Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis,is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.
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PMID:Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. 1220 39

Recent studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies, including hepatocellular carcinoma (HCC), but so far it is unknown whether COX-2 contributes to the malignant growth and whether inhibition of COX-2 function modifies the malignant potential of liver tumors. COX-1 and COX-2 expression was determined in 4 liver tumor cell lines (Hep 3B, HuH-7, Hep G2, Sk-hep1) by Northern hybridization and Western immunoblot. The functional effects of the nonselective inhibitor sulindac sulfide and the COX-2 selective inhibitors SC-58635 and meloxicam were examined by 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide (MTT)-assays and BrdU uptake, morphology, and TUNEL analysis of apoptosis. Apoptosis regulating proteins were analyzed by Western immunoblot. COX-1 and COX-2 expression was demonstrable in all tested liver tumor cell lines. Sulindac sulfide (50 to 400 micromol/L), SC-58635 (6,25 to 400 micromol/L), and meloxicam (6.25 to 400 micromol/L) led to a significant time- and dose-dependent reduction of cell numbers of up to 80% (P <.05). At equimolar concentrations the effect was more pronounced when COX-2 was selectively blocked. COX-2 inhibition induced apoptosis and reduced tumor cell proliferation. Apoptosis after COX-2 inhibition with SC-58635 (50 micromol/L) was independent of BCL-2, BAX, and the phosphorylation status of AKT/PKB and BAD, but correlated with activation of caspase-9, caspase-3, and caspase-6. In conclusion, selective inhibition of COX-2 leads to a marked growth inhibition of human liver tumor cells, based on the induction of apoptosis and inhibition of proliferation and, thus, may offer therapeutic and preventive potential in human hepatocarcinogenesis.
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PMID:Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. 1229 35

Several studies have shown antitumor activities of the melanoma differentiation-associated gene 7 (mda-7) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previously been tested. Therefore, we tested the antitumor activity of an adenoviral vector expressing mda-7 (Ad-mda7) in combination with sulindac against non-small cell lung cancer cells in vitro and in vivo. When treated with Ad-mda7 in combination with sulindac, human lung cancer cells (A549 and H1299) underwent growth suppression resulting in apoptosis. The growth inhibition induced by Ad-mda7 in combination with sulindac was significantly greater than that observed with Ad-mda7 or sulindac alone. Furthermore, the degree of growth inhibition induced using this combination was dose-dependent for sulindac. Treatment with Ad-mda7 in combination with sulindac had no growth inhibitory effects on human normal lung (CCD-16) fibroblasts. We then investigated the mechanism by which sulindac enhances Ad-mda7-mediated apoptosis. Sulindac increased expression of ectopic MDA-7 protein in tumor cells, thereby increasing the expression of downstream effectors RNA-dependent protein kinase, p38MAPK, caspase-9, and caspase-3 and enhancing apoptosis of non-small cell lung cancer cells. Pulse-chase experiments showed that the increased expression of MDA-7 protein in sulindac-treated cells was due to increased half-life of the MDA-7 protein. Finally, treatment of human lung tumor xenografts in nude mice with Ad-mda7 plus sulindac significantly suppressed growth (P = 0.001) compared with Ad-mda7 or sulindac alone. Our results show for the first time that combined treatment with Ad-mda7 plus sulindac enhances growth inhibition and apoptosis of human lung cancer cells. The increased antitumor activity observed with the combination treatment is a result of increased half-life of MDA-7 protein. Regulation of protein turnover is a heretofore-unrecognized mechanism of this nonsteroidal anti-inflammatory drug.
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PMID:Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. 1571

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that induces apoptosis in cultured colon cancer cells and in intestinal epithelia in association with its chemopreventive efficacy. Resistance to sulindac is well documented in patients with familial adenomatous polyposis; however, the molecular mechanisms underlying such resistance remain unknown. We determined the effect of ectopic Bcl-2 expression upon sulindac-induced apoptotic signaling in SW480 human colon cancer cells. Sulindac sulfide activated both the caspase-8-dependent and mitochondrial apoptotic pathways. Ectopic Bcl-2 attenuated cytochrome c release and apoptosis induction compared with SW480/neo cells. Coadministration of sulindac sulfide and the small-molecule Bcl-2 inhibitor HA14-1 increased apoptosis induction and enhanced caspase-8 and caspase-9 cleavage, Bax redistribution, and cytochrome c and second mitochondria-derived activator of caspase release. Given that sulindac sulfide activated caspase-8 and increased membrane death receptor (DR4 and DR5) protein levels, we evaluated its combination with the endogenous death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Coadministration of sulindac sulfide and TRAIL cooperatively enhanced apoptotic signaling as effectively as did HA14-1. Together, these data indicate that HA14-1 or TRAIL can enhance sulindac sulfide-induced apoptosis and represent novel strategies for circumventing Bcl-2-mediated apoptosis resistance in human colon cancer cells.
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PMID:Sulindac sulfide-induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2. 1622 96

Sulindac sulfone (also known as exisulind) and its chemical derivatives are promising anticancer agents capable of inducing apoptosis in a variety of malignant cell types with minimal toxicity to normal cells. Here, we tested the ability of alpha-tocopheryl succinate (TOS), another promising anticancer agent, to sensitize colon cancer cells to exisulind-induced apoptosis. We found that sub-apoptotic doses of TOS greatly enhanced exisulind-induced growth suppression and apoptosis in the HCT116, LoVo and SNU-C4 human colon cancer cell lines. Our results revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8, -9 and -3. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor), z-IETD-FMK (a caspase-8 inhibitor) or z-LEHD-FMK (a caspase-9 inhibitor) blocked TOS and exisulind cotreatment-induced PARP cleavage and apoptosis. Furthermore, TOS/exisulind cotreatment induced JNK phosphorylation, while pretreatment with SP600151 (a JNK inhibitor) partially blocked cotreatment-induced caspase-dependent PARP cleavage and apoptosis. Taken together, these findings indicate that TOS sensitizes human colon cancer cells to exisulind-induced apoptosis. Apoptotic synergy induced by exisulind plus TOS seems likely to be mediated through a mechanism involving activation of caspases and JNK.
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PMID:Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis. 1719 Nov 16

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death.
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PMID:Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury. 2049 52