Proapoptotic protein smac mediates apoptosis in cisplatin. Active enantiomer 3a activates p53 pathway in imr32 cell line. Synergistic cooperation between sunitinib and cisplatin. Cell killing of l1210 cells by cisplatin has been studied using flow cytometry and dna gel. Dna is the accepted target for cisplatin, but recent evidence has shed doubt on dna synthesis as the critical process. Using the hct116 colon carcinoma derived cell line we have.
The combination of tetrandrine and cisplatin induced apoptosis and inhibited proliferation in a synergistic manner. Requirement for erk activation in cisplatininduced apoptosis. Apoptosis induced by cisplatin nephrotoxic injury kidney. Emodin, cisplatin, esophageal cancer, proliferation, combination introduction in the process of carcinoma cell apoptosis, reactive oxygen species ros, plays as a non. Since pax2 suppresses apoptosis during renal development, we reasoned that pax2 may confer resistance to cisplatininduced apoptosis in rcc. The cells between your embryonic fingers died in a process called apoptosis, a common form of programmed cell death. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatininduced cytotoxicity, as well as the contribution of cisplatininduced activation of caspases 37 and conventional calpains.
Due to this complexity and lack of cytotoxic efficiency in mesothelioma. Cisplatindependent upregulation of death receptors 4 and 5 augments induction of apoptosis by tnfrelated apoptosisinducing ligand against esophageal squamous cell carcinoma. The specific mechanisms that trigger apoptosis in response to cisplatin induced dna damage have not yet been defined. Moreover, programmed cell death also might play a role in plant biology solomon, 1999, and apoptosislike cell death mechanisms even have been observed and used as a model system in yeast frohlich, 2000. The completeness of zvadfmkmediated protection against cisplatin or kanamycininduced hair cell death, and the lack of protection by nec1s, suggested that ex vivo, the predominant form of cisplatin and kanamycininduced hair cell death is mediated by caspasedependent apoptosis, without contribution from necroptosis. Moreover, pdia6 functions as an oncogene that inhibits cisplatininduced nsclc cell apoptosis and autophagy via interacting with map4k1 to suppress the jnkcjun signaling pathway. Moreover, addition of nutlin 3a results in a marked decrease in the dose of the two genotoxic drugs, cisplatin and etoposide, required to induce apoptosis in these cells, broadening the therapeutic index of these drugs. In this study, we examined cisplatininduced cell death pathways and iaps in three mesotheliomaderived cell lines. Multiple mechanisms have been implicated in the development of cddp. Thus, the resistance to cisplatin can be caused by the loss of the regulation of apoptosis. Fascinating insights into the origin and evolution of programmed cell death might. Here we show that a synergistic interaction can be achieved between sunitinib and cisplatin through a mechanism involving both the apoptotic and the autophagiclysosomal systems. The interplay between a nonlethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology.
Two discoveries brought cell death from obscurity to a major field of research. Cisplatininduced apoptosis inhibits autophagy, which acts as. Thus, pdia6 may serve as a potential biomarker for nsclc diagnosis and prediction. The platinum drugs represent a unique and important class of antitumor agents. This rapid response to nutlin contrasts with that in other. The relationship between cisplatininduced apoptosis and. Cells were seeded in 6 cm dishes, incubated for 24 h with 10. The development of cisplatin resistant cancer cells, however, quickly diminishes the effectiveness of these drugs and causes treatment failure. However, a major limitation of cddp chemotherapy is serious drug resistance. Imr32 cells were incubated with lowdose cisplatin cddp alone 33 nmoll or in combination with nutlin n3an3b for 1 h, and p53 and actin proteins were analyzed in cell lysates by western blotting. Depending on cell type and concentration, cisplatin induces cytotoxicity, e. Cisplatin induces apoptotic cell death in n18d3 hybrid neurons. The formation of autophagosomes was evident by transmission electron microscopy. We have previously shown that two hat genes, clock and tip60, are overexpressed, and upregulate glutathione biosynthesis and the expression of dna repair genes in cisplatin resistant cells.
Restoration of the immunogenicity of cisplatininduced. Restoration of the immunogenicity of cisplatininduced cancer. Caspase independence of cisplatininduced cell death in mesothelioma cells. Mar 27, 2017 tetrandrine and cisplatin exerted synergistic cytotoxic effects on both cisplatin resistant and cisplatin sensitive a549 cell lines. These differences were accompanied by changes in the expression of proteins involved in dna damage response. L12100 cells incubated for 2 hours with cisplatin progress to the g 2 phase of the cell cycle and are arrested there for several days. Recent laboratory studies confirmed the induction of renal cell apoptosis by cisplatin. The current accepted paradigm about cisplatin mechanism of action is that. Pdf cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of. Increased expression of 4hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathioneoxidized glutathione after cisplatin injection were significantly reversed by srt1720.
The slow cell death reported here appears to occur at the g 2 m transition and may involve events that normally occur at this stage of the cell cycle. Role of inhibitor of apoptosis proteins iaps and caspases. Cellular and molecular studies on cisplatininduced apoptotic. Cisplatin treatment of n18d3 neurons induced cytotoxicity in a dose. Results showed that cisplatin decreased cell survival in 143b 0 cells. Mode of cell death characteristics of the mode of cell death. These data suggest that cell death via the accumulation of cisplatindamaged dna occurs via apoptosis in both the cisplatinresistant and sensitive ovarian cancer cells. Much lower concentrations of cisplatin 8 microm led to apoptosis, which caused loss of the cell monolayer over several days.
These data suggest that cell death via the accumulation of cisplatin damaged dna occurs via apoptosis in both the cisplatin resistant and sensitive ovarian cancer cells. Inhibition of pfkfb3 cooperates with cisplatin to promote cancer cell apoptosis. Tetrandrine and cisplatin exerted synergistic cytotoxic effects on both cisplatinresistant and cisplatinsensitive a549 cell lines. Cell apoptosis was quantitatively detected by a cell death elisa kit as described under experimental procedures. Chemotherapeutic drugs, such as etoposide, adriamycin, mitoxanthrone, cisplatin, and 5fluorouracil. Cisplatin induced cytotoxicity results in higher percentage of cells undergoing apoptosis in mdc1 silenced cell lines. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death. Therefore, the induction of apoptosis from detection and subsequent processing of cisplatininduced dna damage seems to be a long and complex process of cell death. Despite the very large number of studies in this area 2,970 articles on medline on cisplatin apoptosis march 2009, it is controversial whether apoptosis is the primary mode of cell death of human carcinoma cells in response to dna damaging therapeutic drugs, and also whether apoptosis is necessary for the therapeutic effect of such drugs. Enhanced expression of pcaf endows apoptosis resistance in. Through an increased understanding of the specific mechanisms responsible for nephrotoxic cell injury, strategies. Introduction treatment of human ovarian cancer with the dnadamaging agent cisplatin is, initially, an effective means by which to arrest malignancy. Cisplatin forms inter and intrastrand crosslinked dna adducts and its cytotoxicity is mediated by propagation of dna damage recognition signals to downstream pathways involving atr, p53, p73, and mitogenactivated protein kinases, ultimately resulting in apoptosis.
Cisplatin is one of the major chemotherapeutic weapons used against different human cancers, although its mechanism to induce apoptosis is not fully understood. Cisplatin primarily induces cell death by apoptosis and a defect in apoptotic signaling could also confer cisplatin resistance. Considering that downregulation of mettl14 impaired cell proliferation and colony generation, we further analysed whether mettl14 expression influences apoptosis in pancreatic cancer cells after treatment with cisplatin. The presence of wild type p53 has been suggested to be important for cisplatin cytotoxicity, hence we found that cisplatin induced apoptosis in cell lines with functional p53. Enhancing cisplatin sensitivity in mcf7 human breast. Renal cell carcinoma rcc is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy.
Induction of apoptosis in cisplatinsensitive and resistant. Cell death or cell survival will depend on the relative intensity of the signals generated and the crosstalk between the pathways involved. Cisplatininduced apoptosis inhibits autophagy, which acts. Cisplatin resistance in nonsmall cell lung cancer cells is. We have previously shown that two hat genes, clock and tip60, are overexpressed, and upregulate glutathione biosynthesis and the expression of dna repair genes in cisplatinresistant cells. In fact, initiation of apoptosis at the execution phase activation of caspases has been previously reported for the cell killing produced by cytotoxic t lymphocytes golstein et al. The possible contribution of lysosomal proteases to caspasedependent apoptosis in mzcrc1 cell death response to sunitinibcisplatin treatment was examined by inhibiting cathepsin d activity. Srt1720 treatment also suppressed caspase3 activation and apoptotic cell death. Cisplatin and many other platinumbased compounds are important anticancer drugs that are used in treating many cancer types. Pdf mechanisms of cisplatininduced apoptosis and of cisplatin.
Cytotoxic effects of cisplatin occur primarily through apoptosis. The role of apoptosis in cell killing by cisplatin. Pharmacological activation of sirt1 ameliorates cisplatin. Autophagy is a doubleedged sword in the response to chemotherapy. Using morphological and molecular approaches, we characterized cisplatininduced cell necrosis and apoptosis in rat kidney. Original article emodin combined with cisplatin inhibits.
Previous experiments demonstrated that cells progressed to and arrested in the g 2 phase of the cell cycle before dying. An agent often used in cancer treatment, cisplatin may cause acute renal failure after even a single dose. M for 24 h and analysis was done using flow cytometry software. Oct 10, 2003 using morphological and molecular approaches, we characterized cisplatin induced cell necrosis and apoptosis in rat kidney. Rcc cells overexpress the transcription factor, pax2, normally expressed in fetal kidney but downregulated at birth. We have examined the mechanisms of cell death induced by cisplatin in primary cultures of mouse proximal tubular cells. The withdrawal of serum, addition of ionomycin, and treatment. New strategies that reverse cancer cell drug resistance phenotype or sensitize cancer cells to these drugs, therefore, need to. Indeed, cells treated with cytotoxic levels of cisplatin display the biochemical and morphologic features of apoptosis 37.
Since pax2 suppresses apoptosis during renal development, we reasoned that pax2 may confer resistance to cisplatin induced apoptosis in rcc. Analysis of events associated with cell cycle arrest at g. Mechanisms of cisplatininduced cell death in malignant mesothelioma cells. It reacts readily with the n7 position of purines to form a variety of lethal platinumdna adducts, which trigger programmed cell death apoptosis. Apoptosis in human hepatoma cell lines by chemotherapeutic drugs. Cisplatin induced cell death in mesothelioma cell lines was characterised by biochemical mechanisms classically associated with apoptosis including. Mdc1 depletion promotes cisplatin induced cell death in cervical.
Moreover, pdia6 functions as an oncogene that inhibits cisplatin induced nsclc cell apoptosis and autophagy via interacting with map4k1 to suppress the jnkcjun signaling pathway. The antineoplastic activity of cisplatin is rather complex and in light of the published reports it appears that cisplatin may activate several parallel pathways leading to cell cycle arrest and apoptosis depending on the treatment conditions, cell type or concentration. Given the lack of effect of knockdown of xiap and survivin upon drug cytotoxicity we hypothesised that caspase activation may be unnecessary for the effect of cisplatin in these cells. Emodin, cisplatin, esophageal cancer, proliferation, combination introduction in the process of carcinoma cell apoptosis, reactive oxygen species ros, plays as a non age signal role, which induces cell apoptosis through acting on mitochondrion then changes the mitochondria membrane permeability and dysfunction 1, 2.
Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has. Pdf is cisplatininduced cell death always produced by. Mechanisms of cisplatininduced apoptosis and of cisplatin. However, because cisplatin is a nonspecific drug and reacts not only with dna but. Reduction in cell viability as well as increase in the number of cells with fragmented nuclei correlated with cisplatin exposure in a dosedependent. In order to identify potential targets for enhancing the effect of cisplatin in mcf7 cells, a comparative study was done including the same breast cancer cell lines used for comparison of cisplatin sensitivity. To better understand the mechanism of hatrelated drug resistance, we investigated the role of another hat gene, p300cbpassociated factor pcaf. Apoptosis is a vital component of various processes including normal cell turnover, hormonedependent atrophy, proper development and functioning of the immune system, chemicalinduced cell death.
In h460 nsclc cells, caspase8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, fasassociated protein with death domain, acid sphingomyelinase. Apoptosis involves the death of a cell, but it benefits the organism as a whole for instance, by letting fingers develop or eliminating potential cancer cells. We further show that nutlin 3a induces apoptosis in all the neuroblastoma cell lines tested. Regulation of cisplatin induced cell death by protein kinases. In this study, we investigated the effect of mitochondrial dna mtdna depletion on cisplatin. There are two major pathways of apoptotic cell death nunez, benedict et al. A, nutlinmediated apoptosis occurs through the p53 pathway. Cell death induced by cisplatin is due to apoptosis in order to examine the nature of cell death induced by cisplatin, cells collected at various time points posttreatment with 10.
The cell death that occurs during embryogenesis, metamorphosis, endocrinedependent tissue atrophy, and normal tissue turnover is programmed cell death, mediated by a. Consistently, cisplatin treatment barely induced apoptosis or caspase37 activation in the t24r or sw780r cells fig. Overexpression of inhibitor of apoptosis proteins iaps has been described in clinical mesothelioma tumours and proposed as therapeutic targets. Disruption of autophagy through the knockdown of atg5 and beclin 1 may promote cisplatin induced apoptotic cell death in a549 cells. Biochemical events lead to characteristic cell changes and death. Therefore, knockdown of atg5 and beclin 1 by sirna may impair the cisplatin induced activation of autophagy, promote caspase3 cleavage and lead to increased cell death. The mostprominent form of cell death causing rounding up of the cell, retraction of pseudopodes, reduction of cellular volume, condensation of chromatin, fragmentation of the nucleus, almost no changes to cytoplasmic organelles and plasma membrane blebbing. Is cisplatin induced cell death always produced by apoptosis. Inhibition of autophagy promotes cisplatininduced apoptotic. Even in adults, senescent cells are removed and replaced by newly generated cells to maintain homeostasis. Several lines of evidence have shown that improvement of autophagy can minimize or prevent cisplatininduced cytotoxicity in cancer cells and normal. Such drug cooperation results in enhanced growth inhibition and cell death in both mtc cell culture and tumor xenografts. M cisplatin for 36 h, cell viability decreased to 40% of untreated control cells. Mdm2 inhibition sensitizes neuroblastoma to chemotherapy.
Cisplatin, as well as many chemotherapeutic agents, has been recognized to cause cancer cell death through apoptosis, and it is of interest to determine whether apoptosis is also the mechanism of cell death in nephrotoxic injury. Apr 01, 2001 the platinum drugs represent a unique and important class of antitumor agents. Functionally, cisplatin treated rats developed polyuric acute renal failure. Cisplatininduced activation of the mmr proteindependent p73 cell death pathway differs from its activation of p53 in that p73 activation does not involve atr. Restriction of cisplatin induction of acute apoptosis to a. Pdf cisplatindependent upregulation of death receptors. Despite the very large number of studies in this area 2,970 articles on medline on cisplatinapoptosis march 2009, it is controversial whether apoptosis is the primary mode of cell death of human carcinoma cells in response to dna damaging therapeutic drugs, and also whether apoptosis is necessary for the therapeutic effect of such drugs. Using the hct116 colon carcinoma derived cell line we. Apr 10, 2019 ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date.
Cisplatin cisdiamminedichloroplatinum ii is one of the common constituents of firstline treatment after surgery. Male spraguedawley rats n5 per group received a single intraperitoneal injection of either cisplatin 5 mgkg or saline, and were killed on day 5. Cell death induced by cisplatin was studied in chinese hamster ovary cell lines, one proficient and the other deficient 100fold sensitive in dna excision repair. Analysis of events associated with cell cycle arrest at g 2. To better understand the mechanism of hatrelated drug resistance, we investigated the role of another hat gene, p300cbpassociated factor. Cisplatininduced apoptosis proceeds by caspase3dependent. Moreover, it is possible that cisplatin damage to proteins could induce apoptosis at the execution phase level. Cisplatin is an anticancer drug that can induce apoptosis. Conversely, autophagymediated cell death and autophagyinduced apoptosis have also been reported under various circumstances and among different cell types 14,15. The relationship between cisplatininduced apoptosis and p53.
In programmed cell death, cells undergo cellular suicide when they receive certain cues. Downregulation of mettl14 increases apoptosis and autophagy. Although cisplatin, cisdiamminedichloroplatinumii, has been successfully used in the chemotherapy of cancer for more than 25 years, its biochemical mechanism of action is still unclear. This type of damage is consistent with cell death occurring by the process of apoptosis. Mdc1 depletion promotes cisplatin induced cell death in. The specific mechanisms that trigger apoptosis in response to cisplatininduced dna damage have not yet been defined. Expression of bcl2 protein correlates with cisplatin sensitivity in selected breast cancer cell lines.
In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin induced cytotoxicity, as well as the contribution of cisplatin induced activation of caspases 37 and conventional calpains. Translation of cisplatindna adducts into cytotoxicity. Effects of cisplatin on the induction of apoptosis. In this study, we examined cisplatin induced cell death pathways and iaps in three mesotheliomaderived cell lines. Triptolide potentiates lung cancer cells to cisplatin. Nonsmall cell lung cancer nsclc is associated with high incidence and mortality. Cddp 1 is a potent inducer of growth arrest andor apoptosis in most cell types and is among the most effective and widely used chemotherapeutic agents employed for treatment of human cancers. Triptolide potentiates lung cancer cells to cisplatininduced. For many years, neither apoptosis nor programmed cell death was a highly cited term. The absolute effect of cisplatin chemotherapy after five years was shown to be a decrease of lung cancer associated death by 6. New strategies that reverse cancer cell drug resistance phenotype or sensitize cancer cells to these drugs, therefore, need.
Dec, 2010 in contrast to other cytotoxic agents including anthracyclins and oxaliplatin oxp, cisplatin cddp fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer. The exposure of cells to pepstatin a partially blocked caspase3 and parp cleavage in cells treated with cisplatin alone or in combination with. Understanding the molecular events that contribute to druginduced apoptosis, and how tumors evade apoptotic death, provides a paradigm to explain the relationship between cancer genetics and treatment sensitivity and should enable a more rational approach to anticancer. The development of cisplatinresistant cancer cells, however, quickly diminishes the effectiveness of these drugs and causes treatment failure. Some of the signaling discussed in the text has been omitted for clarity cytotoxic action and molecular basis of cisplatin zh siddik 7266 oncogene. Histone acetyltransferase hat regulates transcription. The effect of tetrandrine combined with cisplatin on.
Apoptosis is a mode of cell death believed to account for. Is cisplatininduced cell death always produced by apoptosis. Factors that may be involved in cisplatininduced apoptosis. Defects in apoptosis underpin both tumorigenesis and drug resistance, and because of these defects chemotherapy often fails. Pkm2 inhibitor shikonin overcomes the cisplatin resistance. Regulation of cisplatininduced cell death by protein kinases. The extrinsic pathway is initiated when ligands bind to the tumor necrosis factor. Introduction chemotherapeutic treatment of ovarian cancer often includes cis platin as part of a combineddrug protocol.
Necroptosis and apoptosis contribute to cisplatin and. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal dna fragmentation, and global vague mrna decay. Mechanisms of death induced by cisplatin in proximal. Therefore, the autophagic response may be associated with cisplatin resistance, or it may be associated with apoptotic or autophagic cell death 16. Apoptosis article developmental biology khan academy.
Activation of programmed cell death apoptosis by cisplatin. High concentrations of cisplatin 800 microm led to necrotic cell death over a few hours. Cell shrinkage and morphology were also consistent with this type of cell death. Dna damage induces two distinct modes of cell death in. Acetylation accumulates pfkfb3 in cytoplasm to promote. Mechanisms of cisplatininduced cell death in malignant. Functionally, cisplatintreated rats developed polyuric acute renal failure. Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. In a549rcddp2000 cells, a cisplatin induced g2m cell cycle arrest was lacking and apoptosis was reduced compared to a549 cells, although equitoxic cisplatin concentrations resulted in comparable platinumdna adduct levels. Mechanisms of death induced by cisplatin in proximal tubular. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death.
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