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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Response to genotoxic stress may trigger the activation of distinct mechanisms that serve to promote cell death, including apoptosis and necrosis. In this study we examined the response of human fibroblasts, either proficient or deficient for the damage-activated protein kinase ataxia telangiectasia-mutated (ATM), to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Analysis of both long- and short-term viability shows that both ATM-proficient YZ-5 and ATM-deficient EBS-7 fibroblasts display a cytotoxic response to MNNG. Consistent with activation of apoptosis in response to MNNG, we observed increased caspase-3 cleavage and activity, appearance of fragmented nuclei, and increased staining with annexin V in both ATM-proficient and -deficient fibroblasts. Flow cytometry demonstrated that these cell lines also display a nonapoptotic cell death in response to MNNG. This form of cell death is associated with activation of poly-ADP ribose polymerase (PARP), and analysis of PARP activity indicated increased protein poly(ADP-ribosylation) in YZ-5 when compared to EBS-7. This PARP activity was accompanied by apoptosis-inducing factor release and translocation from the mitochondria to the nucleus. Finally, the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ) or the caspase-3 inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone dramatically diminished the cytotoxic response to MNNG, reinforcing the roles for apoptotic and nonapoptotic cell death in human fibroblasts treated with MNNG. From these findings, we conclude that MNNG induces a heterogeneous death response in human fibroblasts.
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PMID:N-methyl-N'-nitro-N-nitrosoguanidine activates multiple cell death mechanisms in human fibroblasts. 1767 37

In the microenvironment of solid growing tumors, pronounced hypoxia or extracellular acidosis is commonly found. The aim of this study was the analysis of the cytotoxic effect of different chemotherapeutic agents (cisplatin, daunorubicin, docetaxel) under these conditions in vitro. Prostate carcinoma cells (R3327-AT1) were exposed to hypoxia (pO2 < 0.5 mmHg) or extracellular acidosis (pH = 6.6) for 6h. After 3h, cytotoxic drugs were added. The cytotoxic effect was assessed by measuring caspase 3-activity (apoptosis), LDH release (necrosis) and repopulation of the cells after chemotherapy (cell death). Compared to aerobic control conditions, severe hypoxia over 6 h per se led to a slight increase in apoptosis, necrosis and cell death. With all three chemotherapeutic agents, hypoxia led to a reduced (by approx. 25%) caspase 3-activity and a marked increase in necrosis. However, the overall cytotoxicity of the drug was not affected by O2-deficiency. By contrast, during extracellular acidosis, the cytotoxic effect of daunorubicin was reduced by 40%, preferentially due to a marked reduction in apoptosis. With cisplatin and docetaxel no change in overall cell death was detected. However, for daunorubicin the tumor-pH seems to have a strong impact on cytotoxicity. With this chemotherapeutic drug the therapeutic efficacy is markedly reduced in an acidotic environment.
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PMID:Impact of hypoxic and acidic extracellular conditions on cytotoxicity of chemotherapeutic drugs. 1772 60

X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family that selectively binds and inhibits caspase-3, -7 and -9. As such, XIAP is an extremely potent suppressor of apoptosis and an attractive target for cancer treatment. Che-1 is an antiapoptotic agent involved in the control of gene transcription and cell proliferation. Recently, we showed that the checkpoint kinases ATM/ATR and checkpoint kinase 2 physically and functionally interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce transcription of p53, and Che-1 depletion strongly sensitizes tumor cells to anticancer drugs. Here we show that Che-1 activates XIAP expression in response to DNA damage. This effect is mediated by Che-1 phosphorylation and requires NF-kappaB. Notably, we found that XIAP expression is necessary for antiapoptotic activity of Che-1 and that in vivo downregulation of Che-1 by small interference RNA strongly enhanced the cytotoxicity of anticancer drugs.
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PMID:Che-1 activates XIAP expression in response to DNA damage. 1804 76

Drugs developed for the treatment of conditions other than neoplasia can also show promise as potential antitumor agents. The fluoroquinolone antibiotic ciprofloxacin (CPFX) is known to modulate cycle cell progression and apoptosis in cancer cells, and is thought to induce DNA double-strand breaks (DSBs) via topoisomerase II (topo II) inhibition and stabilized cleavage complex (SCC) formation. DSBs trigger Ser-139 phosphorylation of histone H2AX (gammaH2AX) by PI-3-like kinases including ATM; gammaH2AX can serve as a marker of DNA damage when measured in situ using immunocytochemistry and flow cytometry. The aim of the present study was to investigate the relationship between CPFX-mediated DNA damage and induction of apoptosis in human lymphoblastoid cells and phytohaemagglutinin (PHA)-stimulated lymphocytes (Lymphs). Treatment of TK6 cells (wild-type p53) with 100 microg/ml CPFX for 2-10 h produced no increase in gammaH2AX; to the contrary, its level in S phase cells was reduced at 10 h compared to controls. Nevertheless, stabilization of topo IIalpha, ATM Ser-1981 phosphorylation and G(2) arrest was observed in TK6 cells exposed to CPFX for > or = 4 h. However, following 24 h treatment, gammaH2AX was dramatically increased in a sub-population of cells indicating the onset of apoptosis (confirmed by presence of activated caspase 3). CPFX had a similar lack of effect on induction of gammaH2AX at early time points in WTK1 and NH32 cells (devoid of functional p53) and proliferating Lymphs, however, induction of apoptosis was less pronounced than in TK6 cells. Formation of SCC and activation of ATM (but lack of gammaH2AX induction) indicates topo II-mediated chromatin or DNA changes in the absence of DSBs; ATM activation apparently triggers the G(2)M checkpoint leading to G(2) arrest. The subsequent induction of apoptosis appears to be facilitated by functional p53. CPFX may therefore have a potential use as a chemotherapeutic agent in the treatment of lymphoblast-derived cancer.
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PMID:Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation. 1805 76

T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumor-specific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation- and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces gamma-radiation-induced apoptosis as judged by decreased annexin-V/PI staining, caspase-3 activation, and PARP cleavage. TLR9-stimulated cells show heightened accumulation at the G2 cell-cycle phase and increased DNA repair rates. Irradiated, TLR9-engaged cells showed higher levels of phosphorylated Chk1 and Chk2. While the levels of activated ATM in response to IR did not differ between TLR9-stimulated and unstimulated cells, inhibition of ATM/ATR and Chk1/Chk2 kinases abolished the radioprotective effects in TLR9-stimulated cells. In vivo, TLR9-stimulated cells displayed higher radio resistance than TLR9-stimulated MyD88(-/-) T cells and responded to antigenic stimulation after total body irradiation. These findings show, for the first time, that TLR9 engagement on CD4 T cells reduces IR-induced apoptosis by influencing cell-cycle checkpoint activity, potentially allowing for combinatorial immunotherapy and radiotherapy.
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PMID:TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements. 1808 70

Cepharanthine (CEP), a biscoclaurine (bisbenzylisoquinoline) alkaloid isolated from Stephania cepharantha Hayata, is widely used in Japan to treat variety of diseases. Among a plethora of its biological activities CEP was reported to be able to scavenge radicals and prevent lipid peroxidation. We have recently described the phenomenon of constitutive ATM activation (CAA) and histone H2AX phosphorylation (CHP), the events that report DNA damage induced by endogenously generated radicals, the product of oxidative metabolism in otherwise healthy, untreated cells. The aim of the present study was to explore whether CEP can attenuate the level of CAA and CHP, which would indicate on its ability to protect DNA against endogenous oxidants. The data show that indeed the levels of CAA and CHP in human lymphoblastoid TK6 cells were distinctly lowered upon treatment with CEP. Thus, exposure of cells to 8.3 microM CEP for 4 h led to a reduction of the mean level of CAA and CHP by up to 60% and 50%, respectively. At 1.7 microM CEP the reduction of CAA and CHP after 4 h was 35% and 25%, respectively. Cells exposure to CEP led to a decrease in the level of ondogenous oxidants as measured by the ability to oxidate the fluorescent probe 5-(and-6)-carboxy-2',7'-dichloro-dihydro-fluorescein diacetate. No evidence of apoptosis was seen during the first 8 h of treatment with CEP but initiation of apoptosis (caspase-3 activation) was detected in relatively few (< 10%) cells after exposure to 8.3 microM CEP for 24 h. The data strongly suggest that the scavenging properties of CEP provide a protection of DNA from the radicals generated endogenously during oxidative metabolism.
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PMID:Biscoclaurine alkaloid cepharanthine protects DNA in TK6 lymphoblastoid cells from constitutive oxidative damage. 1827 90

Although several tumour types express both AT1 and AT2 angiotensin II receptors, and angiotensin II stimulates cell proliferation, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not effective anti-cancer agents. Development of a biologically active monoclonal antibody (6313/G2) against the AT1 receptor prompted the testing of a recombinant short-chain variable fragment form (R6313/G2) against breast cancer cells in vitro and in vivo. Cell lines MCF-7, MDA-MB-231 and T47D all expressed both receptor subtypes. In vitro, R6313/G2 suppressed cell proliferation in the presence of 100 nM angiotensin II, with IC50s of 30 nM, 153 nM and 2.8 microM for the three cell types respectively; in contrast, the AT1 receptor blocker losartan was effective only in T47D cells, at 25 microM. Studies on MCF-7 and T47D cells showed R6313/G2 also opposed the angiotensin II-induced inhibition of caspase-3/7 activity. In vivo, hollow fibres containing the cell lines were implanted in nu/nu balb-c mice at two sites, s.c. and i.p. Treatments of R6313/G2 at 2.5 nmol/kg and 25 nmol/kg twice per day for 7 days dose dependently reduced cell numbers for all three cell lines, but here MCF-7 cells responded most sensitively and MDA-MB-231 cells least. Although T47D cells were refractory at the s.c. site, growth was inhibited at the i.p. location, and otherwise results were similar at the two sites. In xenografts, MCF-7 cell tumours were dose dependently reduced by R6313/G2, and 13 and 27 nmol/kg R6313/G2 twice/day gave means of 74 and 76% tumour regression after 7 days. The data suggest that the anti-cancer action of R6313/G2 is considerably more effective than AT1 antagonists.
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PMID:Anti-cancer actions of a recombinant antibody (R6313/G2) against the angiotensin II AT1 receptor. 1831 Feb 94

In a previous investigation reduced apoptosis was identified in normal breast tissue from cancer-containing breasts away from the cancer in comparison to age-matched normal breast from women without cancer. The hypothesis for this study was that defects in expression of apoptotic regulatory and DNA repair proteins would facilitate persistence of genetic alterations and predispose to breast cancer development. Using immunohistochemistry normal breast from 120 age-matched women (58 with breast cancer, 62 without) was analysed for proliferation, apoptosis, bcl2, BAX, caspase 3, Hsp27, Hsp70, BRCA1, ATM and BARD1. All assessments were performed without knowledge as to whether it was a cancer case or control. A significant difference was found for apoptotic index which was higher in controls (P < 0.02). There was no change in apoptotic and proliferation index with age for cancer cases unlike controls. Higher expression of bcl2 (P = 0.001) and Hsp27 (P = 0.001) was found in normal breast from cancer-containing breast in comparison to controls. There were no differences in the other proteins. Apoptosis has been found to be reduced in normal breast in a separate cohort of women with breast cancer, along with increased expression of the anti-apoptotic proteins bcl2 and Hsp27. These alterations in apoptotic regulation would enhance tumour development. Further studies are needed to examine the value of these proteins as risk markers.
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PMID:Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts. 1836 76

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.
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PMID:Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. 1851 Sep 30

DNA damage induced apoptosis, along with precise DNA damage repair, is a critical cellular function, and both of these functions are necessary for cancer prevention. The NBS1 protein is known to be a key regulator of DNA damage repair. It acts by forming a complex with Rad50/Mre11 and by activating ATM. We show here that NBS1 regulates a novel p53 independent apoptotic pathway in response to DNA damage. DNA damage induced apoptosis was significantly reduced in NBS1 deficient cells regardless of their p53 status. Experiments using a series of cell lines expressing mutant NBS1 proteins revealed that NBS1 is able to regulate the activation of Bax and Caspase-3 without the FHA, Mre11-binding, or the ATM-interacting domains, whereas the phosphorylation sites of NBS1 were essential for Bax activation. Expression of apoptosis-related transcription factors such as E2F1 and their downstream pro-apoptotic factors were not related to this apoptosis induction. Interestingly, NBS1 regulates a novel Bax activation pathway by disrupting the Ku70-Bax complex which is required for activation of the mitochondrial apoptotic pathway. This dissociation of the Ku70-Bax complex can be mediated by acetylation of Ku70, and NBS1 can function in this process through a protein-protein interaction with Ku70. Thus, NBS1 is a key protein involved in the prevention of carcinogenesis, not only through the precise repair of damaged DNA by homologous recombination (HR) but also by its role in the elimination of inappropriately repaired cells.
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PMID:NBS1 regulates a novel apoptotic pathway through Bax activation. 1864 72


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