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)

The mechanisms of adrenal damage induced by 7,12-dimethylbenz (alpha) anthrancene (DMBA) in 50-day-old female Sprague--Dawley rats were investigated. A single dose of DMBA, either fed (30 mg) per os or injected (6 mg) in a caudal vein, caused inner cortical cell death (cells of the zonae fasciculata and reticularis) by an apoptotic mechanism. Apoptotic cells were identified by cell morphology, and terminal dUTP nick end labeling (TUNEL)-positive cells were seen at 12 hrs post-DMBA, reached a maximum at 36 h, and were accompanied by blood congestion followed by massive hemorrhage leading to post-apoptotic necrosis at 48 and 72 h. The apoptotic cascade involved the up-regulation of Bax, the down-regulation of Bcl-2, and the activation of caspase-3. At 72 h, regeneration as evidenced by the appearance of 5-bromo-2'-deoxyuridine-positive cells began to occur in the damaged inner cortical zones, with the cells proliferating toward the medulla thereafter. Regenerative cells expressed cytochrome P450 11 beta hydroxylase. The damage was repaired but calcification appeared at 2 weeks post-DMBA, leaving bow-shaped lesions in some adrenals.
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PMID:Mechanisms of adrenal damage induced by 7,12-dimethylbenz (alpha) anthrancene in female Sprague--Dawley rats. 1126 59

1. The role of endogenous nitric oxide in rat hepatocyte functionality and survival in cell culture was examined. Towards this aim, cytochrome P450 activities (CYP1A1/2, 2B1, 2A1, 2C11, 2D1, 2E1 and 3A1), liver-specific metabolic functions and cell survival were comparatively evaluated in hepatocytes isolated from the male Sprague-Dawley rat and/or cultured in control conditions or in the presence of N-omega-nitro-L-arginine methyl ester (NAME), an inhibitor of nitric oxide synthesis. 2. Suppression of nitric oxide production by NAME paralleled a substantial preservation of hepatocyte phenotype in culture. The presence of NAME was particularly important during isolation and/or the 6-24h culture. By 24h, beneficial effects were evident in parameters particularly unstable in culture (glycogen content, P450), whereas no changes were produced in well-preserved functions (glucose, urea and albumin synthesis, glutathione, drug-conjugating enzymes). 3. Long-term treatment of hepatocytes with NAME also produced a reduction in caspase 3 activation and in the percentage of spontaneous apoptotic cells, and an increase in cell survival and transcriptional activity as shown by attached cellular protein content and the protein-DNA ratio respectively. 4. In conclusion, inhibition of early endogenous nitric oxide formation is an efficient procedure for obtaining hepatocyte cultures with stable expression of differentiated functions, high cell survival and few signs of cell senescence.
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PMID:Role of endogenous nitric oxide in liver-specific functions and survival of cultured rat hepatocytes. 1149 87

Cyclophosphamide (CPA), a widely used oxazaphosphorine anti-cancer prodrug, is inactive until it is metabolized by cytochrome P450 to yield phosphoramide mustard and acrolein, which alkylate DNA and proteins, respectively. Tumor cells transduced with the human cytochrome P450 gene CYP2B6 are greatly sensitized to CPA, however, the pathway of CPA-induced cell death is unknown. The present study investigates the cytotoxic events induced by CPA in 9L gliosarcoma cells retrovirally transduced with CYP2B6, or induced in wild-type 9L cells treated with mafosfamide (MFA) or 4-hydroperoxyifosfamide (4OOH-IFA), chemically activated forms of CPA and its isomer ifosfamide. CPA and MFA were both shown to effect tumor cell death by stimulating apoptosis, as evidenced by the induction of plasma membrane blebbing, DNA fragmentation, and cleavage of the caspase 3 and caspase 7 substrate poly(ADP-ribose) polymerase (PARP) in drug-treated cells. Caspase 9 was identified as the regulatory upstream caspase activated in 9L cells treated with CPA, MFA, or 4OOH-IFA, implicating the mitochondrial apoptotic pathway in oxazaphosphorine-induced tumor cell death. Correspondingly, expression of the mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma membrane blebbing, and drug-induced cytotoxicity. Conversely, overexpression of the mitochondrial antiapoptotic factor Bcl-2 blocked caspase 9 activation, leading to an inhibition of drug-induced plasma membrane permeability and blebbing, terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity, PARP cleavage, Annexin V positivity, and drug-induced cell death. Although Bcl-2 thus blocked the cytotoxic effects of activated CPA, it did not inhibit the drug's cytostatic effects. CPA induced S-phase cell cycle arrest followed by conversion to an apoptotic pre-G1 state in wild-type 9L cells; by contrast, Bcl-2-expressing 9L cells accumulated in G2/M in response to CPA treatment. Intratumoral expression of Bcl-2 and related family members, including both apoptotic and antiapoptotic factors, is thus an important determinant of the responsiveness of tumor cells to CPA and ifosfamide, both in the context of conventional chemotherapy and in patients sensitized to these oxazaphosphorine drugs by the use of cytochrome P450-based gene therapy.
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PMID:Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells. 1172 34

We employed cDNA microarray analysis to identify, in mammary adenocarcinomas induced by 7,12-dimethylbenz[a] anthracene (DMBA) in the rat, target genes as potential biomarkers for cancer chemoprevention by 1,4-phenylenebis(methylene)selenocyanate (p-XSC). Confirmation of selected genes was conducted by reverse transcription polymerase chain reactions (RT-PCR). The glutathione conjugate, p-XSeSG, a putative metabolite of p-XSC was also employed to test our hypothesis that p-XSeSG is a more effective cancer chemopreventive agent in the mammary cancer model than p-XSC. Mammary adenocarcinomas were induced by a single oral administration of 5 mg DMBA in 0.2 ml olive oil per rat at 50-55 days of age. Consistent with our previous reports, dietary p-XSC at a non-toxic dose (10 p.p.m. as selenium) significantly inhibited adenocarcinoma development, independent of feeding duration. Moreover, p-XSeSG appears to be just as effective as p-XSC when fed after DMBA administration, but was significantly less effective than p-XSC in inhibiting the induction of mammary adenocarcinomas when it was fed before DMBA and continued until termination. To delineate the molecular basis for cancer chemoprevention by organoselenium compounds, we focused our analysis on differential expression of genes known to be involved in DMBA metabolism, as well as those related to cell cycle, cell proliferation and apoptosis. p-XSC and p-XSeSG were significantly and equally effective in inhibiting levels of expression of genes associated with cytochrome P450 isoforms, but the former was more active than the latter in up-regulating the expression of those related to certain phase II enzymes. p-XSC and p-XSeSG were significantly more effective in the up-regulation of pro-apoptotic genes, such as p21CIP1/WAF1, p27KIP1, APO-1 and Caspase-3, while down-regulating cell growth regulatory genes, such as c-myc, cyclin D1, cyclin D2 and proliferating cell nuclear antigen (PCNA). To our knowledge, this is the first report that provides insights into the effects of p-XSC and p-XSeSG at the molecular level that may account for mammary cancer chemoprevention in vivo in the rat.
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PMID:Elucidation of molecular targets of mammary cancer chemoprevention in the rat by organoselenium compounds using cDNA microarray. 1284 80

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.
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PMID:3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. 1455 Jul 50

Transforming growth factor-beta (TGF-beta) induces an oxidative stress process in hepatocytes that mediates its apoptotic activity. To determine the cellular source of the early reactive oxygen species (ROS) generated by fetal rat hepatocytes in response to TGF-beta, we used inhibitors that block different ROS-producing systems. Diphenyleneiodonium, which inhibits NADPH oxidase and other flavoproteins, completely blocked the increase in ROS induced by TGF-beta, coincidently with an impairment of caspase-3 activation and cell death. Rotenone, an inhibitor of the NADH dehydrogenase in mitochondrial complex I, attenuated, but did not completely inhibit, ROS-production, caspase activation, and cell death mediated by TGF-beta. No significant protection was observed with inhibitors of other ROS-producing systems, such as cytochrome P450 (metyrapone), cyclooxygenase (indomethacin), and xanthine oxidase (allopurinol). Additional experiments have indicated that two different mechanisms could be involved in the early ROS production by TGF-beta. First, an inducible (cycloheximide-inhibited) NADPH oxidase-like system could account for the extramitochondrial production of ROS. Second, TGF-beta could increase ROS by a rapid downregulation of antioxidant genes. In particular, intramitochondrial ROS would increase by depletion of MnSOD. Finally, glutathione depletion is a late event and it would be more the consequence than the cause of the increase in ROS induced by TGF-beta.
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PMID:Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-beta in fetal rat hepatocytes. 1473 87

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the dietary carcinogens. At the initial step in the carcinogenic process, its exocyclic amino group is metabolically activated to the hydroxyamino derivative by the cytochrome P450 (CYP) 1A and 1B subfamily and then form DNA adducts, which are considered to be the main cause of DNA damage during the carcinogenic process. On the other hand, our previous study has shown that Trp-P-1 exhibits cytotoxicity to primary cultured rat hepatocytes, via induction of caspase-9-dependent apoptosis without being metabolized by CYP 1A1. In the present study, we investigated what type of DNA damage would be involved in the induction of apoptosis induced by Trp-P-1. When RL-34 cells derived from normal rat liver were treated with a high (30 microM) concentration of Trp-P-1, apoptotic events such as the loss of cell viability, nuclear condensation and the activation of caspase-3 were observed. In these apoptotic cells, intracellular topoisomerase I activity was inhibited and histone H2AX phosphorylation, which occurs after introduction of DNA double-strand breaks (DSBs), was observed in the early phase of the apoptosis. On the other hand, treatment with a non-apoptotic concentration (1 microM) of Trp-P-1 increased the formation of 8-hydroxy-2'-deoxyguanosine. The formation of DNA adducts was detected at almost the same level in both cells exposed to the apoptotic and non-apoptotic concentrations of Trp-P-1. These results indicate that Trp-P-1-induced apoptosis was triggered by DNA DSBs through the inhibition of topoisomerase I but not the formation of DNA adducts.
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PMID:3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) triggers apoptosis by DNA double-strand breaks caused by inhibition of topoisomerase I. 1497 28

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10(-5) mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor kappaB (NFkappaB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFkappaB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.
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PMID:HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. 1549 66

The halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to induce immunotoxicity, but relatively little is known regarding its effects on B-lymphocytes, and on avian B-cells in particular. In this study, the avian bursal pre-B-cell line DT40 was exposed to TCDD ranging from 1 to 500 nM for 1 and 6 h. At 100 nM, TCDD caused a significant increase in the number of apoptotic cells, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay, and induced the expression of the chicken cytochrome P450 1A4 (CYP1A4) mRNA, a hallmark of TCDD exposure. TCDD induced transient upregulation of aryl hydrocarbon receptor (AhR) mRNA. At 100 nM, both caspase 3 and caspase 9 were transiently upregulated after 1 h, but returned to normal levels after 6 h of exposure. Challenge with TCDD after AhR blockade with resveratrol, a competitive AhR antagonist, prevented changes in caspases 3 and 9 and in the AhR message itself, suggesting that the effects of TCDD were mediated via the AhR. TCDD did not cause significant changes in the relative gene expression of caspase 8, Bcl-2 and Bcl-xL. We conclude that avian DT40 pre-B-cells exposed to TCDD are susceptible to apoptosis, likely through activation of executioner caspase 3.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin elicits aryl hydrocarbon receptor-mediated apoptosis in the avian DT40 pre-B-cell line through activation of caspases 9 and 3. 1553 54

We previously showed that inhibition of catalase and glutathione peroxidase activities in rat primary hepatocytes by 3-amino-1,2,4-triazole (ATZ) and mercaptosuccinic acid (MS) results in endogenous oxidative stress and apoptosis. For the present study, we determined whether this apoptosis involved activation of caspase-3, which is known to execute apoptosis in many cell types. ATZ and MS increased levels of reactive oxygen species (ROS) from 3-9 h, just before the onset of chromatin condensation (apoptosis) and decreases in protein thiols. Pretreatment with either SKF, a cytochrome P450 inhibitor, or L-ascorbic acid, an antioxidant, completely suppressed the increase in ROS levels and apoptosis, suggesting that the sustained ROS increases may cause the apoptosis. SKF also abolished the decrease in protein thiol content, further supporting the contribution of the P450 system to increased ROS levels. DEVD-CHO, a caspase-3 inhibitor, even at 1 mM had no effect on apoptosis. Caspase-3 activity remained unchanged and pro-caspase-3 processing was not detected during 18 h incubation with ATZ and MS. Moreover, the amount of unoxidized pro-caspase-3 decreased even below the level of untreated hepatocytes. These findings suggest that the sustained oxidative stress is a major cause for the hepatocyte apoptosis, which occurs independently of the caspase-3 related pathway.
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PMID:Primary hepatocyte apoptosis is unlikely to relate to caspase-3 activity under sustained endogenous oxidative stress. 1576 64


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