Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lack of cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) in mice increases renal proximal tubular cell death and enhances sensitivity to acute renal failure produced by the chemotherapeutic agent cisplatin. We used primary cultures of mouse renal proximal tubular cells (MPTC) grown in optimized culture conditions to investigate the cellular basis for increased apoptosis in p21 knockout mice. Cisplatin (15 microM) activated caspase-3 but not caspase-8 or caspase-9 and produced phosphatidylserine externalization, chromatin condensation, and nuclear fragmentation in wild-type [p21(+/+)] MPTC. Caspase-3 activation and apoptosis were accelerated in cisplatin-treated MPTC lacking p21 [p21(-/-) MPTC]. In contrast to p21(+/+) MPTC, cisplatin activated caspase-9 but not caspase-8 in p21(-/-) MPTC before caspase-3 activation. The caspase-3 inhibitor Asp-Glu-Val-Asp-fluoromethylketone (DEVD-fmk) inhibited caspase-3 activity but did not abolish apoptosis in p21(+/+) and p21(-/-) MPTC. General caspase inhibitor Z-Val-Ala-Asp(OCH3)-fluoromethylketone (ZVAD-fmk) inhibited caspase activity and decreased chromatin condensation by 51% in p21(-/-) but not in p21(+/+) MPTC. However, cisplatin-induced phosphatidylserine externalization was not inhibited by ZVAD-fmk in p21(-/-) MPTC. We conclude that 1) in the presence of p21, cisplatin activates caspase-3 through a mechanism independent of caspase-8 or caspase-9; 2) in the absence of p21, caspase-9 activation precedes caspase-3 activation; 3) the lack of p21 accelerates caspase-3 activation and cisplatin-induced MPTC apoptosis; and 4) MPTC apoptosis is caspase independent in the presence of p21 but partially dependent on caspases in the absence of p21.
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PMID:Lack of a functional p21WAF1/CIP1 gene accelerates caspase-independent apoptosis induced by cisplatin in renal cells. 1274 56

Cisplatin, a commonly used antineoplastic agent, destroys the sensory hair cells in the cochlear and vestibular system leading to irreversible hearing loss and balance problems. Cisplatin-induced hair cell damage presumably occurs by apoptosis. Recent studies suggest that p53 may play an important role initiating cisplatin-induced apoptosis in some cell types. To determine if p53 plays a role in cisplatin-mediated hair cell loss, cochlear and utricular organotypic cultures were prepared from postnatal day 3-4 rats and treated with cisplatin or cisplatin plus pifithrin-alpha (PFT), a p53 inhibitor. Control cultures were devoid of p53 immunolabeling, caspase-1 and caspase-3 labeling and p53 protein was absent from Western blots. Cisplatin (1-10 microg/ml) caused a dose-dependent loss of hair cells in cochlear and utricular cultures, up-regulated phospho-p53 serine 15 immunolabeling, increased the expression of phospho-p53 serine 15 in Western blots from 6 to 48 h after the onset of cisplatin-treatment, and increased caspase-1 and caspase-3 labeling in cochlear and vestibular cultures. Addition of PFT (20-100 microM) to cisplatin-treated cochlear and utricular cultures resulted in a dose-dependent increase in hair cell survival; suppressed the expression of p53 in Western blots and eliminated caspase-1 and caspase-3 labeling in cultures. These results suggest that the tumor suppressor protein, p53, plays a critical role in initiating apoptosis in cochlear and vestibular hair cells. Temporary suppression of p53 with PFT provides significant protection against cisplatin-induced hair cell loss and offers the potential for reducing the ototoxic, vestibulotoxic and neurotoxic side effects of cisplatin.
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PMID:Pifithrin-alpha suppresses p53 and protects cochlear and vestibular hair cells from cisplatin-induced apoptosis. 1284 52

Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be attributed to differential roles of ROS in necrotic and apoptotic cell death. We therefore examined, in this study, the roles of ROS in necrosis and apoptosis induced by cisplatin in primary cultured rabbit proximal tubule. Cisplatin induced necrosis at high concentrations over a few hours and apoptosis at much lower concentrations over longer periods. Necrosis induced by high concentration of cisplatin was prevented by a cell-permeable superoxide scavenger (tiron), hydrogen peroxide scavengers (catalase and pyruvate), and antioxidants (Trolox and deferoxamine), whereas hydroxyl radical scavengers (dimethythiourea and thiourea) did not affect the cisplatin-induced necrosis. However, apoptosis induced by lower concentration of cisplatin was partially prevented by tiron and hydroxyl radical scavengers but not by hydrogen peroxide scavengers and antioxidants. Cisplatin-induced apoptosis was mediated by the signaling pathway that is associated with cytochrome c release from mitochondria and caspase-3 activation. These effects were prevented by tiron and dimethylthiourea but not by catalase. Dimethylthiourea produced a significant protection against cisplatin-induced acute renal failure, and the effect was associated with an inhibition of apoptosis. These results suggest that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis. The protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation.
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PMID:Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. 1453 6

We reported that 50% of cisplatin-induced apoptosis in primary cultures of rabbit renal proximal tubule cells (RPTC) proceeded via caspase-independent mechanisms. This study determined whether caspase-independent apoptosis, using multiple and diverse endpoints, could be produced by toxicants other than cisplatin and in cell models other than RPTC. Cisplatin, staurosporine, vincristine, and A23187 induced RPTC apoptosis after 24 h as indicated by 2- to 2.5-fold increases in annexin V and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining, and 2- to 10-fold increases in cell shrinkage. All toxicants induced 8- to 50-fold increases in caspase-3 activities, which were completely inhibited by the pan caspase inhibitor ZVAD-fmk. However, ZVAD-fmk only decreased cisplatin- and staurosporine-induced annexin V staining and cell shrinkage 30 to 50%, staurosporine-induced TUNEL staining 30%, and did not affect vincristine- or A23187-induced RPTC apoptosis. All toxicants tested induced apoptotic RPTC nuclear morphology. However, similar to its effect on annexin V and TUNEL staining, ZVAD-fmk only partially inhibited toxicant-induced apoptotic nuclear morphology. Cisplatin and staurosporine also induced annexin V staining in the human epithelial cancer cell lines Caki-1 (kidney carcinoma), A549 (lung carcinoma), A172 (glioblastoma), and murine lymphocytic leukemia L1210 cells. Pretreatment with ZVAD-fmk inhibited cisplatin-induced annexin V staining in Caki-1, A172, and A549 cells but had no affect in L1210 cells. Pretreatment with ZVAD-fmk did not decrease staurosporine-induced annexin V staining in Caki-1, A549, L1210, and A172 cells. These results suggest that a significant fraction of apoptosis induced by diverse toxicants in renal epithelial cells and in four different cancer cell lines is caspase-independent.
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PMID:Identification of caspase-independent apoptosis in epithelial and cancer cells. 1502 82

In the present study, we investigated the relation between p21 expression and the sensitivity of testicular germ cell tumor (TGCT) cells to apoptotic stimuli. Despite similar cisplatin-induced wild-type p53 accumulation, the TGCT cell lines Tera and Scha expressed low p21 protein and mRNA levels in comparison to A2780 ovarian cancer cells. Inhibition of the proteasome complex with MG-132 increased p21 protein levels in TGCT cells but much more in A2780 cells, whereas cisplatin had no additional effect on p21 protein levels. Inhibition of caspase-3 activity in TGCT cells with the broad-spectrum caspase inhibitor zVAD-fmk had no effect on p21 levels and also not upon cisplatin treatment. A similar induction of p53 irradiation, in contrast to cisplatin, substantially increased both p21 mRNA and protein expression in Tera cells. Cisplatin-treated Tera cells expressing low p21 protein levels were Fas-sensitive, while irradiation-induced p21, which was mainly localized in the cytosol, rendered irradiated Tera cells resistant to Fas-induced apoptosis. Sensitivity of irradiated Tera cells to Fas-induced apoptosis was restored by short interfering RNA-specific suppression of p21 expression. These results strongly indicate that the low p21 protein levels are caused by reduced p21 gene transcription and sensitize cisplatin-treated TGCT cells to the Fas death pathway.
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PMID:Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis. 1575 32

Cisplatin treatment induces extensive death of the proximal tubules in mice. We also demonstrated that treatment of immortalized mouse proximal tubule cells (TKPTS) with 25 microM cisplatin induces apoptotic death in vitro. Here, we demonstrate that members of the MAPKs such as ERK, JNK, and p38 are all activated after cisplatin treatment both in vivo and in vitro. Because MAPKs mediate cell survival and death, we studied their role in cisplatin-induced cell death in vitro. Apoptosis was confirmed by cell morphology, fluorescence-activated cell-sorting analysis, annexin V/propidium iodide binding, and caspase-3 activation in TKPTS cells. Inhibition of ERK, but not JNK or p38, abolished caspase-3 activation and apoptotic death, suggesting a prodeath role of ERK in cisplatin-induced injury. We also determined that cisplatin-induced ERK as well as caspase-3 activation are epidermal growth factor receptor (EGFR) and c-src dependent because inhibition of these genes inhibited ERK and caspase-3 activation and attenuated apoptotic death. These results suggest that caspase-3 mediates cisplatin-induced cell death in TKPTS cells via an EGFR/src/ERK-dependent pathway. We also suggest that the prodeath effect of ERK is injury type dependent because during oxidant injury, ERK supports survival rather than death in the same cells. We propose that injury-specific outcome diverges downstream from ERK in cisplatin- or H(2)O(2)-mediated cell survival and death.
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PMID:Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. 1514 69

Cisplatin is widely used in the treatment of human tumors, but it is a nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin-induced renal toxicity is greatly reduced through the use of high hydration, a large NaCl supply and mannitol infusion, but the precise mechanisms of these nephroprotective measures are not fully understood. We show here an increase in the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK-2 human tubular cells when the drug incubation was performed in a hypotonic phosphate-buffered saline solution or in human urine ("drag in" transport hypothesis). When 4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic 4 g/l NaCl solution, the platinum accumulation increased in both the cortex and papilla but not in the subcutaneously grafted colon tumors when compared to rats injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl, respectively). The urea and creatinine blood levels were significantly increased, and more apoptotic cells were detected by the caspase-3 cleavage and TUNEL assays in the tubular cells of rats treated with cisplatin in a hypotonic solution compared to animals that received normal or hypertonic solutions. Osmolarity was sometimes low in urine from patients receiving an intravenous hydration for a cisplatin treatment or from healthy volunteers who were given an oral hydration with a 50 g/l glucose solution. Our results show that low urine osmolarity could be a major determinant in the increase of cisplatin-induced nephrotoxicity and justify the widely used concurrent infusion of osmotically active substances during intravenous hydration.
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PMID:Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity. 1518 54

Chemoresistance is a major therapeutic problem and the current knowledge on cellular mechanisms involved is incomplete. In the present study, we have investigated the possible involvement of Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP) in ovarian cancer resistance by comparing chemosensitive (OV2008) and chemoresistant (C13*) ovarian cancer cells treated with cisplatin in vitro, and/or transfected with FLIP sense cDNA or FLIP small interfering RNA (siRNA) and determining FLIP protein content, cleavage of caspase-8 and caspase-3 and apoptosis. Cisplatin significantly decreased FLIP protein level, induced cleavage of caspase-8 and caspase-3 and apoptosis in a concentration-dependent manner in cisplatin-sensitive but not -resistant cells. While overexpression of FLIP-attenuated cisplatin-induced cleavage of caspase-8 and caspase-3 and apoptosis in chemosensitive cells, downregulation of FLIP in chemoresistant cells by siRNA increased apoptosis induced by cisplatin. These results suggest that FLIP plays a significant role in the regulation of apoptosis in human ovarian cancer cells and their sensitivity to cisplatin. This cell survival factor may be an important determinant in chemoresistance in ovarian cancer and may serve as a molecular target for the development of novel therapy for chemoresistant ovarian cancer.
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PMID:Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro. 1525 64

Cisplatin is a commonly used antitumor agent in the treatment of various human cancers, with nephrotoxicity as a major side effect. Cisplatin causes the loss of cell-cell contacts of renal proximal tubular epithelial cells prior to the onset of apoptosis. We studied the involvement of protein kinase C in these events in the renal epithelial cell line LLC-PK1. Cisplatin caused apoptosis in LLC-PK1 cells, which was directly related to the activation of caspase-3 and DNA fragmentation. Apoptosis was almost completely inhibited by the protein kinase C inhibitors bisindolylmaleimide (Bis) I and Go6983 [2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], but not by Go6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole]. Also, in primary cultured rat renal proximal tubular cells, inhibition of protein kinase C (PKC) inhibited apoptosis. Cisplatin also caused the early loss of cell-cell adhesions, which was associated with the altered localization of the adherens junction-associated protein beta-catenin in association with PKC-mediated phosphorylation of the actincapping protein adducin. These events preceded and were independent of caspase activation. beta-Catenin did not dissociate from E-cadherin. Cisplatin-induced loss of cell-cell contacts was associated with the increased formation of F-actin stress fibers, which was inhibited by Bis I and Go6983 as well as dominant-negative PKC-epsilon. Also, the loss of cell-cell adhesions by cisplatin was prevented by Bis I and Go6983. Activation of protein kinase C with phorbol esters promoted cisplatin-induced loss of cell-cell adhesions as well as apoptosis. In conclusion, the combined data fit a model whereby protein kinase C mediates the cisplatin-induced loss of cellular interactions. Such a loss of these interactions has a role in the onset of apoptosis.
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PMID:Protein kinase C mediates cisplatin-induced loss of adherens junctions followed by apoptosis of renal proximal tubular epithelial cells. 1538 33

Cisplatin activates multiple signal transduction pathways associated with cell survival and apoptosis in various cell types. The present study was undertaken to determine the role of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family, in cisplatin-induced apoptosis in human glioma cells. Cisplatin resulted in apoptosis in a dose- and time-dependent manner. Cisplatin-induced apoptosis was prevented by the hydrogen peroxide scavenger pyruvate and the antioxidant N-acetylcysteine, but not by the superoxide scavenger tiron. Western blot analysis demonstrated that cisplatin treatment induced time-dependent activation of ERK, which was inhibited by chemical inhibitors of the MEK signaling pathway (PD98059 and U0126) and N-acetylcysteine. These inhibitors prevented cisplatin-induced cell death. Transient transfection of constitutive active MEK1 increased cisplatin-induced apoptosis. Cisplatin resulted in a reduction in mitochondrial membrane potential and its effect was prevented by N-acetylcysteine and PD98059. Caspase inhibitors (Boc-D-FMK and zDEVD-FMK) protected against cisplatin-induced cell death. Cisplatin-induced activation of caspase-3 was inhibited by N-acetylcysteine and PD98059. Taken together, these findings suggest that the ERK activation plays an active role in mediating cisplatin-induced apoptosis of human glioma cells and functions upstream of mitochondrial dysfunction and caspase activation to the initiate the apoptotic signal.
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PMID:Role of ERK activation in cisplatin-induced apoptosis in A172 human glioma cells. 1547 10


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