Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytotoxic drugs commonly used in cancer therapy promote tumor cell death by inducing apoptosis, but the cell death pathway(s) is likely dependent on the mechanism of drug action. In the present study, we investigated the mechanisms of cell death induced by doxorubicin (DXR) and the novel disaccharide anthracycline MEN 10755, in a human ovarian cancer cell line (A2780). Exposure to either anthracycline induced the up-regulation of several genes known to promote cell cycle arrest and DNA repair (WAF1/p21, GADD45) or apoptosis (bax, Fas). Although the expression of Fas was increased, an antagonistic anti-Fas antibody ZB4 did not inhibit anthracycline-induced apoptosis, suggesting that the stimulation of the Fas receptor did not play a critical role in the induction of apoptosis in this cell line. We also observed that neither MEN 10755 nor DXR were able to induce apoptosis in A2780 cells deprived of the nucleus but retaining an intact mitochondrial function (cytoplasts) and that apoptosis induced by either anthracycline was inhibited by cycloheximide, indicating that it is an active process requiring new protein synthesis. Both the caspases inhibitors, ZVAD-fmk and DEVD-cho, inhibited at similar extent apoptosis induced by either DXR or MEN 10755, suggesting an involvement of caspase-3 in this response. We conclude that, in a tumor cell line of epithelial origin, the apoptosis following exposure to anthracyclines is an active process requiring protein synthesis and drug interaction with nuclear structures. The pathway was Fas-independent but likely involved bax and caspase-3 as effectors of the cascade culminating in apoptosis.
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PMID:Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines. 1116 Jun 8

Cervical cancer is known to be highly associated with viral oncogene E6 and E7 of human papilloma virus. Down-regulation of oncogene expression by antisense-based gene therapy has been extensively studied. To investigate the effect of HPV 16 E6 antisense nucleic acid (AS) on cervical cancer cells, human cervical cancer cell lines, CaSki and SiHa cells harboring HPV 16 genome were transfected with plasmid containing E6(AS). The decreased viability and the apoptotic morphology were observed in E6(AS)-transfected cervical cancer cell lines. By 6 h after transfection, inhibition of E6 splicing, rapid upregulations of p53 and a p53-responsive protein, GADD45, were displayed in E6(AS)-transfected CaSki cells. Furthermore, E6(AS) induced loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into the cytoplasm, and subsequent activation of caspase-9 and caspase-3. These results indicate that HPV 16 E6(AS) induces apoptosis in CaSki cells via upregulation of p53 and release of cytochrome c into cytoplasm, consequently activating procaspase-9 and procaspase-3.
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PMID:HPV E6 antisense induces apoptosis in CaSki cells via suppression of E6 splicing. 1208 99

The breast cancer suppressor protein, BRCA1 plays an important role in mediating cell cycle arrest, apoptosis and DNA responses to DNA damage signals. In this study, we show that BRCA1 level is downregulated during UV-induced apoptosis by caspase-3 mediated cleavage. Cleavage of BRCA1 by caspase-3 produced a fragment that contained the C-terminal of the molecule. Accordingly, treatment of cells with caspase-3 inhibitor or mutation of a specific caspase-3 cleavage site (DLLD) at amino acid 1151-1154 of BRCA1 abolished cleavage and consequential accumulation of the BRCA1 C-terminal fragment. Whereas expression of the non-cleavable BRCA1 (D/A 1154) mutant conferred the resistance phenotype to UV-induced cell death, expression of the cleaved BRCA1 C-terminus induced cell death in the absence of UV. Examination of the mechanism of C-terminus-induced cell death revealed that the cleaved fragment triggers the apoptotic response through activation of BRCA1 downstream effectors, GADD45 and JNK. Altogether, results of our study demonstrate a functional role for caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis.
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PMID:Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis. 1214 54

We have found that ecteinascidin-743 (ET-743) inhibited cell proliferation at 1-10 ng/ml, leading to S and G(2)/M arrest and subsequent apoptosis, and induced early apoptosis without previous cell cycle arrest at 10-100 ng/ml in cancer cells. ET-743-mediated apoptosis, did not involve Fas/CD95. ET-743 induced c-Jun NH(2)-terminal kinase (JNK) and caspase-3 activation, and JNK and caspase inhibition prevented ET-743-induced apoptosis. ET-743 failed to promote apoptosis in caspase-3-deficient MCF-7 cells, further implicating caspase-3 in its proapoptotic action. Overexpression of bcl-2 by gene transfer abrogated ET-743-induced apoptosis, but cells underwent cell cycle arrest. ET-743 triggered cytochrome c release from mitochondria that was inhibited by Bcl-2 overexpression. Inhibition of transcription or protein synthesis did not prevent ET-743-induced apoptosis, but abrogated ET-743-induced cell cycle arrest. Microarray analyses revealed changes in the expression of a small number of cell cycle-related genes (p21, GADD45A, cyclin G2, MCM5, and histones) that suggested their putative involvement in ET-743-induced cell cycle arrest. These data indicate that ET-743 is a very potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways, namely a transcription-dependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3.
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PMID:Differential cytostatic and apoptotic effects of ecteinascidin-743 in cancer cells. Transcription-dependent cell cycle arrest and transcription-independent JNK and mitochondrial mediated apoptosis. 1219 19

Previous research has suggested that repletion of cellular glutathione peroxidase (GPX1) activity by a single injection of Se was dissociated from the Se protection against the pro-oxidant-induced liver necrosis in Se-deficient rodents. Using the GPX1 knockout (GPX1-/-) mice, TUNEL assay, and apoptosis gene expression microarray, we have demonstrated strikingly different impacts of GPX1 knockout on hepatotoxicity and the related signaling induced by an intraperitoneal injection of 12.5 mg paraquat/kg body weight (b.wt.). In both Se-deficient GPX1-/- and wild-type (WT) mice, the paraquat did not induce typical liver necrosis, rather aponecrosis or necrapoptosis, a syncretic process of cell death sharing characteristics of both apoptosis and necrosis. The severity of liver aponecrosis and the associated mortality were reduced to a much greater extent by an injection of Se (ip, 50 microg/kg b.wt. as Na2SeO3) prior to paraquat stress in the WT mice, compared with the GPX1-/- mice. The induced liver aponecrosis seemed to be more apoptotic in the GPX1-/- mice but more necrotic in the WT mice. The paraquat-mediated gene or protein expression of proapoptotic Bax, Bcl-w, and Bcl-X(S), cell survival/death factors GADD45, MDM2, c-Myc, and caspase-3 was upregulated, but that of antiapoptotic Bcl-2 was downregulated in the GPX1-/- mice vs. the WT mice. Overall, these differences between the two groups of mice were related to a low level of liver GPX1 activity in the WT mice that represented < 4% of the normal physiological level. Therefore, the low level of GPX1 activity in the Se-deficient mice can exert a potent role in defending against liver aponecrosis induced by moderate oxidative stress.
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PMID:Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. 1265 81

We have previously shown that arsenic trioxide blocks proliferation and induces apoptosis in human pancreatic cancer cells at low, non-toxic concentrations. The mechanisms of the apoptosis was investigated in MiaPaCa2 and PANC-1 cells that have been previously shown to be responsive to arsenic trioxide. The results show the caspase-3, caspase-7, and caspase-9 are all activated by arsenic trioxide, together with cleavage of the downstream caspase-3 target poly ADP ribose polymerase (PARP). Expression of the anti-apoptosis proteins, Bcl-2 and Mcl-1 expression decreased time-dependently while Bax expression increased. These findings indicate that the Bcl family of proteins, the mitochondrial pathway and activation of the caspase cascade are responsible for arsenic-induced apoptosis. Flow cytometric analysis revealed changes of cell cycle distribution from a G0/G1 phase arrest at 24 hours to G2/M phase arrest at 72 hours following arsenic treatment. The sub-G0/G1 cell population of apoptotic cells was increased at these times. Arsenic increased expression of the P21 protein and decreased levels of cyclin A, cyclin B1 and cyclin D1, but expression of CDK2, CDK4, CDK6, and cyclin E were not affected. Arsenic trioxide markedly enhanced the expression of GADD45 and GADD153 in a time-dependent manner. In summary, arsenic trioxide induced apoptosis in pancreatic cancer cells through activating the caspase cascade via the mitochondrial pathway, GADD expression and by modifying cell cycle progress and changes in several cycle-regulating proteins. This old drug may be valuable for treatment of pancreatic cancer.
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PMID:Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. 1288 67

Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320-400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type.
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PMID:Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis. 1292 21

SJG-136 (NSC 694501) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique multilog differential pattern of activity in the NCI 60-cell line screen (i.e., is COMPARE negative to other cross-linking agents). Given this profile, we undertook a preclinical evaluation of SJG-136 in primary tumor cells derived from 34 B-cell chronic lymphocytic leukemia (B-CLL) patients. SJG-136 induced apoptosis in all of the B-CLL samples tested with a mean LD50 value (the concentration of drug required to kill 50% of the cells) of 9.06 nmol/L. Its cytotoxicity was undiminished in B-CLL cells derived from patients treated previously, those with unmutated VH genes, and those with p53 mutations (P=0.17; P=0.63; P=0.42, respectively). SJG-136-induced apoptosis was associated with the activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor Z-LEHD-FMK. Furthermore, SJG-136 did not trigger the phosphorylation of p53 or the up-regulation of GADD45 expression in B-CLL cells whereas the cross-linking agent chlorambucil elicited both of these effects. This suggests that SJG-136 cross-linking adducts are not subject to p53-mediated DNA excision repair mechanisms in B-CLL cells. Taken together, these data demonstrate a novel mechanism of action for SJG-136 that appears to circumvent the effects of poor prognostic markers. This unique cytotoxicity profile warrants further investigation and supports the evaluation of this agent in Phase I clinical trials for patients with B-CLL.
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PMID:The novel sequence-specific DNA cross-linking agent SJG-136 (NSC 694501) has potent and selective in vitro cytotoxicity in human B-cell chronic lymphocytic leukemia cells with evidence of a p53-independent mechanism of cell kill. 1537 93

Tumors expressing the ABL oncoproteins (BCR/ABL, TEL/ABL, v-ABL) can avoid apoptosis triggered by DNA damaging agents. The tumor suppressor protein p53 is an important activator of apoptosis in normal cells; conversely its functional loss may cause drug resistance. The ABL oncoprotein-p53 paradigm represents the relationship between an oncogenic tyrosine kinase and a tumor suppressor gene. Here we show that BCR/ABL oncoproteins employ p53 to induce resistance to DNA damage in myeloid leukemia cells. Cells transformed by the ABL oncoproteins displayed accumulation of p53 upon DNA damage. In contrast, only a modest increase of p53 expression followed by activation of caspase-3 were detected in normal cells expressing endogenous c-ABL. Phosphatidylinositol-3 kinase-like protein kinases (ATR and also ATM) -dependent phosphorylation of p53-Ser15 residue was associated with the accumulation of p53, and stimulation of p21(Waf-1) and GADD45, resulting in G(2)/M delay in BCR/ABL cells after genotoxic treatment. Inhibition of p53 by siRNA or by the temperature-sensitive mutation reduced G(2)/M accumulation and drug resistance of BCR/ABL cells. In conclusion, accumulation of the p53 protein contributed to prolonged G(2)/M checkpoint activation and drug resistance in myeloid cells expressing the BCR/ABL oncoproteins.
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PMID:BCR/ABL recruits p53 tumor suppressor protein to induce drug resistance. 1549 10

Arsenic trioxide is valuable for treatment of promyelocytic leukemia, but less attention has been paid to its therapeutic potential for other cancers. In this study, the effects of arsenic trioxide were tested in human pancreatic (AsPC-1), colonic (HT-29), and breast (MCF-7) cancer cells. In all three cancer cell lines, arsenic trioxide inhibited proliferation in a concentration and time-dependent manner, as measured by 3H-methyl thymidine incorporation and cell counting. Coincident with inhibition of growth, arsenic trioxide induced marked morphologic changes, including reduced cytoplasmic volume, membrane blebbing, and nuclear condensation consistent with apoptosis. Propidium iodide DNA staining at 24 hours revealed cell cycle arrest in the G0/G1 phase and an increase in the S phase, while at 72 hr there was G2/M phase arrest with a marked increase in the sub-G0/G1, apoptotic cell population. The DNA fragmentation induced by arsenic trioxide was confirmed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay in all cell lines. Western blot analysis revealed activation of caspase -3, -7, and -9 by arsenic trioxide. Caspase-3 activity was confirmed by demonstrating cleavage of its downstream target, poly ADP-ribose polymerase (PARP). Expression of the antiapoptosis protein, Bcl-2, was time-dependently decreased. In contrast, arsenic trioxide markedly enhanced the expression of the p21 protein, GADD45 and GADD153, in a time-dependent manner. These findings suggest that arsenic trioxide has potential as a therapeutic agent for these cancers.
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PMID:Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells. 1549 60


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