and NMF) and three non-toxins (Caeruelein, Dinitrophenol and Rosiglitazone). We identified three gene transcripts with exceptional predictive performance towards liver toxicity and/or changes in histopathology. The three genes were: glucokinase regulatory protein (GCKR), ornithine aminotransferase (OAT) and Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase) (Cyp2C29). RT-PCR for these three genes was performed and four additional compounds were included for validation. The quantitative RT-PCR analysis confirmed the findings based on the microarray data and using the three genes a classification rate of 55 of 57 samples was achieved for the classification of not toxic versus toxic. The single most promising biomarker (OAT) alone resulted in a surprisingly 100% correctly classified samples. OAT has not previously been linked to toxicity and cell death in the literature and the novel finding represents a putative hepatotoxicity biomarker. PMID:17503021

  7. Severe Psoriasis Flare After Anti-Programmed Death Ligand 1 (PD-L1) Therapy for Metastatic Non-Small Cell Lung Cancer (NSCLC).

    Science.gov (United States)

    Chia, Puey Ling; John, Thomas

    2016-06-01

    Immunomodulatory agents that target PD-1 and its ligand (PD-L1) are being increasingly used in the management of lung cancer. Potential immune-related adverse events include dermatological complications which mostly are of low grade severity. The use of immune checkpoint inhibitors may lead to the exacerbation of autoimmune conditions. We report a case of a documented psoriasis flare with anti-PD-1 treatment for lung cancer. PMID:27163740

  8. Combined treatment with fenretinide and indomethacin induces AIF-mediated, non-classical cell death in human acute T-cell leukemia Jurkat cells

    Energy Technology Data Exchange (ETDEWEB)

    Hojka-Osinska, Anna, E-mail: hojka@immuno.iitd.pan.wroc.pl [Laboratory of Tumor Molecular Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw (Poland); Ziolo, Ewa, E-mail: ziolo@immuno.iitd.pan.wroc.pl [Laboratory of Tumor Molecular Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw (Poland); Rapak, Andrzej, E-mail: rapak@immuno.iitd.pan.wroc.pl [Laboratory of Tumor Molecular Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, 53-114 Wroclaw (Poland)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer The combination of fenretinide and indomethacin induces a high level of cell death. Black-Right-Pointing-Pointer Apoptotic pathway is caspase-independent. Black-Right-Pointing-Pointer Jurkat cells undergo AIF-mediated cell death. -- Abstract: Currently used cytotoxic drugs in cancer therapy have a similar mechanism of action and low specificity. Applied simultaneously, they show an additive effect with strong side effects. Clinical trials with the use of different agents in cancer therapy show that the use of these compounds alone is not very effective in fighting cancer. An alternative solution could be to apply a combination of these agents, because their combination has a synergistic effect on some cancer cells. Therefore, in our investigations we examined the effects of a synthetic retinoid-fenretinide when combined with a non-steroidal anti-inflammatory drug-indomethacin on the process of apoptosis in the acute human T-cell leukemia cell line Jurkat. We demonstrate that treatment with the combination of the tested compounds induces the death of cells, that is peculiar and combines features of apoptosis as well as non-apoptotic cell death. In detail we observed, cell membrane permeabilization, phosphatydylserine exposure, no oligonucleosomal DNA fragmentation, no caspase-3 activation, but apoptosis inducing factor (AIF) nuclear translocation. Taken together these results indicate, that Jurkat cells after treatment with a combination of fenretinide and indomethacin undergo AIF-mediated programmed cell death.

  9. Combined treatment with fenretinide and indomethacin induces AIF-mediated, non-classical cell death in human acute T-cell leukemia Jurkat cells

    International Nuclear Information System (INIS)

    Highlights: ► The combination of fenretinide and indomethacin induces a high level of cell death. ► Apoptotic pathway is caspase-independent. ► Jurkat cells undergo AIF-mediated cell death. -- Abstract: Currently used cytotoxic drugs in cancer therapy have a similar mechanism of action and low specificity. Applied simultaneously, they show an additive effect with strong side effects. Clinical trials with the use of different agents in cancer therapy show that the use of these compounds alone is not very effective in fighting cancer. An alternative solution could be to apply a combination of these agents, because their combination has a synergistic effect on some cancer cells. Therefore, in our investigations we examined the effects of a synthetic retinoid-fenretinide when combined with a non-steroidal anti-inflammatory drug–indomethacin on the process of apoptosis in the acute human T-cell leukemia cell line Jurkat. We demonstrate that treatment with the combination of the tested compounds induces the death of cells, that is peculiar and combines features of apoptosis as well as non-apoptotic cell death. In detail we observed, cell membrane permeabilization, phosphatydylserine exposure, no oligonucleosomal DNA fragmentation, no caspase-3 activation, but apoptosis inducing factor (AIF) nuclear translocation. Taken together these results indicate, that Jurkat cells after treatment with a combination of fenretinide and indomethacin undergo AIF-mediated programmed cell death.

  10. A statistical model for multidimensional irreversible electroporation cell death in tissue

    Directory of Open Access Journals (Sweden)

    Rubinsky Boris

    2010-02-01

    Full Text Available Abstract Background Irreversible electroporation (IRE is a minimally invasive tissue ablation technique which utilizes electric pulses delivered by electrodes to a targeted area of tissue to produce high amplitude electric fields, thus inducing irreversible damage to the cell membrane lipid bilayer. An important application of this technique is for cancer tissue ablation. Mathematical modelling is considered important in IRE treatment planning. In the past, IRE mathematical modelling used a deterministic single value for the amplitude of the electric field required for causing cell death. However, tissue, particularly cancerous tissue, is comprised of a population of different cells of different sizes and orientations, which in conventional IRE are exposed to complex electric fields; therefore, using a deterministic single value is overly simplistic. Methods We introduce and describe a new methodology for evaluating IRE induced cell death in tissue. Our approach employs a statistical Peleg-Fermi model to correlate probability of cell death in heterogeneous tissue to the parameters of electroporation pulses such as the number of pulses, electric field amplitude and pulse length. For treatment planning, the Peleg-Fermi model is combined with a numerical solution of the multidimensional electric field equation cast in a dimensionless form. This is the first time in which this concept is used for evaluating IRE cell death in multidimensional situations. Results We illustrate the methodology using data reported in literature for prostate cancer cell death by IRE. We show how to fit this data to a Fermi function in order to calculate the critical statistic parameters. To illustrate the use of the methodology, we simulated 2-D irreversible electroporation protocols and produced 2-D maps of the statistical distribution of cell death in the treated region. These plots were compared to plots produced using a deterministic model of cell death by IRE and

  11. Metallodrug induced apoptotic cell death and survival attempts are characterizable by Raman spectroscopy

    Science.gov (United States)

    le Roux, K.; Prinsloo, L. C.; Meyer, D.

    2014-09-01

    Chrysotherapeutics are under investigation as new or additional treatments for different types of cancers. In this study, gold complexes were investigated for their anticancer potential using Raman spectroscopy. The aim of the study was to determine whether Raman spectroscopy could be used for the characterization of metallodrug-induced cell death. Symptoms of cell death such as decreased peak intensities of proteins bonds and phosphodiester bonds found in deoxyribose nucleic acids were evident in the principal component analysis of the spectra. Vibrational bands around 761 cm-1 and 1300 cm-1 (tryptophan, ethanolamine group, and phosphatidylethanolamine) and 1720 cm-1 (ester bonds associated with phospholipids) appeared in the Raman spectra of cervical adenocarcinoma (HeLa) cells after metallodrug treatment. The significantly (p treatment could be a molecular signature of induced apoptosis since both the co-regulated phosphatidylserine and phosphatidylethanolamine are externalized during cell death. Treated cells had significantly higher levels of glucose and glycogen vibrational peaks, indicative of a survival mechanism of cancer cells under chemical stress. Cancer cells excrete chemotherapeutics to improve their chances of survival and utilize glucose to achieve this. Raman spectroscopy was able to monitor a survival strategy of cancer cells in the form of glucose uptake to alleviate chemical stress. Raman spectroscopy was invaluable in obtaining molecular information generated by biomolecules affected by anticancer metallodrug treatments and presents an alternative to less reproducible, conventional biochemical assays for cytotoxicity analyses.

  12. Disrupting the oncogenic synergism between nucleolin and Ras results in cell growth inhibition and cell death.

    Directory of Open Access Journals (Sweden)

    Sari Schokoroy

    Full Text Available BACKGROUND: The ErbB receptors, Ras proteins and nucleolin are major contributors to malignant transformation. The pleiotropic protein nucleolin can bind to both Ras protein and ErbB receptors. Previously, we have demonstrated a crosstalk between Ras, nucleolin and the ErbB1 receptor. Activated Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 levels. The three oncogenes synergistically facilitate anchorage independent growth and tumor growth in nude mice. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we used several cancer cell lines. The effect of Ras and nucleolin inhibition was determined using cell growth, cell death and cell motility assays. Protein expression was determined by immunohistochemistry. We found that inhibition of Ras and nucleolin reduces tumor cell growth, enhances cell death and inhibits anchorage independent growth. Our results reveal that the combined treatment affects Ras and nucleolin levels and localization. Our study also indicates that Salirasib (FTS, Ras inhibitor reduces cell motility, which is not affected by the nucleolin inhibitor. CONCLUSIONS/SIGNIFICANCE: These results suggest that targeting both nucleolin and Ras may represent an additional avenue for inhibiting cancers driven by these oncogenes.

  13. Spiritual Values and Death Anxiety: Implications for Counseling With Terminal Cancer Patients.

    Science.gov (United States)

    Gibbs, Harriett Weidman; Achterberg-Lawlis, Jeanne

    1978-01-01

    Results indicate cancer patients depend strongly on perceived strength of religious beliefs and values in coping with imminent death. Low fear of death was associated with previous experience with a dying person. Death anxiety scale score for cancer patients was significantly lower than for other populations. (Author/BEF)

  14. Chemical -induced apoptotic cell death in tomato cells : involvement of caspase-like proteases

    NARCIS (Netherlands)

    Jong, de A.J.; Hoeberichts, F.A.; Yakimova, E.T.; Maximova, E.; Woltering, E.J.

    2000-01-01

    A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian cells. This chemical-induced cell death was accompanied by the characte

  15. Activation-Induced Cell Death in T Cells and Autoimmunity

    Institute of Scientific and Technical Information of China (English)

    JianZhang; XuemeiXu; YongLiu

    2004-01-01

    Activation-induced cell death (AICD), which results from the interaction between Fas and Fas ligand, is responsible for maintaining tolerance to self-antigen. A defect in AICD may lead to development of autoimmunity. During the last several years, much progress has been made in understanding the mechanism(s) of AICD and its potential role in the pathogenesis of autoimmune diseases. In this review, we summarize the most recent progress on the regulation of the susceptibility of T cells to AICD and its possible involvement in autoimmune diseases.

  16. Fermented Brown Rice Extract Causes Apoptotic Death of Human Acute Lymphoblastic Leukemia Cells via Death Receptor Pathway.

    Science.gov (United States)

    Horie, Yukiko; Nemoto, Hideyuki; Itoh, Mari; Kosaka, Hiroaki; Morita, Kyoji

    2016-04-01

    Mixture of brown rice and rice bran fermented with Aspergillus oryzae, designated as FBRA, has been reported to reveal anti-carcinogenic and anti-inflammatory effects in rodents. Then, to test its potential anti-cancer activity, the aqueous extract was prepared from FBRA powder, and the effect of this extract on human acute lymphoblastic leukemia Jurkat cells was directly examined. The exposure to FBRA extract reduced the cell viability in a concentration- and time-dependent manner. The reduction of the cell viability was accompanied by the DNA fragmentation, and partially restored by treatment with pan-caspase inhibitor. Further studies showed that FBRA extract induced the cleavage of caspase-8, -9, and -3, and decreased Bcl-2 protein expression. Moreover, the expression of tBid, DR5, and Fas proteins was enhanced by FBRA extract, and the pretreatment with caspase-8 inhibitor, but not caspase-9 inhibitor, restored the reduction of the cell viability induced by FBRA extract. These findings suggested that FBRA extract could induce the apoptotic death of human acute lymphoblastic leukemia cells probably through mainly the death receptor-mediated pathway and supplementarily through the tBid-mediated mitochondrial pathway, proposing the possibility that FBRA was a potential functional food beneficial to patients with hematological cancer. PMID:26769704

  17. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1 receptor pathway

    Directory of Open Access Journals (Sweden)

    Momtaz P

    2014-11-01

    Full Text Available Parisa Momtaz,1,2 Michael A Postow1,2 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Weill Cornell Medical College, New York, NY, USA Abstract: T-lymphocytes have the potential to recognize cancer antigens as foreign and therefore eliminate them. However, immune checkpoints such as cytotoxic T-lymphocyte-associated antigen (CTLA-4 and programmed cell death (PD-1 receptor and its ligands (PD-L1, PD-L2 suppress the activity of T-lymphocytes. Advances in the understanding of immunology and its role in cancer have led to the development of immune checkpoint inhibitors that block CTLA-4 and PD-1 and result in durable responses in patients with a wide range of cancers. PD-1 and PD-L1 inhibitors are currently in many stages of clinical investigation, and the anti-PD-1 antibody, pembrolizumab, was recently approved by the US Food and Drug Administration. Many questions remain to be answered, such as the optimal administration schedule, biomarkers that associate with benefit, and potential for use of PD-1 agents in combination approaches. Nonetheless, immunotherapy with PD-1 blocking antibodies is now becoming an integral part in the management of cancer. Keyword: immune checkpoints, immunotherapy, programmed cell death protein-1, cytotoxic T-lymphocyte antigen 4

  18. T-helper-1-cell cytokines drive cancer into senescence

    OpenAIRE

    Braumüller, Heidi; Wieder, Thomas; Brenner, Ellen; Aßmann, Sonja; Hahn, Matthias; Alkhaled, Mohammed; Schilbach, Karin; Essmann, Frank; Kneilling, Manfred; Griessinger, Christoph; Ranta, Felicia; Ullrich, Susanne; Mocikat, Ralph; Braungart, Kilian; Mehra, Tarun

    2013-01-01

    Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from ...

  19. Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy.

    Science.gov (United States)

    Son, Keum-Joo; Choi, Ki Ryung; Lee, Seog Jae; Lee, Hyunah

    2016-02-01

    Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT(+) CD11c(+) cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy. PMID:26937234

  20. p31comet-Induced Cell Death Is Mediated by Binding and Inactivation of Mad2.

    Directory of Open Access Journals (Sweden)

    Hyun-Jin Shin

    Full Text Available Mad2, a key component of the spindle checkpoint, is closely associated with chromosomal instability and poor prognosis in cancer. p31comet is a Mad2-interacting protein that serves as a spindle checkpoint silencer at mitosis. In this study, we showed that p31comet-induced apoptosis and senescence occur via counteraction of Mad2 activity. Upon retroviral transduction of p31comet, the majority of human cancer cell lines tested lost the ability to form colonies in a low-density seeding assay. Cancer cells with p31comet overexpression underwent distinct apoptosis and/or senescence, irrespective of p53 status, confirming the cytotoxicity of p31comet. Interestingly, both cytotoxic and Mad2 binding activities were eliminated upon deletion of the C-terminal 30 amino acids of p31comet. Point mutation or deletion of the region affecting Mad2 binding additionally abolished cytotoxic activity. Consistently, wild-type Mad2 interacting with p31comet, but not its non-binding mutant, inhibited cell death, indicating that the mechanism of p31comet-induced cell death involves Mad2 inactivation. Our results clearly suggest that the regions of p31comet affecting interactions with Mad2, including the C-terminus, are essential for induction of cell death. The finding that p31comet-induced cell death is mediated by interactions with Mad2 that lead to its inactivation is potentially applicable in anticancer therapy.

  1. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    Science.gov (United States)

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit. PMID:26250412

  2. Investigation of the selenium metabolism in cancer cell lines

    DEFF Research Database (Denmark)

    Lunøe, Kristoffer; Gabel-Jensen, Charlotte; Stürup, Stefan; Andresen, Lars; Skov, Søren; Gammelgaard, Bente

    2011-01-01

    The aim of this work was to compare different selenium species for their ability to induce cell death in different cancer cell lines, while investigating the underlying chemistry by speciation analysis. A prostate cancer cell line (PC-3), a colon cancer cell line (HT-29) and a leukaemia cell line...... incubated with cells for 24 h and the induction of cell death was measured using flow cytometry. The amounts of total selenium in cell medium, cell lysate and the insoluble fractions was determined by ICP-MS. Speciation analysis of cellular fractions was performed by reversed phase, anion exchange and size...... exclusion chromatography and ICP-MS detection. The selenium compounds exhibited large differences in their ability to induce cell death in the three cell lines and the susceptibilities of the cell lines were different. Full recovery of selenium in the cellular fractions was observed for all Se compounds...

  3. Stochastic model for computer simulation of the number of cancer cells and lymphocytes in homogeneous sections of cancer tumors

    CERN Document Server

    Castellanos-Moreno, Arnulfo; Corella-Madueño, Adalberto; Gutiérrez-López, Sergio; Rosas-Burgos, Rodrigo

    2014-01-01

    We deal with a small enough tumor section to consider it homogeneous, such that populations of lymphocytes and cancer cells are independent of spatial coordinates. A stochastic model based in one step processes is developed to take into account natural birth and death rates. Other rates are also introduced to consider medical treatment: natural birth rate of lymphocytes and cancer cells; induced death rate of cancer cells due to self-competition, and other ones caused by the activated lymphocytes acting on cancer cells. Additionally, a death rate of cancer cells due to induced apoptosis is considered. Weakness due to the advance of sickness is considered by introducing a lymphocytes death rate proportional to proliferation of cancer cells. Simulation is developed considering different combinations of the parameters and its values, so that several strategies are taken into account to study the effect of anti-angiogenic drugs as well the self-competition between cancer cells. Immune response, with the presence ...

  4. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model

    OpenAIRE

    Ni Xiao; Suhail Mahmoud M; Yang Qing; Cao Amy; Fung Kar-Ming; Postier Russell G; Woolley Cole; Young Gary; Zhang Jingzhe; Lin Hsueh-Kung

    2012-01-01

    Abstract Background Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have bee...

  5. Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

    International Nuclear Information System (INIS)

    Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 oC for 1 h) and X-ray (5 or 10 Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

  6. Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Schildkopf, Petra, E-mail: petra.schildkopf@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Frey, Benjamin, E-mail: benjamin.frey@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Mantel, Frederick, E-mail: frederick.mantel@web.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Ott, Oliver J., E-mail: oliver.ott@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Weiss, Eva-Maria, E-mail: eva-maria.weiss@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Sieber, Renate, E-mail: renate.sieber@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Janko, Christina, E-mail: christina.janko@uk-erlangen.de [Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Sauer, Rolf, E-mail: rolf.sauer@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Fietkau, Rainer, E-mail: rainer.fietkau@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany); Gaipl, Udo S., E-mail: udo.gaipl@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuernberg (Germany)

    2010-01-01

    Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 {sup o}C for 1 h) and X-ray (5 or 10 Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

  7. Breast Cancer Patients with High Density Mammograms Do Not Have Increased Risk of Death

    Science.gov (United States)

    ... density mammograms do not have increased risk of death High mammographic breast density, which is a marker ... does not seem to increase the risk of death among breast cancer patients, according to a study ...

  8. Stress Management in Cyst-Forming Free-Living Protists: Programmed Cell Death and/or Encystment

    Directory of Open Access Journals (Sweden)

    Naveed Ahmed Khan

    2015-01-01

    Full Text Available In the face of harsh conditions and given a choice, a cell may (i undergo programmed cell death, (ii transform into a cancer cell, or (iii enclose itself into a cyst form. In metazoans, the available evidence suggests that cellular machinery exists only to execute or avoid programmed cell death, while the ability to form a cyst was either lost or never developed. For cyst-forming free-living protists, here we pose the question whether the ability to encyst was gained at the expense of the programmed cell death or both functions coexist to counter unfavorable environmental conditions with mutually exclusive phenotypes.

  9. Stress Management in Cyst-Forming Free-Living Protists: Programmed Cell Death and/or Encystment

    Science.gov (United States)

    Khan, Naveed Ahmed; Iqbal, Junaid

    2015-01-01

    In the face of harsh conditions and given a choice, a cell may (i) undergo programmed cell death, (ii) transform into a cancer cell, or (iii) enclose itself into a cyst form. In metazoans, the available evidence suggests that cellular machinery exists only to execute or avoid programmed cell death, while the ability to form a cyst was either lost or never developed. For cyst-forming free-living protists, here we pose the question whether the ability to encyst was gained at the expense of the programmed cell death or both functions coexist to counter unfavorable environmental conditions with mutually exclusive phenotypes. PMID:25648302

  10. Chemotherapy in heterogeneous cultures of cancer cells with interconversion

    International Nuclear Information System (INIS)

    Recently, the interconversion between differentiated and stem-like cancer cells has been observed. Here, we model the in vitro growth of heterogeneous cell cultures in the presence of interconversion from differentiated cancer cells to cancer stem cells (CSCs), showing that, by targeting only CSC with cytotoxic agents, it is not always possible to eradicate cancer. We have determined the kinetic conditions under which cytotoxic agents in in vitro heterogeneous cultures of cancer cells eradicate cancer. In particular, we have shown that the chemotherapeutic elimination of in vitro cultures of heterogeneous cancer cells is effective only if it targets all cancer cell types, and if the induced death rates for the different subpopulations of cancer cell types are large enough. The quantitative results of the model are compared and validated with experimental data. (paper)

  11. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Directory of Open Access Journals (Sweden)

    Laila Ziko

    2015-01-01

    Full Text Available Cisplatin (CisPt is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2 cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death. Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death.

  12. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    International Nuclear Information System (INIS)

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  13. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  14. Programmed Cell Death and Postharvest Deterioration of Horticultural Produce

    NARCIS (Netherlands)

    Woltering, E.J.; Iakimova, E.T.

    2010-01-01

    Programmed cell death (PCD) is a process where cells or tissues are broken down in an orderly and predictable manner, whereby nutrients are re-used by other cells, tissues or plant parts. The process of (petal) senescence shows many similarities to autophagic PCD in animal cells including a massive

  15. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

    International Nuclear Information System (INIS)

    Prodigiosin is a bacterial tripyrrole pigment with potent cytotoxicity against diverse human cancer cell lines. Endoplasmic reticulum (ER) stress is initiated by accumulation of unfolded or misfolded proteins in the ER lumen and may induce cell death when irremediable. In this study, the role of ER stress in prodigiosin-induced cytotoxicity was elucidated for the first time. Comparable to the ER stress inducer thapsigargin, prodigiosin up-regulated signature ER stress markers GRP78 and CHOP in addition to activating the IRE1, PERK and ATF6 branches of the unfolded protein response (UPR) in multiple human breast carcinoma cell lines, confirming prodigiosin as an ER stress inducer. Prodigiosin transcriptionally up-regulated CHOP, as evidenced by its promoting effect on the CHOP promoter activity. Of note, knockdown of CHOP effectively lowered prodigiosin's capacity to evoke PARP cleavage, reduce cell viability and suppress colony formation, highlighting an essential role of CHOP in prodigiosin-induced cytotoxic ER stress response. In addition, prodigiosin down-regulated BCL2 in a CHOP-dependent manner. Importantly, restoration of BCL2 expression blocked prodigiosin-induced PARP cleavage and greatly enhanced the survival of prodigiosin-treated cells, suggesting that CHOP-dependent BCL2 suppression mediates prodigiosin-elicited cell death. Moreover, pharmacological inhibition of JNK by SP600125 or dominant-negative blockade of PERK-mediated eIF2α phosphorylation impaired prodigiosin-induced CHOP up-regulation and PARP cleavage. Collectively, these results identified ER stress-mediated cell death as a mode-of-action of prodigiosin's tumoricidal effect. Mechanistically, prodigiosin engages the IRE1–JNK and PERK–eIF2α branches of the UPR signaling to up-regulate CHOP, which in turn mediates BCL2 suppression to induce cell death. Highlights: ► Prodigiosin is a bacterial tripyrrole pigment with potent anticancer effect. ► Prodigiosin is herein identified as an

  16. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Mu-Yun [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Lu, Chien-Hsing [Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Yang, Shu-Yi [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Ho, Tsing-Fen [Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China)

    2012-12-15

    Prodigiosin is a bacterial tripyrrole pigment with potent cytotoxicity against diverse human cancer cell lines. Endoplasmic reticulum (ER) stress is initiated by accumulation of unfolded or misfolded proteins in the ER lumen and may induce cell death when irremediable. In this study, the role of ER stress in prodigiosin-induced cytotoxicity was elucidated for the first time. Comparable to the ER stress inducer thapsigargin, prodigiosin up-regulated signature ER stress markers GRP78 and CHOP in addition to activating the IRE1, PERK and ATF6 branches of the unfolded protein response (UPR) in multiple human breast carcinoma cell lines, confirming prodigiosin as an ER stress inducer. Prodigiosin transcriptionally up-regulated CHOP, as evidenced by its promoting effect on the CHOP promoter activity. Of note, knockdown of CHOP effectively lowered prodigiosin's capacity to evoke PARP cleavage, reduce cell viability and suppress colony formation, highlighting an essential role of CHOP in prodigiosin-induced cytotoxic ER stress response. In addition, prodigiosin down-regulated BCL2 in a CHOP-dependent manner. Importantly, restoration of BCL2 expression blocked prodigiosin-induced PARP cleavage and greatly enhanced the survival of prodigiosin-treated cells, suggesting that CHOP-dependent BCL2 suppression mediates prodigiosin-elicited cell death. Moreover, pharmacological inhibition of JNK by SP600125 or dominant-negative blockade of PERK-mediated eIF2α phosphorylation impaired prodigiosin-induced CHOP up-regulation and PARP cleavage. Collectively, these results identified ER stress-mediated cell death as a mode-of-action of prodigiosin's tumoricidal effect. Mechanistically, prodigiosin engages the IRE1–JNK and PERK–eIF2α branches of the UPR signaling to up-regulate CHOP, which in turn mediates BCL2 suppression to induce cell death. Highlights: ► Prodigiosin is a bacterial tripyrrole pigment with potent anticancer effect. ► Prodigiosin is herein identified

  17. Cancer Stem Cells, Cancer Cell Plasticity and Radiation Therapy

    OpenAIRE

    Vlashi, Erina; Pajonk, Frank

    2014-01-01

    Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be ...

  18. How Taxol/paclitaxel kills cancer cells

    OpenAIRE

    Weaver, Beth A

    2014-01-01

    Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, r...

  19. Breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    MatthewJNaylor

    2013-08-01

    Full Text Available Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumours are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs. Understanding how CSCs form and how they contribute to the pathology of breast cancer will greatly aid the pursuit of novel therapies targeted at eliminating these cells. This review will summarise what is currently known about the origins of breast CSCs, their role in disease progression and ways in which they may be targeted therapeutically.

  20. Low-frequency quantitative ultrasound imaging of cell death in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Sadeghi-Naini, Ali; Falou, Omar; Czarnota, Gregory J. [Imaging Research – Physical Science, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5 (Canada); Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5 (Canada); Papanicolau, Naum; Tadayyon, Hadi [Imaging Research – Physical Science, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5 (Canada); Lee, Justin [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5 (Canada); Zubovits, Judit [Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Sadeghian, Alireza [Department of Computer Science, Ryerson University, Toronto, Ontario M5B 2K3 (Canada); Karshafian, Raffi [Department of Physics, Ryerson University, Toronto, Ontario M5B 2K3 (Canada); Al-Mahrouki, Azza; Giles, Anoja [Imaging Research – Physical Science, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Kolios, Michael C. [Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5, Canada and Department of Physics, Ryerson University, Toronto, Ontario M5B 2K3 (Canada)

    2013-08-15

    Purpose: Currently, no clinical imaging modality is used routinely to assess tumor response to cancer therapies within hours to days of the delivery of treatment. Here, the authors demonstrate the efficacy of ultrasound at a clinically relevant frequency to quantitatively detect changes in tumors in response to cancer therapies using preclinical mouse models.Methods: Conventional low-frequency and corresponding high-frequency ultrasound (ranging from 4 to 28 MHz) were used along with quantitative spectroscopic and signal envelope statistical analyses on data obtained from xenograft tumors treated with chemotherapy, x-ray radiation, as well as a novel vascular targeting microbubble therapy.Results: Ultrasound-based spectroscopic biomarkers indicated significant changes in cell-death associated parameters in responsive tumors. Specifically changes in the midband fit, spectral slope, and 0-MHz intercept biomarkers were investigated for different types of treatment and demonstrated cell-death related changes. The midband fit and 0-MHz intercept biomarker derived from low-frequency data demonstrated increases ranging approximately from 0 to 6 dBr and 0 to 8 dBr, respectively, depending on treatments administrated. These data paralleled results observed for high-frequency ultrasound data. Statistical analysis of ultrasound signal envelope was performed as an alternative method to obtain histogram-based biomarkers and provided confirmatory results. Histological analysis of tumor specimens indicated up to 61% cell death present in the tumors depending on treatments administered, consistent with quantitative ultrasound findings indicating cell death. Ultrasound-based spectroscopic biomarkers demonstrated a good correlation with histological morphological findings indicative of cell death (r{sup 2}= 0.71, 0.82; p < 0.001).Conclusions: In summary, the results provide preclinical evidence, for the first time, that quantitative ultrasound used at a clinically relevant frequency

  1. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined.

    Directory of Open Access Journals (Sweden)

    Hyemi Lee

    Full Text Available Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high/CD24(low cells of MCF-7 cells and, CD44(high/CD24(high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

  2. Hepatic Leukemia Factor Promotes Resistance To Cell Death: Implications For Therapeutics and Chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation.

  3. Death for survival: what do we know about innate immunity and cell death in insects?

    Directory of Open Access Journals (Sweden)

    DM Cooper

    2011-09-01

    Full Text Available Insects are the most diverse and prolific animal group on Earth, and as such, important lessons can be taken from the elements that contribute to their evolutionary success. This review examines insect immunity and how insects combat infection with the pathogens they encounter: bacteria, viruses, fungi and parasites. Structural barriers, cellular and humoral responses and cell death all respond to specific immunological threats and contribute to the robust repertoire of immune strategies employed by insects. We discuss the strategies used by insects to combat pathogen infection and focus on what is currently known about cell death and its role in insect immunity.

  4. Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

    International Nuclear Information System (INIS)

    High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death. - Highlights: • Nuclear DAMP complexes (nDCs) selectively induce cell death in macrophages, but not cancer cells. • TNFα-mediated oxidative stress is required for nDC-induced death. • RAGE-mediated Akt activation is required for nDC-induced TNFα release. • Blocking RAGE and TNFα inhibits nDC-induced macrophage cell death

  5. Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ruochan [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Fu, Sha; Fan, Xue-Gong [Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Lotze, Michael T.; Zeh, Herbert J. [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Kang, Rui, E-mail: kangr@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2015-03-13

    High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death. - Highlights: • Nuclear DAMP complexes (nDCs) selectively induce cell death in macrophages, but not cancer cells. • TNFα-mediated oxidative stress is required for nDC-induced death. • RAGE-mediated Akt activation is required for nDC-induced TNFα release. • Blocking RAGE and TNFα inhibits nDC-induced macrophage cell death.

  6. Rate of death of hypoxic cells in multicell spheroids

    International Nuclear Information System (INIS)

    The rate of death of hypoxic cells was measured in multicell spheroids, which are considered to model in vitro the microenvironments surrounding such cells within solid tumors. Two types of experiments were performed: (1) All of the cells in spheroids were made hypoxic (less than 100 ppM O2) and the total number of viable cells was determined by clonogenic assay at later times up to 7 days. The rate of death of cells appeared biphasic. At least 15% of the cells died within the first 6 hr. The rate of development of histological changes in the spheroids suggested that the innermost cells were most sensitive. The more peripheral layers of cells died much more slowly so that there was still about 5% survival and a significant number of histologically normal cells at 6 days. Changes in the glucose concentration in the medium (from one-third to three times normal) during exposure to hypoxia had little effect on the survival time of these outer cells. (2) The cells in the inner half of spheroids grown in 20% O2 were made hypoxic by equilibrating the growth medium with 5% O2, and the number of resistant hypoxic cells at different times later was determined after a radiation dose of 3500 rad. The number of surviving clonogenic cells after this dose of radiation decreased with a half-time for cell death of 3 hr. These results indicate that the rate of death of hypoxic cells in the central regions of spheroids is much more rapid than has been reported for monolayer cultures, although the resistance of the outer cells is similar to or greater than monolayers. Since spheroids may model the necrosis and other microenvironments near chronically hypoxic cells in tumors, the relatively rapid rate of death of hypoxic cells demonstrated here must be considered in evaluating their contribution to the size of the radiation-resistant hypoxic fraction and possible mechanisms which might contribute to the phenomenon of reoxygenation

  7. Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease

    Science.gov (United States)

    New results from the NCI-sponsored PLCO Cancer Screening Trial show that screening for ovarian cancer with transvaginal ultrasound (TVU) and the CA-125 blood test did not result in fewer deaths from the disease compared with usual care.

  8. Gene expression analysis of cell death induction by Taurolidine in different malignant cell lines

    International Nuclear Information System (INIS)

    The anti-infective agent Taurolidine (TRD) has been shown to have cell death inducing properties, but the mechanism of its action is largely unknown. The aim of this study was to identify potential common target genes modulated at the transcriptional level following TRD treatment in tumour cell lines originating from different cancer types. Five different malignant cell lines (HT29, Chang Liver, HT1080, AsPC-1 and BxPC-3) were incubated with TRD (100 μM, 250 μM and 1000 μM). Proliferation after 8 h and cell viability after 24 h were analyzed by BrdU assay and FACS analysis, respectively. Gene expression analyses were carried out using the Agilent -microarray platform to indentify genes which displayed conjoint regulation following the addition of TRD in all cell lines. Candidate genes were subjected to Ingenuity Pathways Analysis and selected genes were validated by qRT-PCR and Western Blot. TRD 250 μM caused a significant inhibition of proliferation as well as apoptotic cell death in all cell lines. Among cell death associated genes with the strongest regulation in gene expression, we identified pro-apoptotic transcription factors (EGR1, ATF3) as well as genes involved in the ER stress response (PPP1R15A), in ubiquitination (TRAF6) and mitochondrial apoptotic pathways (PMAIP1). This is the first conjoint analysis of potential target genes of TRD which was performed simultaneously in different malignant cell lines. The results indicate that TRD might be involved in different signal transduction pathways leading to apoptosis

  9. The intersection of cell death and inflammasome activation.

    Science.gov (United States)

    Vince, James E; Silke, John

    2016-06-01

    Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes. PMID:27066895

  10. Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Ira O Racoma

    Full Text Available Glioblastoma is the most aggressive and common type of malignant brain tumor in humans, with a median survival of 15 months. There is a great need for more therapies for the treatment of glioblastoma. Naturally occurring phytochemicals have received much scientific attention because many exhibit potent tumor killing action. Thymoquinone (TQ is the bioactive compound of the Nigella sativa seed oil. TQ has anti-oxidant, anti-inflammatory and anti-neoplastic actions with selective cytotoxicity for human cancer cells compared to normal cells. Here, we show that TQ selectively inhibits the clonogenicity of glioblastoma cells as compared to normal human astrocytes. Also, glioblastoma cell proliferation could be impaired by chloroquine, an autophagy inhibitor, suggesting that glioblastoma cells may be dependent on the autophagic pathway for survival. Exposure to TQ caused an increase in the recruitment and accumulation of the microtubule-associated protein light chain 3-II (LC3-II. TQ also caused an accumulation of the LC3-associated protein p62, confirming the inhibition of autophagy. Furthermore, the levels of Beclin-1 protein expression were unchanged, indicating that TQ interferes with a later stage of autophagy. Finally, treatment with TQ induces lysosome membrane permeabilization, as determined by a specific loss of red acridine orange staining. Lysosome membrane permeabilization resulted in a leakage of cathepsin B into the cytosol, which mediates caspase-independent cell death that can be prevented by pre-treatment with a cathepsin B inhibitor. TQ induced apoptosis, as determined by an increase in PI and Annexin V positive cells. However, apoptosis appears to be caspase-independent due to failure of the caspase inhibitor z-VAD-FMK to prevent cell death and absence of the typical apoptosis related signature DNA fragmentation. Inhibition of autophagy is an exciting and emerging strategy in cancer therapy. In this vein, our results describe a

  11. Plant programmed cell death and the point of no return

    NARCIS (Netherlands)

    Doorn, van W.G.

    2005-01-01

    The point of no return during programmed cell death (PCD) is defined as the step beyond which the cell is irreversibly committed to die. Some plant cells can be saved before this point by inducing the formation of functional chloroplasts. A visibly senescent tissue will then become green again and l

  12. Fingerprints in cancer cells

    International Nuclear Information System (INIS)

    Gene research has shown that factors causing cancer, or carcinogens, may leave marks typical of each particular carcinogen (fingerprints) in the genotype of the cell. Radiation, for instance, may leave such fingerprints in a cancer cell. In particular, the discovery of a gene called p53 has yielded much new information on fingerprints. It has been discovered, for example, that toxic fungus and UV-radiation each leave fingerprints in the p53 gene. Based on the detection of fingerprints, it may be possible in the future to tell a cancer patient what factor had trigged the maglinancy

  13. The process and promotion of radiation-induced cell death

    International Nuclear Information System (INIS)

    Radiation-induced cell death is divided into reproductive and interphase death, whose process can be revealed by time-lapse observations. Pedigree analyses of progenies derived from a surviving progenitor cell have shown that moribund cells appear in clusters among cells which are apparently undamaged (lethal sectoring). Sister cell fusion, which likely results from chromosome bridge, is the most frequently observed cell abnormality leading to reproductive death. While interphase death does not occur unless the dose exceeds 10 Gy for low LET radiation such as X-rays, high-LET radiation is very effective at inducing interphase death (RBE: ≅3 at 230 keV/μm). Expression or fixation of potentially lethal damage (PLD) is closely associated with cell cycle events and enhanced by inducing premature chromosome condensation (PCC) at a nonpermissive temperature in tsBN2 cells with a ts-defect in RCC1 protein (a regulator of chromatin condensation) which monitors the completion of DNA replication. Furthermore, higher-order structural changes in nuclear matrix such as induced by leptomycin B, an inhibitor of CRM1 (chromosome region maintenance) protein, also play an important role in the fixation of PLD. (author)

  14. Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity.

    Science.gov (United States)

    Roque-Navarro, Lourdes; Chakrabandhu, Krittalak; de León, Joel; Rodríguez, Sandra; Toledo, Carlos; Carr, Adriana; de Acosta, Cristina Mateo; Hueber, Anne-Odile; Pérez, Rolando

    2008-07-01

    Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid-containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4(+) T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab')(2) but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy. PMID:18645013

  15. Targeted therapy for squamous cell lung cancer

    OpenAIRE

    Liao, Rachel G.; Watanabe, Hideo; Meyerson, Matthew; Hammerman, Peter S.

    2012-01-01

    Lung squamous cell carcinoma (SqCC) is the second most common subtype of non-small-cell lung cancer and leads to 40,000–50,000 deaths per year in the USA. Management of non-small-cell lung cancer has dramatically changed over the past decade with the introduction of targeted therapeutic agents for genotypically selected individuals with lung adenocarcinoma. These agents lead to improved outcomes, and it has now become the standard of care to perform routine molecular genotyping of lung adenoc...

  16. Pro-apoptotic NOXA is implicated in atmospheric-pressure plasma-induced melanoma cell death

    Science.gov (United States)

    Ishaq, M.; Bazaka, K.; Ostrikov, K.

    2015-11-01

    Atmospheric-pressure plasma (APP) has been successfully used to treat several types of cancers in vivo and in vitro, with the effect being primarily attributed to the generation of reactive oxygen species (ROS). However, the mechanisms by which APP induces apoptosis in cancer cells require further elucidation. In this study, the effects of APP on the expression of 500 genes in melanoma Mel007 cancer cells were examined. Pro-apoptotic phorbol-12-myristate-13-acetate-induced protein (PMAIP1), also known as NOXA, was highly expressed as a result of APP treatment in a dose-dependent manner. Blocking of ROS using scavenger NAC or silencing of NOXA gene by RNA interference inhibited the APP-induced NOXA genes upregulation and impaired caspases 3/7 mediated apoptosis, confirming the important role plasma-generated ROS species and pro-apoptotic NOXA play in APP-induced cancer cell death.

  17. Prostate cancer stem cells

    OpenAIRE

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  18. Measuring Cell Death by Propidium Iodide Uptake and Flow Cytometry.

    Science.gov (United States)

    Crowley, Lisa C; Scott, Adrian P; Marfell, Brooke J; Boughaba, Jeanne A; Chojnowski, Grace; Waterhouse, Nigel J

    2016-01-01

    Propidium iodide (PI) is a small fluorescent molecule that binds to DNA but cannot passively traverse into cells that possess an intact plasma membrane. PI uptake versus exclusion can be used to discriminate dead cells, in which plasma membranes become permeable regardless of the mechanism of death, from live cells with intact membranes. PI is excited by wavelengths between 400 and 600 nm and emits light between 600 and 700 nm, and is therefore compatible with lasers and photodetectors commonly available in flow cytometers. This protocol for PI staining can be used to quantitate cell death in most modern research facilities and universities. PMID:27371595

  19. T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

    Science.gov (United States)

    Chiu, Chang-Fang; Weng, Jing-Ru; Jadhav, Appaso; Wu, Chia-Yung; Sargeant, Aaron M.; Bai, Li-Yuan

    2016-01-01

    T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy. PMID:27537872

  20. Comprehensive genomic characterization of squamous cell lung cancers

    NARCIS (Netherlands)

    Hammerman, Peter S.; Lawrence, Michael S.; Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Sivachenko, Andrey; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Sougnez, Carrie; Imielinski, Marcin; Helman, Elena; Hernandez, Bryan; Pho, Nam H.; Meyerson, Matthew; Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Sipahimalani, Payal; Stoll, Dominik; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron S. N.; Chuah, Eric; Coope, Robin J. N.; Corbett, Richard; Dhalla, Noreen; Guin, Ranabir; Hirst, Anhe Carrie; Hirst, Martin; Holt, Robert A.; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Mungall, Karen; Nip, Ka Ming; Olshen, Adam; Schein, Jacqueline E.; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard; Zeng, Thomas; Zhao, Yongjun; Jones, Steven J. M.; Marra, Marco A.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Hammerman, Peter S.; Getz, Gad; Meyerson, Matthew; Protopopov, Alexei; Zhang, Jianhua; Hadjipanayis, Angela; Lee, Semin; Xi, Ruibin; Yang, Lixing; Ren, Xiaojia; Zhang, Hailei; Shukla, Sachet; Chen, Peng-Chieh; Haseley, Psalm; Lee, Eunjung; Chin, Lynda; Park, Peter J.; Kucherlapati, Raju; Socci, Nicholas D.; Liang, Yupu; Schultz, Nikolaus; Borsu, Laetitia; Lash, Alex E.; Viale, Agnes; Sander, Chris; Ladanyi, Marc; Auman, J. Todd; Hoadley, Katherine A.; Wilkerson, Matthew D.; Shi, Yan; Liquori, Christina; Meng, Shaowu; Li, Ling; Turman, Yidi J.; Topal, Michael D.; Tan, Donghui; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Jones, Corbin D.; Mieczkowski, Piotr A.; Singh, Darshan; Wu, Junyuan; Gulabani, Anisha; Dolina, Peter; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew G.; Mose, Lisle E.; Jefferys, Stuart R.; Balu, Saianand; O'Connor, Brian D.; Prins, Jan F.; Liu, Jinze; Chiang, Derek Y.; Hayes, D. Neil; Perou, Charles M.; Cope, Leslie; Danilova, Ludmila; Weisenberger, Daniel J.; Maglinte, Dennis T.; Pan, Fei; Van den Berg, David J.; Triche, Timothy; Herman, James G.; Baylin, Stephen B.; Laird, Peter W.; Getz, Gad; Noble, Michael; Voet, Doug; Saksena, Gordon; Gehlenborg, Nils; DiCara, Daniel; Zhang, Jinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Lawrence, Michael S.; Zou, Lihua; Sivachenko, Andrey; Lin, Pei; Stojanov, Petar; Jing, Rui; Cho, Juok; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill; Park, Peter J.; Chin, Lynda; Schultz, Nikolaus; Sinha, Rileen; Ciriello, Giovanni; Cerami, Ethan; Gross, Benjamin; Jacobsen, Anders; Gao, Jianjiong; Aksoy, B. Arman; Weinhold, Nils; Ramirez, Ricardo; Taylor, Barry S.; Antipin, Yevgeniy; Reva, Boris; Shen, Ronglai; Mo, Qianxing; Seshan, Venkatraman; Paik, Paul K.; Ladanyi, Marc; Sander, Chris; Akbani, Rehan; Zhang, Nianxiang; Broom, Bradley M.; Casasent, Tod; Unruh, Anna; Wakefield, Chris; Cason, R. Craig; Baggerly, Keith A.; Weinstein, John N.; Haussler, David; Benz, Christopher C.; Stuart, Joshua M.; Zhu, Jingchun; Szeto, Christopher; Scott, Gary K.; Yau, Christina; Ng, Sam; Goldstein, Ted; Waltman, Peter; Sokolov, Artem; Ellrott, Kyle; Collisson, Eric A.; Zerbino, Daniel; Wilks, Christopher; Ma, Singer; Craft, Brian; Wilkerson, Matthew D.; Auman, J. Todd; Hoadley, Katherine A.; Du, Ying; Cabanski, Christopher; Walter, Vonn; Singh, Darshan; Wu, Junyuan; Gulabani, Anisha; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew G.; Mose, Lisle E.; Jefferys, Stuart R.; Balu, Saianand; Marron, J. S.; Liu, Yufeng; Wang, Kai; Liu, Jinze; Prins, Jan F.; Hayes, D. Neil; Perou, Charles M.; Creighton, Chad J.; Zhang, Yiqun; Travis, William D.; Rekhtman, Natasha; Yi, Joanne; Aubry, Marie C.; Cheney, Richard; Dacic, Sanja; Flieder, Douglas; Funkhouser, William; Illei, Peter; Myers, Jerome; Tsao, Ming-Sound; Penny, Robert; Mallery, David; Shelton, Troy; Hatfield, Martha; Morris, Scott; Yena, Peggy; Shelton, Candace; Sherman, Mark; Paulauskis, Joseph; Meyerson, Matthew; Baylin, Stephen B.; Govindan, Ramaswamy; Akbani, Rehan; Azodo, Ijeoma; Beer, David; Bose, Ron; Byers, Lauren A.; Carbone, David; Chang, Li-Wei; Chiang, Derek; Chu, Andy; Chun, Elizabeth; Collisson, Eric; Cope, Leslie; Creighton, Chad J.; Danilova, Ludmila; Ding, Li; Getz, Gad; Hammerman, Peter S.; Hayes, D. Neil; Hernandez, Bryan; Herman, James G.; Heymach, John; Ida, Cristiane; Imielinski, Marcin; Johnson, Bruce; Jurisica, Igor; Kaufman, Jacob; Kosari, Farhad; Kucherlapati, Raju; Kwiatkowski, David; Ladanyi, Marc; Lawrence, Michael S.; Maher, Christopher A.; Mungall, Andy; Ng, Sam; Pao, William; Peifer, Martin; Penny, Robert; Robertson, Gordon; Rusch, Valerie; Sander, Chris; Schultz, Nikolaus; Shen, Ronglai; Siegfried, Jill; Sinha, Rileen; Sivachenko, Andrey; Sougnez, Carrie; Stoll, Dominik; Stuart, Joshua; Thomas, Roman K.; Tomaszek, Sandra; Tsao, Ming-Sound; Travis, William D.; Vaske, Charles; Weinstein, John N.; Weisenberger, Daniel; Wheeler, David; Wigle, Dennis A.; Wilkerson, Matthew D.; Wilks, Christopher; Yang, Ping; Zhang, Jianjua John; Jensen, Mark A.; Sfeir, Robert; Kahn, Ari B.; Chu, Anna L.; Kothiyal, Prachi; Wang, Zhining; Snyder, Eric E.; Pontius, Joan; Pihl, Todd D.; Ayala, Brenda; Backus, Mark; Walton, Jessica; Baboud, Julien; Berton, Dominique L.; Nicholls, Matthew C.; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter A.; Alonso, Shelley; Sanbhadti, Rashmi N.; Barletta, Sean P.; Greene, John M.; Pot, David A.; Tsao, Ming-Sound; Bandarchi-Chamkhaleh, Bizhan; Boyd, Jeff; Weaver, JoEllen; Wigle, Dennis A.; Azodo, Ijeoma A.; Tomaszek, Sandra C.; Aubry, Marie Christine; Ida, Christiane M.; Yang, Ping; Kosari, Farhad; Brock, Malcolm V.; Rogers, Kristen; Rutledge, Marian; Brown, Travis; Lee, Beverly; Shin, James; Trusty, Dante; Dhir, Rajiv; Siegfried, Jill M.; Potapova, Olga; Fedosenko, Konstantin V.; Nemirovich-Danchenko, Elena; Rusch, Valerie; Zakowski, Maureen; Iacocca, Mary V.; Brown, Jennifer; Rabeno, Brenda; Czerwinski, Christine; Petrelli, Nicholas; Fan, Zhen; Todaro, Nicole; Eckman, John; Myers, Jerome; Rathmell, W. Kimryn; Thorne, Leigh B.; Huang, Mei; Boice, Lori; Hill, Ashley; Penny, Robert; Mallery, David; Curley, Erin; Shelton, Candace; Yena, Peggy; Morrison, Carl; Gaudioso, Carmelo; Bartlett, Johnm. S.; Kodeeswaran, Sugy; Zanke, Brent; Sekhon, Harman; David, Kerstin; Juhl, Hartmut; Van Le, Xuan; Kohl, Bernard; Thorp, Richard; Tien, Nguyen Viet; Van Bang, Nguyen; Sussman, Howard; Phu, Bui Duc; Hajek, Richard; PhiHung, Nguyen; Khan, Khurram Z.; Muley, Thomas; Shaw, Kenna R. Mills; Sheth, Margi; Yang, Liming; Buetow, Ken; Davidsen, Tanja; Demchok, John A.; Eley, Greg; Ferguson, Martin; Dillon, Laura A. L.; Schaefer, Carl; Guyer, Mark S.; Ozenberger, Bradley A.; Palchik, Jacqueline D.; Peterson, Jane; Sofia, Heidi J.; Thomson, Elizabeth; Meyerson, Matthew

    2012-01-01

    Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment.

  1. Triptolide induces apoptotic cell death of human cholangiocarcinoma cells through inhibition of myeloid cell leukemia-1

    International Nuclear Information System (INIS)

    Cholangiocarcinoma (CCA), a devastating neoplasm, is highly resistant to current chemotherapies. CCA cells frequently overexpress the antiapoptotic protein myeloid cell leukemia-1(Mcl-1), which is responsible for its extraordinary ability to evade cell death. Triptolide, a bioactive ingredient extracted from Chinese medicinal plant, has been shown to inhibit cell proliferation and induce apoptosis in several cancers. CCK-8 assay was performed to detect cell survival rate in vitro. DAPI staining and Flow cytometry were used to analyze apoptosis. Western blot was performed to determine the expression levels of caspase-3, caspase-7, caspase-9, PARP, and Mcl-1. Quantitative real-time PCR and immunofluorescence were used to detect the expression levels of Mcl-1. The nude mice xenograft model was used to evaluate the antitumor effect of triptolide in vivo. Triptolide reduced cell viability in cholangiocarcinoma cell lines in a dose- and time-dependent manner, with IC50 values of 12.6 ± 0.6 nM, 20.5 ± 4.2 nM, and 18.5 ± 0.7 nM at 48 h for HuCCT1, QBC939, and FRH0201 respectively. Triptolide induced apoptosis in CCA cell lines in part through mitochondrial pathway. Using quantitative real-time PCR, western blot and immunofluorescence, we have shown that triptolide downregulates Mcl-1 mRNA and protein levels. Furthermore, triptolide inhibited the CCA growth in vivo. Triptolide has profound antitumor effect on CCA, probably by inducing apoptosis through inhibition of Mcl-1. Triptolide would be a promising therapeutic agent for CCA

  2. Bax-induced cell death in Candida albicans.

    Science.gov (United States)

    De Smet, Kris; Eberhardt, Ines; Reekmans, Rieka; Contreras, Roland

    2004-12-01

    Bax is a pro-apoptotic member of the Bcl-2 family of proteins involved in the regulation of genetically programmed cell death in mammalian cells. It has been shown that heterologous expression of Bax in several yeast species, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe and Pichia pastoris, also induces cell death. In this study we investigated the effects of Bax expression in the pathogenic yeast Candida albicans. Cell death inducing expression of Bax required a synthetic BAX gene that was codon-optimized for expression in Candida albicans. Expression of this BAX gene resulted in growth inhibition and cell death. By fusing Bax with the yeast enhanced green fluorescent protein of Aequoria victoria, the cell death-inducing effect of Bax was increased due to reduced proteolytic degradation of Bax. Using this fusion protein we showed that, upon expression in C. albicans, Bax co-localizes with the mitochondria. Furthermore, we showed for the first time that expression of Bax in yeast causes the mitochondria, which are normally distributed throughout the cell, to cluster in the perinuclear region. PMID:15565645

  3. Stem Cells and Cancer

    International Nuclear Information System (INIS)

    Stem cell research has thrived over the last years due to their therapeutic and regenerative potential. Scientific breakthroughs in the field are immediately translated from the scientific journals to the mass media, which is not surprising as the characterisation of the molecular mechanisms that regulate the biology of stem cells is crucial for the treatment of degenerative and cardiovascular diseases, as well as cancer. In the Molecular Oncology Unit at Ciemat we work to unravel the role of cancer stem cells in tumour development, and to find new antitumor therapies. (Author)

  4. Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Ch(a)vez-Gal(a)n L; Arenas-Del Angel MC; Zenteno E; Ch(a)vez R; Lascurain R

    2009-01-01

    One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8+T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lyric molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis.

  5. Staurosporine induces different cell death forms in cultured rat astrocytes

    International Nuclear Information System (INIS)

    Astroglial cells are frequently involved in malignant transformation. Besides apoptosis, necroptosis, a different form of regulated cell death, seems to be related with glioblastoma genesis, proliferation, angiogenesis and invasion. In the present work we elucidated mechanisms of necroptosis in cultured astrocytes, and compared them with apoptosis, caused by staurosporine. Cultured rat cortical astrocytes were used for a cell death studies. Cell death was induced by different concentrations of staurosporine, and modified by inhibitors of apoptosis (z-vad-fmk) and necroptosis (nec-1). Different forms of a cell death were detected using flow cytometry. We showed that staurosporine, depending on concentration, induces both, apoptosis as well as necroptosis. Treatment with 10−7 M staurosporine increased apoptosis of astrocytes after the regeneration in a staurosporine free medium. When caspases were inhibited, apoptosis was attenuated, while necroptosis was slightly increased. Treatment with 10−6 M staurosporine induced necroptosis that occurred after the regeneration of astrocytes in a staurosporine free medium, as well as without regeneration period. Necroptosis was significantly attenuated by nec-1 which inhibits RIP1 kinase. On the other hand, the inhibition of caspases had no effect on necroptosis. Furthermore, staurosporine activated RIP1 kinase increased the production of reactive oxygen species, while an antioxidant BHA significantly attenuated necroptosis. Staurosporine can induce apoptosis and/or necroptosis in cultured astrocytes via different signalling pathways. Distinction between different forms of cell death is crucial in the studies of therapy-induced necroptosis

  6. Cancer Stem Cells in Pancreatic Cancer

    International Nuclear Information System (INIS)

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer

  7. Early cell death detection with digital holographic microscopy.

    Directory of Open Access Journals (Sweden)

    Nicolas Pavillon

    Full Text Available BACKGROUND: Digital holography provides a non-invasive measurement of the quantitative phase shifts induced by cells in culture, which can be related to cell volume changes. It has been shown previously that regulation of cell volume, in particular as it relates to ionic homeostasis, is crucially involved in the activation/inactivation of the cell death processes. We thus present here an application of digital holographic microscopy (DHM dedicated to early and label-free detection of cell death. METHODS AND FINDINGS: We provide quantitative measurements of phase signal obtained on mouse cortical neurons, and caused by early neuronal cell volume regulation triggered by excitotoxic concentrations of L-glutamate. We show that the efficiency of this early regulation of cell volume detected by DHM, is correlated with the occurrence of subsequent neuronal death assessed with the widely accepted trypan blue method for detection of cell viability. CONCLUSIONS: The determination of the phase signal by DHM provides a simple and rapid optical method for the early detection of cell death.

  8. Metallodrug induced apoptotic cell death and survival attempts are characterizable by Raman spectroscopy

    Science.gov (United States)

    le Roux, K.; Prinsloo, L. C.; Meyer, D.

    2014-09-01

    Chrysotherapeutics are under investigation as new or additional treatments for different types of cancers. In this study, gold complexes were investigated for their anticancer potential using Raman spectroscopy. The aim of the study was to determine whether Raman spectroscopy could be used for the characterization of metallodrug-induced cell death. Symptoms of cell death such as decreased peak intensities of proteins bonds and phosphodiester bonds found in deoxyribose nucleic acids were evident in the principal component analysis of the spectra. Vibrational bands around 761 cm-1 and 1300 cm-1 (tryptophan, ethanolamine group, and phosphatidylethanolamine) and 1720 cm-1 (ester bonds associated with phospholipids) appeared in the Raman spectra of cervical adenocarcinoma (HeLa) cells after metallodrug treatment. The significantly (p cancer cells under chemical stress. Cancer cells excrete chemotherapeutics to improve their chances of survival and utilize glucose to achieve this. Raman spectroscopy was able to monitor a survival strategy of cancer cells in the form of glucose uptake to alleviate chemical stress. Raman spectroscopy was invaluable in obtaining molecular information generated by biomolecules affected by anticancer metallodrug treatments and presents an alternative to less reproducible, conventional biochemical assays for cytotoxicity analyses.

  9. Talking about death with children with incurable cancer: perspectives from parents.

    OpenAIRE

    Geerst, I.M.M. van der; Heuvel-Eibrink, M.M. van den; Vliet, L.M. van; Pluijm, S. M. F.; Streng, I.C.; Michiels, E.M.C.; Pieters, R; Darlington A.S.E.

    2015-01-01

    Objective: To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer. Study design: We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conver...

  10. Markers of small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Sharma SK

    2004-05-01

    Full Text Available Abstract Lung cancer is the number one cause of cancer death; however, no specific serum biomarker is available till date for detection of early lung cancer. Despite good initial response to chemotherapy, small-cell lung cancer (SCLC has a poor prognosis. Therefore, it is important to identify molecular markers that might influence survival and may serve as potential therapeutic targets. The review aims to summarize the current knowledge of serum biomarkers in SCLC to improve diagnostic efficiency in the detection of tumor progression in lung cancer. The current knowledge on the known serum cytokines and tumor biomarkers of SCLC is emphasized. Recent findings in the search for novel diagnostic and therapeutic molecular markers using the emerging genomic technology for detecting lung cancer are also described. It is believed that implementing these new research techniques will facilitate and improve early detection, prognostication and better treatment of SCLC.

  11. Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Adam Cisterne

    Full Text Available Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1. There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers.

  12. Silencer of Death Domains Controls Cell Death through Tumour Necrosis Factor-Receptor 1 and Caspase-10 in Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Khan, Naveed I.; Welschinger, Robert; Basnett, Jordan; Fung, Carina; Rizos, Helen; Bradstock, Kenneth F.; Bendall, Linda J.

    2014-01-01

    Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL) cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC) incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1). There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD) was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers. PMID:25061812

  13. Programmed cell death in plants: A chloroplastic connection

    OpenAIRE

    Ambastha, Vivek; Tripathy, Baishnab C; Tiwari, Budhi Sagar

    2015-01-01

    Programmed cell death (PCD) is an integral cellular program by which targeted cells culminate to demise under certain developmental and pathological conditions. It is essential for controlling cell number, removing unwanted diseased or damaged cells and maintaining the cellular homeostasis. The details of PCD process has been very well elucidated and characterized in animals but similar understanding of the process in plants has not been achieved rather the field is still in its infancy that ...

  14. Photothermal reshaping of gold nanorods prevents further cell death

    International Nuclear Information System (INIS)

    The combined use of phosphatidylcholine passivated gold nanorods (PC-NRs) and pulsed near-infrared (near-IR) irradiation resulted in cell death. Pulsed near-IR laser irradiation also induced reshaping of PC-NRs into spherical nanoparticles. Since reshaped particles showed no absorption in the near-IR region, successive laser irradiation did not affect cells. Photo-reshaping of PC-NRs is expected to be advantageous in preventing unwanted cell damage following destruction of target cells

  15. Diagnosis of Cell Death by Means of Infrared Spectroscopy

    OpenAIRE

    Zelig, Udi; Kapelushnik, Joseph; Moreh, Raymond; Mordechai, Shaul; Nathan, Ilana

    2009-01-01

    Fourier transform infrared (FTIR) spectroscopy has been established as a fast spectroscopic method for biochemical analysis of cells and tissues. In this research we aimed to investigate FTIR's utility for identifying and characterizing different modes of cell death, using leukemic cell lines as a model system. CCRF-CEM and U937 leukemia cells were treated with arabinoside and doxorubicin apoptosis inducers, as well as with potassium cyanide, saponin, freezing-thawing, and H2O2 necrosis induc...

  16. Porcine circovirus-2 capsid protein induces cell death in PK15 cells

    International Nuclear Information System (INIS)

    Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization

  17. Porcine circovirus-2 capsid protein induces cell death in PK15 cells

    Energy Technology Data Exchange (ETDEWEB)

    Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark; Czub, Markus

    2014-11-15

    Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.

  18. Anti-Yo Antibody Uptake and Interaction with Its Intracellular Target Antigen Causes Purkinje Cell Death in Rat Cerebellar Slice Cultures: A Possible Mechanism for Paraneoplastic Cerebellar Degeneration in Humans with Gynecological or Breast Cancers

    OpenAIRE

    Greenlee, John E.; Clawson, Susan A; Hill, Kenneth E; Wood, Blair; Clardy, Stacey L.; Tsunoda, Ikuo; Carlson, Noel G.

    2015-01-01

    Anti-Yo antibodies are immunoglobulin G (IgG) autoantibodies reactive with a 62 kDa Purkinje cell cytoplasmic protein. These antibodies are closely associated with paraneoplastic cerebellar degeneration in the setting of gynecological and breast malignancies. We have previously demonstrated that incubation of rat cerebellar slice cultures with patient sera and cerebrospinal fluid containing anti-Yo antibodies resulted in Purkinje cell death. The present study addressed three fundamental quest...

  19. Mitochondrial regulation of cell death: a phylogenetically conserved control

    Directory of Open Access Journals (Sweden)

    Lorenzo Galluzzi

    2016-02-01

    Full Text Available Mitochondria are fundamental for eukaryotic cells as they participate in critical catabolic and anabolic pathways. Moreover, mitochondria play a key role in the signal transduction cascades that precipitate many (but not all regulated variants of cellular demise. In this short review, we discuss the differential implication of mitochondria in the major forms of regulated cell death.

  20. Cancer Stem Cells

    OpenAIRE

    Aurelio Lorico; Eric Deutsch; Bo Lu; Shih-Hwa Chiou

    2011-01-01

    Cancer Stem Cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. A number of cell surface markers such as CD44, CD24, and CD133 are often used to identify and enrich CSCs. A regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways controls the CSC properties. The clinical relevance of CSCs has been strengthened by emerging evidence,...

  1. Public reaction to the death of Steve Jobs: implications for cancer communication.

    Science.gov (United States)

    Myrick, Jessica Gall; Noar, Seth M; Willoughby, Jessica Fitts; Brown, Jennifer

    2014-01-01

    The present study aimed to examine the public reaction to the death of Steve Jobs, focusing on general and cancer-specific information seeking and interpersonal communication. Shortly after Jobs's death, employees from a large university in the Southeastern United States (N = 1,398) completed a web-based survey. Every employee had heard about Steve Jobs's death, and 97% correctly identified pancreatic cancer as the cause of his death. General (50%) and pancreatic cancer-specific (7%) information seeking, as well as general (74%) and pancreatic cancer-specific (17%) interpersonal communication, took place in response to Steve Jobs's death. In multivariate logistic regression analyses controlling for demographics and several cancer-oriented variables, both identification with Steve Jobs and cancer worry in response to Steve Jobs's death significantly (p < .05) predicted pancreatic cancer information seeking as well as interpersonal communication about pancreatic cancer. Additional analyses revealed that cancer worry partially mediated the effects of identification on these outcome variables. Implications of these results for future research as well as cancer prevention and communication efforts are discussed. PMID:24716627

  2. Bioengineering Embryonic Stem Cell Microenvironments for the Study of Breast Cancer

    OpenAIRE

    Yubing Xie; Bridget M. Mooney; Nurazhani Abdul Raof

    2011-01-01

    Breast cancer is the most prevalent disease amongst women worldwide and metastasis is the main cause of death due to breast cancer. Metastatic breast cancer cells and embryonic stem (ES) cells display similar characteristics. However, unlike metastatic breast cancer cells, ES cells are nonmalignant. Furthermore, embryonic microenvironments have the potential to convert metastatic breast cancer cells into a less invasive phenotype. The creation of in vitro embryonic microenvironments will enab...

  3. HPMA conjugates and immunogenic cancer cell death

    Czech Academy of Sciences Publication Activity Database

    Kovář, Lubomír; Etrych, Tomáš; Kabešová, Martina; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

    2009-01-01

    Roč. 39, - (2009), s. 523-523. ISSN 0014-2980. [European Congress of Immunology /2./. 13.09.2009-16.09.2009, Berlin] Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : doxorubicin * tumor Subject RIV: EC - Immunology

  4. Betanin-Enriched Red Beetroot (Beta vulgaris L.) Extract Induces Apoptosis and Autophagic Cell Death in MCF-7 Cells.

    Science.gov (United States)

    Nowacki, Laëtitia; Vigneron, Pascale; Rotellini, Laura; Cazzola, Hélène; Merlier, Franck; Prost, Elise; Ralanairina, Robert; Gadonna, Jean-Pierre; Rossi, Claire; Vayssade, Muriel

    2015-12-01

    Recent studies have pointed out the preventive role of beetroot extracts against cancers and their cytotoxic activity on cancer cells. Among many different natural compounds, these extracts contained betanin and its stereoisomer isobetanin, which belongs to the betalain group of highly bioavailable antioxidants. However, a precise identification of the molecules responsible for this tumor-inhibitory effect was still required. We isolated a betanin/isobetanin concentrate from fresh beetroots, corresponding to the highest purified betanin extract used for studying anticancer activities of these molecules. The cytotoxicity of this betanin-enriched extract was then characterized on cancer and normal cells and we highlighted the death signalling pathways involved. Betanin/isobetanin concentrate significantly decreased cancer cell proliferation and viability. Particularly in MCF-7-treated cells, the expressions of apoptosis-related proteins (Bad, TRAILR4, FAS, p53) were strongly increased and the mitochondrial membrane potential was altered, demonstrating the involvement of both intrinsic and extrinsic apoptotic pathways. Autophagosome vesicles in MCF-7-treated cells were observed, also suggesting autophagic cell death upon betanin/isobetanin treatment. Importantly, the betanin-enriched extract had no obvious effect towards normal cell lines. Our data bring new insight to consider the betanin/isobetanin mix as therapeutic anticancer compound, alone or in combination with classical chemotherapeutic drugs, especially in functional p53 tumors. PMID:26463240

  5. Modeling cell-death patterning during biofilm formation

    International Nuclear Information System (INIS)

    Self-organization by bacterial cells often leads to the formation of a highly complex spatially-structured biofilm. In such a bacterial biofilm, cells adhere to each other and are embedded in a self-produced extracellular matrix (ECM). Bacillus substilis bacteria utilize localized cell-death patterns which focuses mechanical forces to form wrinkled sheet-like structures in three dimensions. A most intriguing feature underlying this biofilm formation is that vertical buckling and ridge location is biased to occur in region of high cell-death. Here we present a spatially extended model to investigate the role of the bacterial secreted ECM during the biofilm formation and the self-organization of cell-death. Using this reaction-diffusion model we show that the interaction between the cell's motion and the ECM concentration gives rise to a self-trapping instability, leading to variety of cell-death patterns. The resultant spot patterns generated by our model are shown to be in semi-quantitative agreement with recent experimental observation. (paper)

  6. Influence on cell death of high frequency motion of magnetic nanoparticles during magnetic hyperthermia experiments

    Science.gov (United States)

    Hallali, N.; Clerc, P.; Fourmy, D.; Gigoux, V.; Carrey, J.

    2016-07-01

    Studies with transplanted tumors in animals and clinical trials have provided the proof-of-concept of magnetic hyperthermia (MH) therapy of cancers using iron oxide nanoparticles. Interestingly, in several studies, the application of an alternating magnetic field (AMF) to tumor cells having internalized and accumulated magnetic nanoparticles (MNPs) into their lysosomes can induce cell death without detectable temperature increase. To explain these results, among other hypotheses, it was proposed that cell death could be due to the high-frequency translational motion of MNPs under the influence of the AMF gradient generated involuntarily by most inductors. Such mechanical actions of MNPs might cause cellular damages and participate in the induction of cell death under MH conditions. To test this hypothesis, we developed a setup maximizing this effect. It is composed of an anti-Helmholtz coil and two permanent magnets, which produce an AMF gradient and a superimposed static MF. We have measured the MNP heating power and treated tumor cells by a standard AMF and by an AMF gradient, on which was added or not a static magnetic field. We showed that the presence of a static magnetic field prevents MNP heating and cell death in standard MH conditions. The heating power of MNPs in an AMF gradient is weak, position-dependent, and related to the presence of a non-zero AMF. Under an AMF gradient and a static field, no MNP heating and cell death were measured. Consequently, the hypothesis that translational motions could be involved in cell death during MH experiments is ruled out by our experiments.

  7. Cancer Stem Cells in Breast Cancer

    OpenAIRE

    Fumitaka Takeshita; Tomohiro Fujiwara; Takahiro Ochiya; Makiko Ono; Ryou-u Takahashi

    2011-01-01

    The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cel...

  8. Signal transduction events in aluminum-induced cell death in tomato suspension cells

    NARCIS (Netherlands)

    Iakimova, E.T.; Kapchina-Toteva, V.M.; Woltering, E.J.

    2007-01-01

    In this study, some of the signal transduction events involved in AlCl3-induced cell death in tomato (Lycopersicon esculentum Mill.) suspension cells were elucidated. Cells treated with 100 ¿M AlCl3 showed typical features of programmed cell death (PCD) such as nuclear and cytoplasmic condensation.

  9. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines

    OpenAIRE

    Higuchi, M; Kudo, T; Suzuki, S.; Evans, TT; Sasaki, R.; Wada, Y; Shirakawa, T.; Sawyer, JR; Gotoh, A

    2006-01-01

    Prostate cancer progresses from an androgen-dependent to androgen-independent stage after androgen ablation therapy. Mitochondrial DNA plays a role in cell death and metastatic competence. Further, heteroplasmic large-deletion mitochondrial DNA is verycommon in prostate cancer. To investigate the role of mitochondrial DNA in androgen dependence of prostate cancers, we tested the changes of normal and deleted mitochondrial DNA in accordance with the progression of prostate cancer. We demonstra...

  10. Programmed Cell Death During Female Gametophyte Development

    Energy Technology Data Exchange (ETDEWEB)

    Drews, Gary, N.

    2004-09-15

    Endosperm is a storage tissue in the angiosperm seed that is important both biologically and agriculturally. Endosperm is biologically important because it provides nutrients to the embryo during seed development and agriculturally important because it is a significant source of food, feed, and industrial raw materials. Approximately two-thirds of human calories are derived from endosperm, either directly or indirectly through animal feed. Furthermore, endosperm is used as a raw material for numerous industrial products including ethanol. A major event in endosperm development is the transition between the syncytial phase, during which the endosperm nuclei undergo many rounds of mitosis without cytokinesis, and the cellularized phase, during which cell walls form around the endosperm nuclei. Understanding how the syncytial-cellular transition is regulated is agriculturally important because it influences seed size, seed sink strength, and grain weight. However, the molecular processes controlling this transition are not understood. This project led to the identification of the AGL62 gene that regulates the syncytial-cellular transition during endosperm development. AGL62 is expressed during the syncytial phase and suppresses endosperm cellularization during this period. AGL62 most likely does so by suppressing the expression of genes required for cellularization. At the end of the syncytial phase, the FIS PcG complex suppresses AGL62 expression, which allows expression of the cellularization genes and triggers the initiation of the cellularized phase. Endosperm arises following fertilization of the central cell within the female gametophyte. This project also led to the identification of the AGL80 gene that is required for development of the central cell into the endosperm. Within the ovule and seed, AGL80 is expressed exclusively in the central cell and uncellularized endosperm. AGL80 is required for expression of several central cell-expressed genes, including

  11. Preference for place-of-death among terminally ill cancer patients in Denmark

    DEFF Research Database (Denmark)

    Neergaard, Mette Asbjørn; Jensen, Anders Bonde; Sondergaard, Jens;

    2011-01-01

    Scand J Caring Sci; 2011 Preference for place-of-death among terminally ill cancer patients in Denmark Achieving home death is often seen as an important endpoint in palliative care, but no studies of the preferred place-of-death have yet been conducted in Scandinavia. Furthermore, we do not know...... if professionals' report on deceased patients' preference of place-of-death is a valid information. The aim of this study was to describe where terminally ill Danish cancer patients prefer to die and to determine if their preference changed during the palliative period, as reported retrospectively by...... had died from 1 March to 30 November 2006 and were identified through merging of health registers. Relatives returned 198 questionnaires about patients' preferred place-of-death, GPs 333 and CNs 201. The study showed that most terminally ill cancer patients preferred home death (up to 80.7%). The...

  12. Quantum algorithm for programmed cell death of Caenorhabditis elegans

    International Nuclear Information System (INIS)

    During the development of Caenorhabditis elegans, through cell divisions, a total of exactly 1090 cells are generated, 131 of which undergo programmed cell death (PCD) to result in an adult organism comprising 959 cells. Of those 131, exactly 113 undergo PCD during embryogenesis, subdivided across the cell lineages in the following fashion: 98 for AB lineage; 14 for MS lineage; and 1 for C lineage. Is there a law underlying these numbers, and if there is, what could it be? Here we wish to show that the count of the cells undergoing PCD complies with the cipher laws related to the algorithms of Shor and of Grover

  13. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors

    OpenAIRE

    Subramanian, Chitra; Opipari, Anthony W.; Bian, Xin; Castle, Valerie P; Kwok, Roland P S

    2005-01-01

    Histone deacetylase inhibitors (HDACIs) are therapeutic drugs that inhibit deacetylase activity, thereby increasing acetylation of many proteins, including histones. HDACIs have antineoplastic effects in preclinical and clinical trials and are being considered for cancers with unmet therapeutic need, including neuroblastoma (NB). Uncertainty of how HDACI-induced protein acetylation leads to cell death, however, makes it difficult to determine which tumors are likely to be responsive to these ...

  14. The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

    OpenAIRE

    Lee Sun; Kim Yong-Jun; Kim Jee-Youn; Park Jae-Hoon

    2009-01-01

    Abstract Background The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenot...

  15. Role of mitochondria on muscle cell death and meat tenderization.

    Science.gov (United States)

    Sierra, Verónica; Oliván, Mamen

    2013-05-01

    The possibility that mitochondria are involved in cellular dysfunction is particularly high in situations associated with increases in free radical activity, like hypoxia or ischemia; therefore its potential role in the muscle post-mortem metabolism is reviewed. In the dying muscle, different routes of cell death catabolism (apoptosis, autophagy) may occur having great influence on the process of conversion of muscle into meat. Mitochondria are the first and also one of the main organelles affected by post-mortem changes; therefore they are decisive in the subsequent cellular responses influencing the pathway to cell demise and thus, the final meat quality. Depending on the cell death programme followed by muscle cells after exsanguination, diverse proteases would be activated to a different extent, which is also reviewed in order to understand how they affect meat tenderization. This review also summarizes recent patents relating cell death processes and meat tenderness. Further research is encouraged as there is still a need of knowledge on cell death post-mortem processes to increase our understanding of the conversion of muscle into meat. PMID:23432120

  16. Importance of Molecular Features of Non–Small Cell Lung Cancer for Choice of Treatment

    OpenAIRE

    Moran, Cesar

    2011-01-01

    Lung cancer is the leading cause of cancer-related deaths in the United States. Approximately 85% of lung cancer is categorized as non–small cell lung cancer, and traditionally, non–small cell lung cancer has been treated with surgery, radiation, and chemotherapy. Targeted agents that inhibit the epidermal growth factor receptor pathway have been developed and integrated into the treatment regimens in non–small cell lung cancer. Currently, approved epidermal growth factor receptor inhibitors ...

  17. Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

    Science.gov (United States)

    Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J; Cheng, Qiang Shawn; D'Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M; Gonzalez Guzman, Michael J; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Ryan, Elizabeth P; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H; Lowe, Leroy; Park, Hyun Ho

    2015-06-01

    Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID:26106145

  18. Hydrogen Peroxide Produced by Oral Streptococci Induces Macrophage Cell Death

    OpenAIRE

    Okahashi, Nobuo; Nakata, Masanobu; Sumitomo, Tomoko; Terao, Yutaka; Kawabata, Shigetada

    2013-01-01

    Hydrogen peroxide (H2O2) produced by members of the mitis group of oral streptococci plays important roles in microbial communities such as oral biofilms. Although the cytotoxicity of H2O2 has been widely recognized, the effects of H2O2 produced by oral streptococci on host defense systems remain unknown. In the present study, we investigated the effect of H2O2 produced by Streptococcus oralis on human macrophage cell death. Infection by S. oralis was found to stimulate cell death of a THP-1 ...

  19. Dihydroartemisinin inhibits cell proliferation via AKT/GSK3β/cyclinD1 pathway and induces apoptosis in A549 lung cancer cells

    OpenAIRE

    Liao, Kui; Li, Juan; Wang, Zhiling

    2014-01-01

    Lung cancer is the most common cause of cancer-related death in the world. The main types of lung cancer are small cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC); non small cell lung carcinoma (NSCLC) includes squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, Non small cell lung carcinoma accounts for about 80% of the total lung cancer cases. Dihydroartemisinin (DHA) inhibits cell proliferation and induces apoptosis in several cancer cell lines. The...

  20. Extragonadal Germ Cell Cancer (EGC)

    Science.gov (United States)

    ... Testicular Cancer Resource Center Extragonadal Germ Cell Cancer (EGC) 95% of all testicular tumors are germ cell ... seen in young adults. Patients with mediastinal nonseminomatous EGC are typically classed as poor risk patients because ...

  1. Sensory hair cell death and regeneration in fishes

    Directory of Open Access Journals (Sweden)

    Gopinath Rajadinakaran

    2015-04-01

    Full Text Available Sensory hair cells are specialized mechanotransductive receptors required for hearing and vestibular function. Loss of hair cells in humans and other mammals is permanent and causes reduced hearing and balance. In the early 1980’s, it was shown that hair cells continue to be added to the inner ear sensory epithelia in cartilaginous and bony fishes. Soon thereafter, hair cell regeneration was documented in the chick cochlea following acoustic trauma. Since then, research using chick and other avian models has led to great insights into hair cell death and regeneration. However, with the rise of the zebrafish as a model organism for studying disease and developmental processes, there has been an increased interest in studying sensory hair cell death and regeneration in its lateral line and inner ears. Advances derived from studies in zebrafish and other fish species include understanding the effect of ototoxins on hair cells and finding otoprotectants to mitigate ototoxin damage, the role of cellular proliferation versus direct transdifferentiation during hair cell regeneration, and elucidating cellular pathways involved in the regeneration process. This review will summarize research on hair cell death and regeneration using fish models, indicate the potential strengths and weaknesses of these models, and discuss several emerging areas of future studies.

  2. Antagonism between curcumin and the topoisomerase II inhibitor etoposide: A study of DNA damage, cell cycle regulation and death pathways

    OpenAIRE

    Saleh, Ekram M; El-Awady, Raafat A.; Eissa, Nadia A.; Abdel-Rahman, Wael M.

    2012-01-01

    The use of combinations of chemotherapy and natural products has recently emerged as a new method of cancer therapy, relying on the capacity of certain natural compounds to trigger cell death with low doses of chemotherapeutic agents and few side effects. The current study aims to evaluate the modulatory effects of curcumin (CUR), Nigella sativa (NS) and taurine on etoposide (ETP) cytotoxicity in a panel of cancer cell lines and to identify their underlying mechanisms.

  3. The influence of the surface chemistry of silver nanoparticles on cell death

    International Nuclear Information System (INIS)

    The influence of the surface chemistry of silver nanoparticles (AgNPs) on p53 mediated cell death was evaluated using human dermal fibroblast (HDF) and lung cancer (A549) cells. The citrate reduced AgNPs (C-AgNPs) were modified with either lactose (L-AgNPs) or a 12-base long oligonucleotide (O-AgNPs). Both unmodified and modified AgNPs showed increased concentration and time dependent cytotoxicity and genotoxicity causing an increased p53 up-regulation within 6 h and led to apoptotic or necrotic cell deaths. The C-AgNPs induced more cytotoxicity and cellular DNA damage than the surface modified AgNPs. Modifying the C-AgNPs with lactose or the oligonucleotide reduced both necrotic and apoptotic cell deaths in the HDF cells. The C-AgNPs caused an insignificant necrosis in A549 cells whereas the modified AgNPs caused necrosis and apoptosis in both cell types. Compared to the O-AgNPs, the L-AgNPs triggered more cellular DNA damage, which led to up-regulation of p53 gene inducing apoptosis in A549 cells compared to HDF cells. This suggests that the different surface chemistries of the AgNPs cause different cellular responses that may be important not only for their use in medicine but also for reducing their toxicity. (paper)

  4. Cancer Stem Cells in Pancreatic Cancer

    OpenAIRE

    Karl-Walter Jauch; Hendrik Seeliger; Hanno Niess; Qi Bao; Andrea Renner; Yue Zhao; Bruns, Christiane J.

    2010-01-01

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC t...

  5. Widely Used Type 2 Diabetes Drug May Reduce Cancer Death Risk

    Science.gov (United States)

    ... news/fullstory_158338.html Widely Used Type 2 Diabetes Drug May Reduce Cancer Death Risk Older women taking metformin saw a ... study found that for women with type 2 diabetes and cancer, the odds of dying from cancer appeared to ...

  6. Hydrogen peroxide produced by oral Streptococci induces macrophage cell death.

    Directory of Open Access Journals (Sweden)

    Nobuo Okahashi

    Full Text Available Hydrogen peroxide (H2O2 produced by members of the mitis group of oral streptococci plays important roles in microbial communities such as oral biofilms. Although the cytotoxicity of H2O2 has been widely recognized, the effects of H2O2 produced by oral streptococci on host defense systems remain unknown. In the present study, we investigated the effect of H2O2 produced by Streptococcus oralis on human macrophage cell death. Infection by S. oralis was found to stimulate cell death of a THP-1 human macrophage cell line at multiplicities of infection greater than 100. Catalase, an enzyme that catalyzes the decomposition of H2O2, inhibited the cytotoxic effect of S. oralis. S. oralis deletion mutants lacking the spxB gene, which encodes pyruvate oxidase, and are therefore deficient in H2O2 production, showed reduced cytotoxicity toward THP-1 macrophages. Furthermore, H2O2 alone was capable of inducing cell death. The cytotoxic effect seemed to be independent of inflammatory responses, because H2O2 was not a potent stimulator of tumor necrosis factor-α production in macrophages. These results indicate that streptococcal H2O2 plays a role as a cytotoxin, and is implicated in the cell death of infected human macrophages.

  7. Molecular Basis of the Anti-Cancer Effects of Genistein Isoflavone in LNCaP Prostate Cancer Cells.

    OpenAIRE

    Hartmann J; Zoeller R; Esiobu N; Rathinavelu A; Kumi-Diaka J; Merchant K; Johnson M

    2011-01-01

    Background: Prostate cancer is the most common form of non-skin cancer within the United States and the second leading cause of cancer deaths. Survival rates for the advanced disease remain relatively low, and conventional treatments may be accompanied by significant side effects. As a result, current research is aimed at alternative or adjuvant treatments that will target components of the signal transduction, cell-cycle and apoptosis pathways, to induce cell death with little or no toxic si...

  8. Interaction of CSR1 with XIAP Reverses Inhibition of Caspases and Accelerates Cell Death

    OpenAIRE

    Zheng, Zhong-Liang; Tan, Lang-Zhu; Yu, Yan P.; Michalopoulos, George; Luo, Jian-Hua

    2012-01-01

    Cellular Stress Response 1 (CSR1) is a tumor suppressor gene that is located at 8p21, a region that is frequently deleted in prostate cancer as well as a variety of human malignancies. Previous studies have indicated that the expression of CSR1 induces cell death. In this study, we found that CSR1 interacts with X-linked Inhibitor of Apoptosis Protein (XIAP), using yeast two-hybrid screening analyses. XIAP overexpression has been found in many human cancers, and forced expression of XIAP bloc...

  9. Melatonin Prevents Chemical-Induced Haemopoietic Cell Death

    Directory of Open Access Journals (Sweden)

    Sara Salucci

    2014-04-01

    Full Text Available Melatonin (MEL, a methoxyindole synthesized by the pineal gland, is a powerful antioxidant in tissues as well as within cells, with a fundamental role in ameliorating homeostasis in a number of specific pathologies. It acts both as a direct radical scavenger and by stimulating production/activity of intracellular antioxidant enzymes. In this work, some chemical triggers, with different mechanisms of action, have been chosen to induce cell death in U937 hematopoietic cell line. Cells were pre-treated with 100 µM MEL and then exposed to hydrogen peroxide or staurosporine. Morphological analyses, TUNEL reaction and Orange/PI double staining have been used to recognize ultrastructural apoptotic patterns and to evaluate DNA behavior. Chemical damage and potential MEL anti-apoptotic effects were quantified by means of Tali® Image-Based Cytometer, able to monitor cell viability and apoptotic events. After trigger exposure, chromatin condensation, micronuclei formation and DNA fragmentation have been observed, all suggesting apoptotic cell death. These events underwent a statistically significant decrease in samples pre-treated with MEL. After caspase inhibition and subsequent assessment of cell viability, we demonstrated that apoptosis occurs, at least in part, through the mitochondrial pathway and that MEL interacts at this level to rescue U937 cells from death.

  10. A Lactose-Binding Lectin from the Marine Sponge Cinachyrella Apion (Cal Induces Cell Death in Human Cervical Adenocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Adriana Uchoa

    2012-03-01

    Full Text Available Cancer represents a set of more than 100 diseases, including malignant tumors from different locations. Strategies inducing differentiation have had limited success in the treatment of established cancers. Marine sponges are a biological reservoir of bioactive molecules, especially lectins. Several animal and plant lectins were purified with antitumor activity, mitogenic, anti-inflammatory and antiviral, but there are few reports in the literature describing the mechanism of action of lectins purified from marine sponges to induce apoptosis in human tumor cells. In this work, a lectin purified from the marine sponge Cinachyrella apion (CaL was evaluated with respect to its hemolytic, cytotoxic and antiproliferative properties, besides the ability to induce cell death in tumor cells. The antiproliferative activity of CaL was tested against HeLa, PC3 and 3T3 cell lines, with highest growth inhibition for HeLa, reducing cell growth at a dose dependent manner (0.5–10 µg/mL. Hemolytic activity and toxicity against peripheral blood cells were tested using the concentration of IC50 (10 µg/mL for both trials and twice the IC50 for analysis in flow cytometry, indicating that CaL is not toxic to these cells. To assess the mechanism of cell death caused by CaL in HeLa cells, we performed flow cytometry and western blotting. Results showed that lectin probably induces cell death by apoptosis activation by pro-apoptotic protein Bax, promoting mitochondrial membrane permeabilization, cell cycle arrest in S phase and acting as both dependent and/or independent of caspases pathway. These results indicate the potential of CaL in studies of medicine for treating cancer.

  11. Cytokine signaling for proliferation, survival, and death in hematopoietic cells.

    Science.gov (United States)

    Miyajima, A; Ito, Y; Kinoshita, T

    1999-04-01

    The survival, proliferation, and differentiation of hematopoietic cells are regulated by cytokines. In the absence of cytokines, hematopoietic cells not only stop proliferation, but undergo apoptosis. This strict dependency of hematopoietic cells on cytokines is an important mechanism that maintains the homeostasis of blood cells. Cytokines induce various intracellular signaling pathways by activating the receptor-associated Janus kinases (Jaks), and distinct signals are responsible for cell cycle progression and cell survival. Induction of signals for cell cycle progression without suppressing apoptosis results in apoptotic cell death, indicating the essential role of anti-apoptotic signaling for cell growth. In hematopoietic cells, Ras, a cellular protooncogen product, and phosphatidylinositol 3 kinase are involved in the suppression of apoptosis. Cytokine depletion not only turns off anti-apoptotic signaling, but also actively induces cell death by activating caspases, a distinct family of cysteine proteases. Alterations in the mechanisms of cytokine signaling for cell cycle progression and anti-apoptotic function are implicated in hematological disorders. PMID:10222650

  12. Investigation of the selenium metabolism in cancer cell lines

    DEFF Research Database (Denmark)

    Lunøe, Kristoffer; Gabel-Jensen, Charlotte; Stürup, Stefan;

    2011-01-01

    The aim of this work was to compare different selenium species for their ability to induce cell death in different cancer cell lines, while investigating the underlying chemistry by speciation analysis. A prostate cancer cell line (PC-3), a colon cancer cell line (HT-29) and a leukaemia cell line...... (Jurkat E6-1) were incubated with five selenium compounds representing inorganic as well as organic Se compounds in different oxidation states. Selenomethionine (SeMet), Se-methylselenocysteine (MeSeCys), methylseleninic acid (MeSeA), selenite and selenate in the concentration range 5-100 mu M were...... incubated with cells for 24 h and the induction of cell death was measured using flow cytometry. The amounts of total selenium in cell medium, cell lysate and the insoluble fractions was determined by ICP-MS. Speciation analysis of cellular fractions was performed by reversed phase, anion exchange and size...

  13. Effect of platinum nanoparticles on cell death induced by ultrasound in human lymphoma U937 cells.

    Science.gov (United States)

    Jawaid, Paras; Rehman, Mati Ur; Hassan, Mariame Ali; Zhao, Qing Li; Li, Peng; Miyamoto, Yusei; Misawa, Masaki; Ogawa, Ryohei; Shimizu, Tadamichi; Kondo, Takashi

    2016-07-01

    In this study, we report on the potential use of platinum nanoparticles (Pt-NPs), a superoxide dismutase (SOD)/catalase mimetic antioxidant, in combination with 1MHz ultrasound (US) at an intensity of 0.4W/cm(2), 10% duty factor, 100Hz PRF, for 2min. Apoptosis induction was assessed by DNA fragmentation assay, cell cycle analysis and Annexin V-FITC/PI staining. Cell killing was confirmed by cell counting and microscopic examination. The mitochondrial and Ca(2+)-dependent pathways were investigated. Caspase-8 expression and autophagy-related proteins were detected by spectrophotometry and western blot analysis, respectively. Intracellular reactive oxygen species (ROS) elevation was detected by flow cytometry, while extracellular free radical formation was assessed by electron paramagnetic resonance spin trapping spectrometry. The results showed that Pt-NPs exerted differential effects depending on their internalization. Pt-NPs functioned as potent free radical scavengers when added immediately before sonication while pre-treatment with Pt-NPs suppressed the induction of apoptosis as well as autophagy (AP), and resulted in enhanced cell killing. Dead cells displayed the features of pyknosis. The exact mode of cell death is still unclear. In conclusion, the results indicate that US-induced AP may contribute to cell survival post sonication. To our knowledge this is the first study to discuss autophagy as a pro-survival pathway in the context of US. The combination of Pt-NPs and US might be effective in cancer eradication. PMID:26964942

  14. Autophagic components contribute to hypersensitive cell death in Arabidopsis

    DEFF Research Database (Denmark)

    Hofius, Daniel; Schultz-Larsen, Torsten; Joensen, Jan; Tsitsigiannis, Dimitrios I; Petersen, Nikolaj H T; Mattsson, Ole; Jørgensen, Lise Bolt; Jones, Jonathan D G; Mundy, John; Petersen, Morten

    2009-01-01

    Autophagy has been implicated as a prosurvival mechanism to restrict programmed cell death (PCD) associated with the pathogen-triggered hypersensitive response (HR) during plant innate immunity. This model is based on the observation that HR lesions spread in plants with reduced autophagy gene...

  15. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Lee J. Martin

    2010-03-01

    Full Text Available Alzheimer’s disease (AD, Parkinson’s disease (PD and amyotrophic lateral sclerosis (ALS are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.

  16. Retinal Cell Death Caused by Sodium Iodate Involves Multiple Caspase-Dependent and Caspase-Independent Cell-Death Pathways

    Directory of Open Access Journals (Sweden)

    Jasmin Balmer

    2015-07-01

    Full Text Available Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO3 both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (35 mg/kg. Morphological changes in the retina post NaIO3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE cells, primary retinal cells, and the cone photoreceptor (PRC cell line 661W were assessed in vitro after NaIO3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1 was administered to the NaIO3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO3-treated animals. In vitro, NaIO3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO3.

  17. Induction of cell death by chemotherapeutic methylating agents

    International Nuclear Information System (INIS)

    The mechanism of cell death induced by O6 MeG has been investigated and inhibition of homologous recombination as a strategy for sensitization of tumor cells against methylating agents SN1. Dependence of the cell cycle was determined toxic responses triggered by O''6 MeG and evaluated by proliferation assays if apoptotic cells have originated exclusively from the second post-treatment cycle. Dependence of O''6 MeG was found at DSB formation. The activation of the control points of the cell cycle and induction of apoptosis is generated during the second cell cycle. Additionally, a portion of the cells has been determined that triggers apoptosis in subsequent generations in the second cell cycle. Inhibition of homologous recombination has been a reasonable strategy to increase SN1 alkylating agent effectiveness. Evidence has been provided in NHEJ dependent inhibition of DNA-PK that not significantly sensitizes the glioblastoma cells against temozolomide

  18. Ubiquitin at the crossroad of cell death and survival