Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of the key enzyme in DNA synthesis, thymidylate synthase (TS), by 5-fluorouracil (5-FU) and the novel antifolate raltitrexed (Tomudex; ZD1694), induces dTTP depletion, resulting in DNA strand breaks, which can initiate pathways leading to an apoptotic mode of cell death. We studied 5-FU- and ZD1694-induced TS inhibition in relation to the expression of p53, p21, Bcl-2 and Bax in six colon carcinoma cell lines, two with a wild-type (wt) p53 (Lovo, LS174T) and four with a mutant (mt) p53 (WiDr, WiDr/F, HT29 and SW948) phenotype. In untreated cells, a reciprocal correlation between p53 and Bcl-2 was found: in cells with a low wt p53, Bcl-2 expression was present; whilst in cells with mt p53, Bcl-2 expression was not detectable. Exposure to 5-FU (50 and 100 microM) and ZD1694 (50 and 100 nM) for 24 and 48 h induced p53 and p21 expression in wt p53 cells, but not in mt p53 cells. TS was induced approximately 2-10-fold in all cell lines. TS induction was highest after ZD1694 exposure in the mt p53 cells HT29 and WiDr/F (6-10-fold). After 5-FU treatment, TS was present both as the free enzyme and in the ternary complex; however, predominantly as the ternary complex between TS, FdUMP and 5,10-methylenetetrahydrofolate. In wt p53 cells, both drugs increased Bax expression up to 5-fold, whereas in mt p53 cells, only a very slight induction was found. In wt p53 cells, Bcl-2 expression hardly changed after drug treatment. These results indicate a p53-independent induction of TS but a regulatory role of wt p53 in the synthesis of Bax in the colon carcinoma cell lines after TS inhibition.
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PMID:Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed. 1078 98

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new cytokine that was proposed to specifically induce apoptosis of cancer cells. In tumor cells that are resistant to the cytokine, subtoxic concentrations of chemotherapeutic drugs can restore the response to TRAIL. The present study further explores the mechanisms that determine tumor cell sensitivity to TRAIL by comparing four human colon carcinoma cell lines We show that colon cancer cell sensitivity to TRAIL-induced apoptosis and cytotoxicity correlates with the expression of the death receptors TRAIL-R1 and TRAIL-R2 at the cell surface, as determined by now cytometry, whereas the two decoy receptors TRAIL-R3 and TRAIL-R4 can be detected only in permeabilized cells. Clinically relevant concentrations of cisplatin and doxorubicin sensitize the most resistant colon cancer cell lines to TRAIL-induced cell death without modifying the expression nor the localization of TRAIL receptors in these cells. TRAIL induces the activation of procaspase-8 and triggers caspase-dependent apoptosis off colon cancer cells. Cytotoxic drugs lower the signaling threshold required for TRAIL-induced procaspase-8 activation. In turn, caspase-8 cleaves Bid, a BH3 domain-containing proapoptotic molecule of the Bcl-2 family and activates effector caspases. Together, these data indicate that chemotherapeutic drugs sensitize colon tumor cells to TRAIL-mediated caspase-8 activation and apoptosis.
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PMID:Anticancer agents sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated caspase-8 activation and apoptosis. 1124 78

The tumor suppressor p53 is an inducer of cell cycle arrest and programmed cell death (apoptosis). The ability of p53 to induce cell cycle arrest is linked to its ability to induce transcription of genes such as the cyclin-dependent kinase inhibitor p21. However, the dependence of p53-mediated apoptosis on transcriptional activation remains controversial. Ectopic expression of a temperature-sensitive (ts) p53 allele induced expression of p53 target genes and elicited both G1 and G2/M cell cycle arrest upon shift to the permissive temperature. Ectopic expression of the same ts p53 allele with two additional point mutations (Gln22, Ser23) that abolish p53-transcriptional activation did not induce p53 target genes and G1 nor G2/M cell cycle arrest. In HCT116 colon carcinoma cells ectopic expression of wild type p53 does not elicit apoptosis whereas p53 mutant deficient in trans-activation induces apoptosis. The ability of wild type p53 to induce apoptosis is restored in HCT116 cells that are null for p21. However, the trans-activation deficient mutant of p53 is still more potent mediator of apoptosis than wild type p53 in the p21 null cells. Although the ability of Gln22,Ser23 to trans-activate p53 target genes is diminished, it retains the ability to repress Bcl-2 expression. Thus, we conclude that while ectopic expression of wild type p53 can induce both G1 and G2/M arrest, in a p21 dependent manner, without apoptosis, a p53 mutant defective in trans-activation elicits apoptosis without inducing cell cycle arrest. Further, the anti-apoptotic function of p53 is dependent on trans-activation and is linked to cell cycle arrest. The results strongly suggest that the trans-activation deficient mutant is a more potent inducer of apoptosis because it lost its anti-apoptotic function and retains its ability to repress pro-apoptotic genes such as Bcl-2. Taken together, the results imply that employing a trans-activation deficient p53 in gene therapy approaches or the use of drugs that convert mutant p53 to a trans-activation-independent mediator of apoptosis may be much more efficient therapeutic approaches than current approaches that employ wild type p53.
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PMID:A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function. 1131 99

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in tumor cell lines, whereas normal cells appear to be protected from its cytotoxic effects. Therefore TRAIL holds promise as a potential therapeutic agent against cancer. To elucidate some of the critical factors that contribute to TRAIL resistance, we performed a genetic screen in the human colon carcinoma cell line SW480 by infecting this TRAIL-sensitive cell line with a human placental cDNA retroviral library and isolating TRAIL-resistant clones. Characterization of the resulting clones for inhibitors of TRAIL-induced death (ITIDs) led to the isolation of c-FLIP(S), Bax inhibitor 1, and Bcl-XL as candidate suppressors of TRAIL signaling. We have demonstrated that c-FLIP(S) and Bcl-XL are sufficient when overexpressed to convey resistance to TRAIL treatment in previously sensitive cell lines. Furthermore both c-FLIP(S) and Bcl-XL protected against overexpression of the TRAIL receptors DR4 and KILLER/DR5. When c-FLIP(S) and Bcl-XL were overexpressed together in SW480 and HCT 116, an additive inhibitory effect was observed after TRAIL treatment suggesting that these two molecules function in the same pathway in the cell lines tested. Furthermore, we have demonstrated for the first time that a proapoptotic member of the Bcl-2 family, Bax, is required for TRAIL-mediated apoptosis in HCT 116 cells. Surprisingly, we have found that the serine/threonine protein kinase Akt, which is an upstream regulator of both c-FLIP(S) and Bcl-XL, is not sufficient when overexpressed to protect against TRAIL in the cell lines tested. These results suggest a key role for c-FLIP(S), Bcl-XL, and Bax in determining tumor cell sensitivity to TRAIL.
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PMID:Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. 1148 1

Efficacy of chemotherapy in advanced stages of colorectal tumours is limited. The quinolone antibiotic ciprofloxacin was recently shown to inhibit growth and to induce apoptosis in human bladder carcinomas cells. We investigated the effect of ciprofloxacin on colon carcinoma lines in vitro. CC-531, SW-403 and HT-29 colon carcinoma and HepG2 hepatoma cells (control cells) were exposed to ciprofloxacin. Proliferation was assessed by bromodeoxyuridine-incorporation into DNA and apoptosis was measured by flow cytometry after propidium iodide or JC-1 staining. Expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax was analyzed by semiquantitative Western blot analysis and activity of caspases 3, 8 and 9 by substrate-cleavage assays. Ciprofloxacin suppressed DNA synthesis of all colon carcinoma cells time- and dose-dependently, whereas the hepatoma cells remained unaffected. Apoptosis reached its maximum between 200 and 500 microg ml(-1). This was accompanied by an upregulation of Bax and of the activity of caspases 3, 8 and 9, and paralleled by a decrease of the mitochondrial membrane potential. Ciprofloxacin decreases proliferation and induces apoptosis of colon carcinoma cells, possibly in part by blocking mitochondrial DNA synthesis. Therefore, qualification of ciprofloxacin as adjunctive agent for colorectal cancer should be evaluated.
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PMID:Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. 1187 13

Impaired apoptosis of T-lymphocytes is involved in the development of chronic inflammatory disorders. Previously we have shown that the anti-inflammatory drug sulfasalazine induces apoptosis in a murine T-lymphocyte cell line. The aims of the present study were to expand these observations to human systems and to analyse the molecular basis for sulfasalazine-induced apoptosis. Sulfasalazine induces apoptosis both in Jurkat cells, a human T-leukaemia cell line (ED50 value approximately 1.0 mM), and in primary human peripheral blood T-lymphocytes (ED50 value approximately 0.5 mM). In contrast SW620 colon carcinoma cells or primary human synoviocytes are not affected at these concentrations suggesting a cell type-specific sensitivity to sulfasalazine. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (deltapsi(m)). Sulfasalazine causes cytochrome c release from mitochondria and subsequent activation of caspase-3 and downstream substrates. However, the pan-caspase inhibitor Z-VAD.fmk fails to inhibit sulfasalazine-induced apoptosis. Sulfasalazine stimulates mitochondrio-nuclear translocation of the novel apoptogenic factor apoptosis-inducing factor (AIF) and triggers large-scale DNA fragmentation, a characteristic feature of AIF-mediated apoptosis. Sulfasalazine-induced DeltaPsi(m) loss, AIF redistribution, and cell death are fully prevented by overexpression of Bcl-2. In conclusion, our data suggest that sulfasalazine-induced apoptosis of T-lymphocytes is mediated by mitochondrio-nuclear translocation of AIF and occurs in a caspase-independent fashion. Sulfasalazine-induced apoptosis by AIF and subsequent clearance of T-lymphocytes might thus provide the molecular basis for the beneficial therapeutic effects of sulfasalazine in the treatment of chronic inflammatory diseases.
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PMID:Molecular mechanisms of sulfasalazine-induced T-cell apoptosis. 1238 74

The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms. Evidence indicates that COX-2 may regulate apoptosis and can influence the malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes and induce apoptosis in colorectal cancer cell lines, which may contribute to their antitumor effects. To determine whether forced COX-2 expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon carcinoma cells were stably transfected with the COX-2 cDNA, and two clones overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a dosage-dependent manner. Forced COX-2 expression significantly attenuated induction of apoptosis by all three of the drugs compared with parental HCT-15 cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2-overexpressing cells showed reduced cytochrome c and caspase activation, relative to parental cells. A specific inhibitor of caspase-3 restored cell survival after drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2 expression significantly attenuates apoptosis induction by NSAIDs and 5-FU through predominant inhibition of the cytochrome c-dependent apoptotic pathway. COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced apoptotic susceptibility.
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PMID:Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. 1241 64

Sodium salicylate is known to induce apoptosis in a variety of cancer cells. However, the molecular mechanism for salicylate-induced apoptosis is yet unclear. Here we show that in HCT116 colon carcinoma cells, 10 mM sodium salicylate induces caspase-3 activation and degradation of its substrates, poly(ADP-ribose) polymerase (PARP), beta-catenin, and retinoblastoma (Rb). In contrast, sodium salicylate did not exert any significant effects on the expression of Fas L that is implicated in extrinsic apoptotic pathway and the levels of Bcl-2 family proteins, Bcl-2, Bcl-xsl, and Bad, which are involved in intrinsic apoptotic pathway, and anti-apoptotic molecules, c-IAP1 and HSP73. In addition, 10 mM salicylate induced p53 tumor suppressor protein that plays an important role in cell cycle arrest or apoptosis and the induction seemed to be linked to its phosphorylation at Set 15. To investigate the signal pathways for salicylate-induced apoptosis, we examined the effects of sodium salicylate on protein kinase activities. Sodium salicylate activated p38MAPK through phosphorylation at Thr 180/Tyr 182 and Akt/PKB at Ser 473, whereas it partially activated ERK1/2 through its phosphorylation at Thr 202/Tyr 204. We also show that SB203580 (a specific p38MAPK inhibitor), but not other protein kinase inhibitors (PD98059, LY294002, and wortmannin), significantly prevented salicylate-induced apoptosis. These results suggest that sodium salicylate-induced apoptosis in HCT116 colorectal cancer cells is mediated by p38MAPK.
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PMID:Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. 1285 2

beta-Lapachone is a naturally occurring quinone obtained from the bark of the lapacho tree (Tabebuia avellanedae) with cancer chemopreventive properties. The objective of the present study was to investigate the effect of beta-lapachone on the cell growth and apoptosis in human colon carcinoma tumor cell line HCT-116. Exposure of HCT-116 cells to beta-lapachone resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy and flow cytometric analysis. This increase in apoptosis was associated with a decrease in Bcl-2 protein expression, an increase in caspase-3 activity, a decrease in intact poly(ADP-ribose) polymerase protein levels and degradation of beta-catenin. After beta-lapachone treatment, the nuclear protein levels of NF-kappaB and the activity of NF-kappaB-DNA binding were markedly decreased. beta-Lapachone treatment also resulted in inhibition of the transcriptional activity of NF-kappaB-luciferase reporter plasmid suggesting that beta-lapachone-induced apoptosis may be partly regulated through the inactivation of NF-kappaB.
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PMID:beta-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. 1459 80

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have chemopreventive activity against colorectal tumors. Although the molecular mechanism has not been fully established, it is thought to involve the ability of NSAIDs to induce apoptosis. Because the majority of colon carcinomas are known to overexpress antiapoptotic proteins such as survivin and Bcl-2 and show only limited ability to undergo apoptosis, we hypothesized that the ability of sulindac to cause regression of adenomas and to inhibit colon carcinogenesis is mediated, at least in part, by down-regulation of one or more of these antiapoptotic proteins. To test this hypothesis, we exposed HT-29 colon carcinoma cells to sulindac. Sulindac induced a sustained decrease in mRNA and protein expression for survivin but not for Bcl-2. This finding suggests that sulindac is selectively acting through a survivin-related pathway. This is consistent with our earlier finding that inhibition of the beta-catenin:T-cell factor 4 (Tcf-4) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces beta-catenin degradation, which would reduce Tcf-4 activation. This suggests that the beta-catenin:Tcf-4:survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.
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PMID:The chemopreventive agent sulindac attenuates expression of the antiapoptotic protein survivin in colorectal carcinoma cells. 1461 Feb 17


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