Research open access reactive oxygen speciesmediated. Resveratrol enhances the effect of cisplatin on apoptosis in a549 cells. Ampkmediated autophagy inhibits apoptosis in cisplatin. Synergistic killing of lung cancer cells by cisplatin and.
We have examined the mechanisms of cell death induced by cisplatin in primary cultures of mouse proximal tubular cells. To determine whether combination treatmentinduced cell death was related to apoptosis, a549 cells were treated with resveratrol 2. Besides, autophagy and paraptosis were considered as caspaseindependent programmed cell death, which played key roles in activation of cell death for the cells resistance to apoptosis broker et al. Since apoptosis is the primary mode of cell death induced by cisplatin, the role of apoptosis and apoptosis related gene products in cisplatin resistance was investigated in four human cisplatin resistant cell lines of different tumour type. In addition, at high doses, cisplatin could damage molecules involved in cellular energy supply i. Bnip3 is a bh3only protein involved in cell death through mediating apoptosis. Ml, which selecupr inhibits cisplainmediated apoptosis fig. The number of cisplatin treated cells identi fied as apoptotic at any one time was never 1% of the total cell number present on addition of drug. Pdf is cisplatininduced cell death always produced by. Moreover, it has been hypothesized that in a tissue or cell population, apoptosis and necrosis might be two extremes of a continuum of possible types of cell demise. A number of studies have identified that cisplatin can induce endoplasmic reticulum er stress and nucleusindependent apoptotic signaling 710.
Cisplatin is a highly effective chemotherapeutic agent but displays significant ototoxic side effects. Cisplatin and resveratrol induce apoptosis and autophagy. Dec 12, 2020 cisplatin induced aki is characterised by increased apoptosis of renal tubular epithelial cells, and the results of the present study demonstrated that pstpip2 suppresses epithelial cell apoptosis. However, the cordycepin plus cisplatin cell death among the three hnscc cell lines as compared cotreatment significantly induced more phosphorp38 protein to cordycepin or cisplatin treatment alone, and an enhanced between 12 hours to 36 hours among the oc3, oecm1, and effect could be observed in the oc3 cells. It is therefore very important to clarify the mechanism by which anticancer agents induce apoptotic cell death for the further improvement of treatment. Hederagenin induces apoptosis in cisplatinresistant head. Cisplatin induced cell death is believed to be mediated by its interaction with nuclear dna eastman, 1999. Cisplatin use is limited by resistance and severe side effects. Mar 11, 2020 enhanced apoptosis in mdc1 knocked down cells upon cisplatin exposure followed by increased p53 serine 15 phosphorylation. Cisplatin could also induce typical apoptosis in p53de. Mechanisms of cisplatininduced apoptosis and of cisplatin. Apoptosis as a model of cell deathone potentially important mechanism of translation of cisplatin dna damage into cell death is apoptosis.
Antioxidant xanthone derivatives induce cell cycle arrest and. Oct 02, 2007 h460 cells to apoptotic cell death induced by cisplatin and determined its regulatory mechanisms. Dtt, on the other hand, is a wellknown er stress inducer and induces cell apoptosis via upr. Cisplatin primarily induces cell death by apoptosis and a defect in apoptotic signaling could also confer cisplatin resistance. The goal of these studies was to examine the role of p53, caspase 3, 8, and 9, and mitochondria in the signaling of cisplatin induced apoptosis. Role of p53 in cisplatininduced tubular cell apoptosis. This discovery represents a paradigm shift in the field, because until now it was believed that oxidative stress and apoptosis cell death caused cisplatin.
Research paper upregulation of acetylcholinesterase. 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. Cisplatininduced apoptosis inhibits autophagy, which acts. This yielded 1,972 hits march 2006 and 100 of these publications published 20022005 were examined. Oct 01, 1999 as the cisplatin concentration increased beyond 50. Bnip3 was reported to contribute to both spontaneous and drug. The current accepted paradigm about cisplatin mechanism of action is that. In contrast, over expression of txnl1 in bgc823ddp and sgc7901ddp cells lead to higher cisplatin induced apoptosis and cell death.
The selective compounds 2 and 8 induced an accumulation of ntub1 cells in the g1 phase arrest and cellular apoptosis by the increase of ros level. The clinical development of the neutral, square planar, coordination complex cis diamminedichloroplatinumii cisplatin, marked in the 1970s a watershed in the treatment of cancer. Apoptosis induced by cisplatin nephrotoxic injury sciencedirect. The biochemical mechanisms of cisplatin cytotoxicity involve the binding of the drug to dna and nondna targets and the subsequent induction of cell death through apoptosis, necrosis, or both. The withdrawal of serum, addition of ionomycin, and treatment. However, combination rituximab cisplatin treatment demonstrated that by 24 h, 45% of cells were sensitized and induced to undergo cell death fig. Txnl1 induces apoptosis in cisplatin resistant human. An mtt assay was used to quantitate cell death viability following 24 h exposure to cisplatin. Cisplatin induced aki is characterised by increased apoptosis of renal tubular epithelial cells, and the results of the present study demonstrated that pstpip2 suppresses epithelial cell apoptosis.
Cisplatin causes cell death via tab1 regulation of p53. Apr 01, 2001 the platinum drugs represent a unique and important class of antitumor agents. Apoptosis is known as a major mechanism of cisplatin induced cell death in renal tubular cells. Necrostatin1 nec1 inhibits necroptosis, a nonapoptotic cell death pathway. A biochemical hallmark of apoptosis is the characteristic degradation of the genomic. Therefore, it has been proposed that p21waf1cip1 decreases cisplatin nephrotoxicity by decreasing the number of injured cells that enter the cell cycle and undergo mitosis with damaged dna, which results in cell death by either apoptosis or oncosis 28. First, p38a is activated by tab1 to phosphorylate p53 nterminal sites, leading to selective induction of p53 targets such as noxa. Nec1 protects against nonapoptotic cell death in cisplatin. Acute apoptosis by cisplatin requires induction of reactive. Second, mdmx is stabilized in a tab1dependent manner and is required for cell death after cisplatin treatment. Silenced expression of ache and p53 decrease cell apoptosis all groups of mcf7 treated with cisplatin 100. Apoptosis is a typeof cell deaththat is caspase dependent. Cisplatininduced apoptosis in p53deficient renal cells via. Paris saponin iiinduced paraptosisassociated cell death.
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. Two days after drug addition there was a decrease from 85% to 29% cells in ga. Pdf cordycepin and cisplatininduced apoptosis dove. Mdc1 depletion promotes cisplatin induced cell death in. The platinum drugs represent a unique and important class of antitumor agents.
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. This cell death is dependent on ripk3 and on necrosome formation via autocrine. Peroxide is a key mediator of bcl2 downregulation and. The combination treatment of cisplatin and resveratrol cddprsv synergistically induced apoptosis, as evidenced by typical cell morphological changes, the appearance of subg0g1 peak, an increase in the annexin v. Receptor interactive protein kinase 3 promotes cisplatin. The results showed that while cisplatin alone caused about 25% cell death in a549 cells, wogonin synergistically sensitized a549 cells to cisplatin induced cell death in a dosedependent manner fig.
In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis resistant esophageal cancer cells. Effects of cisplatin on the induction of apoptosis. Autophagy delays apoptosis in renal tubular epithelial cells. Saikosaponins and cisplatin cotreatment potentiates apoptosis in cancer cells cisplatin can induce two distinct modes of cell death, apoptosis and necrosis, in cancer cells 22,23. Regulation of cisplatin induced cell death by protein kinases. Saikosaponins were also reported to activate apoptosis in hepatoma cells. Apoptosisinducing activity of cisplatin anticancer research. Apoptosis and reactive oxygen species ros were evaluated by flow cytometry. May 15, 2012 cisplatin is a highly effective chemotherapeutic agent but displays significant ototoxic side effects.
Esophageal cancer role of stressactivated map kinase p38 in. Apoptosis induced by cisplatin was mediated through the mitochondrial death pathway, which requires caspase9 activation and is regulated by bcl2. Cisdiamminedichloroplatinum or cisplatin is an inorganic compound that is widely used as a therapy of cancers. In fact, in cisplatin resistant keratinocytes transformed by hras oncogene, a high dose of cisplatin 312 microm induces characteristic features of necrotic cell death. Induction of apoptosis in cisplatinsensitive and resistant. Inhibition of cisplatin induced autophagy blocks the formation of autopha. 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. To evaluate the apoptotic rate in the cell lines on cisplatin exposure, we performed annexin v and pi labelling after 24 h of treatment and monitored the cells by fcm. Nov 01, 2020 apoptosis was regarded as the major pattern of cell death. Pdf it is generally accepted that dna damage and subsequent induction of apoptosis may be the primary cytotoxic mechanism of cisplatin. Mir1825p protects inner ear hair cells from cisplatin. Dec 15, 2000 that elevated erk activity contributed to cell death by cisplatin was supported by several observations. Apoptosis induced by cisplatin nephrotoxic injury core.
Requirement for erk activation in cisplatininduced apoptosis. Treatment of the cells with cisplatin induced rapid generation of multiple oxidative species and a concomitant increase in apoptotic cell death. Cell cycle and apoptosis as already known from literature studies, plumbagin is able to arrest the cell cycle. A number of studies have identified that cisplatin can induce endoplasmic reticulum er stress and nucleusindependent apoptotic signaling 7 10. Cisplatininduced apoptosis is enhanced by hypoxia and by. Hpv16 e6 rna interference enhances cisplatin and death. The combination of cisplatin and 2 significantly enhanced the cell death in ntub1 cells. Cells were seeded into 96well plates at a density of 20,000 cells well. In fact, both types of cell death have been found in the same population of cisplatin treated cells pestell et al. Thus, inhibition of caspases during apoptotic cell death can block apoptosis. Also, in mouse collecting duct cells, cisplatin induces apoptosis lee et al. Cisplatin in combination with programmed cell death protein 5. The most prominent change seen in the cochlea after cisplatin administration consists of loss of outer hair cells. The main difference between the two key types of cell death, apoptosis and necrosis are.
Effect of pax2sirna and cisplatin on rcc cell survival and apoptosis is additive we examined whether pax2 inactivation might add to the cell death caused by cisplatin exposure in vitro. Proteasome inhibitor lactacystin enhances cisplatin. Translation of cisplatin dna adducts into cytotoxicity. May 15, 2020 in lung cancer cell line a549, cisplatin. The apoptosis involved the caspasedependent pathway, while the necroptosis involved the activation of the way. Both emodin and cisplatin inhibited cell proliferation and promoted apoptosis p cisplatin signifi. In the present study, we demonstrate that i cisplatin induced death machinery inhibits the basal autophagic process in melanoma cells, as a further tool contributing to cell demise, and ii autophagy exogenously induced by calpains inhibitors or by. Uptake of the drug by the renal cells is energy often used in cancer treatment, cisplatin.
Cisplatin in combination with programmed cell death protein 5 increases antitumor activity in prostate cancer cells by promoting apoptosis. Caki1 and achn cells were treated with pax2sirnas or controlsirnas for 24 h, followed by exposure to various doses of cisplatin 10160mmoll for a. We aim to evaluate the effect of nec1 in the toxic kidney injury model by cisplatin. Txnl1 induces apoptosis in cisplatin resistant human gastric. The present study investigated the underlying mechanisms of synergistic killing by radiosensitization and cisplatin, with a focus on the growth inhibition, apoptosis and autophagy of non. Following 24 h incubation, cisplatin was added at concentrations from 0100.
Mechanisms of cisplatininduced cell death in malignant. Hederagenin induces apoptosis in cisplatinresistant head and. Treatment for 48 hours with the substance caused variation in the cell cycle. Inhibition of cisplatin induced autophagy blocks the formation of autophagosomes and enhances cisplatin induced caspase3, 6, and 7 activation, nuclear fragmentation and apoptosis. Plumbagin induces cell cycle arrest and apoptosis in a431. Research paper upregulation of acetylcholinesterase mediated.
Cisplatinresistance and cell death in malignant pleural. Saikosaponins were also reported to activate apoptosis in hepatoma cells 7. M produced timedependent apoptosis in rptcs, causing cell shrinkage, a 50fold increase in caspase 3 activity, a 4fold. Cisplatin is known to induce cell death via apoptosis in many cell types, by damaging dna and disturbing nuclear function. Berberine in combination with cisplatin induces necroptosis. Pdf is cisplatininduced cell death always produced by apoptosis. Overexpression of inhibitor of apoptosis proteins iaps has been described in clinical mesothelioma tumours and proposed as therapeutic.
Pax2 inactivation enhances cisplatininduced apoptosis in. Reactive oxygen species in apoptosis induced by cisplatin. Wogonin potentiates cisplatininduced cancer cell apoptosis. Apoptosis induced by cisplatin was mediated through the mitochondrial death pathway which requires. Acute kidney injury aki is a clinical problem of high incidence and mortality. The caspases are a family of proteases that play a key role in the execution of apoptosis. Considerable evidence indicates that cisplatin can kill cells through the induction of apoptosis eastman, 1999. We show that cisplatin could induce bax activation, cytochrome c release, and apoptosis in primary cultures of p53de. Cisplatin is a commonly used drug for chemotherapy, however, whether it may be used synergistically with radiotherapy remains unclear. Cisplatin treatment of nih3t3 cultures induces a form of. To investigate the roles of mir183, 96, and 182 in cisplatin induced hair cell apoptosis, we monitored mir183, 96, and 182 expression levels during 24 h of 3 and 20. Antioxidant xanthone derivatives induce cell cycle arrest.
Study shows how cisplatin chemotherapy leads to neuronal. Several mechanisms are believed to mediate cisplatin induced apoptosis. Acute apoptosis by cisplatin requires induction of. M of cisplatin required to induce acute apoptosis of hct116 cells reflected the usage by other investigators, we carried out a pubmed search for the terms cisplatin and apoptosis. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis resistant cancer. Rituximab modifies the cisplatinmitochondrial signaling. Role of apoptosis and apoptosisrelated proteins in the. Cisplatin cisdiamminedichloroplatinum ii is the best singleagent chemotherapy for mpm, but platinumbased combination therapies give the best overall response rates. The other mechanism that could perpetuate resistance of the cisplatin to tumor cells is the increased repair of the damaged dna.
Apoptosis induced by cisplatin was mediated through the mitochondrial. Elucidation of the molecular mechanisms of cisplatin nephrotoxicity may lead to the development. Autophagy delays apoptosis in renal tubular epithelial. Cell proliferation was measured by 34,5dimethylthiazol2yl2,5diphenyltetrazolium bromide mtt. Apoptosis did not occur by 12 h in cells treated with the combination therapy.
Original article unfolded protein response suppresses. Due to this complexity and lack of cytotoxic efficiency in mesothelioma. We have also recently demonstrated that autophagy induction is an immediate response of renal tubular epithelial cell exposure to cisplatin. Er stress is involved in cisplatin induced hcc cell apoptosis regulation. Moreover, our results demonstrated that the mechanism of txnl1 regulating cisplatin induced apoptosis was closely associated with bcl2 mediated mitochondria apoptosis pathway. Is cisplatininduced cell death always produced by apoptosis.
Therefore, the induction of apoptosis from detection and subsequent processing of cisplatin induced dna damage seems to be a long and complex process of cell death. The intracellular changes consistent with the induction of autophagy were also observed in nontumorigenic nih3t3 mouse fibroblast cell line treated with cisplatin 26, but the role of autophagy in cell survival apoptosis was not investigated in this study. Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Introduction chemotherapeutic treatment of ovarian cancer often includes cis platin as part of a combineddrug protocol. Lack of a functional p21waf1cip1 gene accelerates caspase.
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