Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.
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PMID:Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth. 1093 52

Sulindac possesses an inhibitory effect on colorectal cancer development. Rat colon cancer cells, ACL-15, inoculated subcutaneously in F344 rats were used. Sulindac was administered at 8 mg/kg twice daily for 7 consecutive days. Sulindac group and control group were compared regarding tumor volume and body weight. At sacrifice, the tumors were collected and examined for tumor-infiltrating lymphocytes, apoptotic index, and microvessel density. The tumor volume in the sulindac group was significantly smaller than that in the control group. Body weight, microvessel density, and tumor-infiltrating lymphocyte score were not significantly different between the two groups. The apoptotic index was significantly higher in the sulindac group than in the control group. Sulindac inhibited tumor growth by inducing apoptosis. These findings may be helpful in designing new treatment strategies in colorectal cancer patients.
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PMID:Sulindac inhibits growth of rat colon carcinoma by inducing apoptosis. 1111 Nov 76

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert COX-dependent effects by distinct mechanisms.
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PMID:Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells. 1111 42

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac is associated with a decreased mortality from colorectal cancer. Sulindac causes regression of precancerous adenomatous polyps and inhibits the growth of cultured colon cell lines. Whereas induction of apoptotic cell death is thought to account for the growth inhibitory effect of sulindac, less is known about its biochemical mechanism(s) of action. Sulindac is metabolized in vivo to sulfide and sulfone derivatives. Both the sulfide and sulfone metabolites of sulindac as well as more potent cyclic GMP-dependent phosphodiesterase inhibitors were shown to cause inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation at doses (40-600 microM) and times (1-5 days) consistent with the induction of apoptosis by the drugs. Treatment of HCT116 human colon cancer cells with the specific mitogen-activated protein kinase kinase, U0126 (5-50 microM) resulted in a time- and dose-dependent inhibition of ERK1/2 phosphorylation, and induction of apoptosis. U0126 treatment (20 microM) increased basal apoptosis, and potentiated the apoptotic effect of sulindac sulfide and sulindac sulfone. These results suggest that the inhibition of ERK1/2 phosphorylation is responsible for at least part of the induction of programmed cell death by sulindac metabolites. Inhibition of ERK1/2 activity may, therefore, be a useful biochemical target for the development of chemopreventive and chemotherapeutic drugs for human colon cancer.
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PMID:Inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and induction of apoptosis by sulindac metabolites. 1124 63

(-)-Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit anti-cancer activity. Sulindac is also well known as a cancer-preventive agent against colon cancer, but its usage is restricted because of its adverse effects, as exemplified by gastrointestinal bleeding. In the present study, we examined whether a combination of EGCG and sulindac shows synergistic effects for cancer-preventive activity for rat colon carcinogenesis induced by azoxymethane (AOM); we examined the number of aberrant crypt foci (ACF) representing preneoplastic lesions, the argyrophilic nucleolar organizer region (AgNOR) as an indicator of cell proliferation, and the incidence of apoptosis. The AOM treatment induced an average of 46.2+/-4.9 ACF/colon, and sulindac and EGCG significantly reduced the incidence of ACF/colon to 21.4+/-3.4 and 19.5+/-5.8, respectively (P<0.01). The co-treatment with EGCG and sulindac resulted in significantly reduced ACF formation (10.0+/-3.2; P<0.01). The results of the AgNOR analysis indicated that the treatment with EGCG and/or sulindac suppressed AOM-induced cell proliferation. The present results also revealed that the combination of EGCG and sulindac synergistically enhanced apoptosis significantly (P<0.01). Thus, our findings suggest that EGCG with sulindac synergistically suppresses ACF formation by enhancing apoptosis and, therefore, that EGCG is a suitable candidate for use in combination with cancer-preventive agents, such as sulindac, to reduce their adverse effects.
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PMID:Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane. 1180 30

Apoptosis dysfunction in metastases has been suggested to participate in their poor response to conventional anticancer treatments. To address this question, we have analyzed the sensitivity to cell death induced by non-steroid anti-inflammatory drug, Sulindac, the most common drug used in colon cancer chemotherapy, 5-fluorouracil (5-FU) and the short chain fatty acid, butyrate (Bu) in cell lines derived from a primary colorectal tumor (ALT-I) as well as the liver (ALT-F) and the lymph-node (ALT-G) metastases. We have previously shown both in vitro by analyzing anchorage-independent cell proliferation and in vivo by subcutaneous injection into athymic nude mice that the ALT-F and ALT-G cells were more tumorigenic than the primary ALT-I cells. All these cell lines, derived from an untreated patient, were highly resistant to apoptosis induced by 5-FU and Sulindac but were sensitive to Bu-induced apoptosis. The resistance to apoptosis was, as quantified by the induction of caspase activity and the relative percentage of apoptotic cells, higher in the metastatic cell lines, than in the ALT cell line. When compared to the primary tumor, more anti-apoptotic bcl-2 and less pro-apoptotic bax were expressed in the liver and lymph node metastatic cell lines. Quite remarkably, the expression of bax was up-regulated during Bu-treatment, a feature that could explain its powerful pro-apoptotic activity.
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PMID:Resistance to apoptosis is increased during metastatic dissemination of colon cancer. 1196 82

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

Colorectal cancer is the second leading cause of cancer death in the United States. Nonsteroidal anti-inflammatory drugs including sulindac are promising chemopreventive agents for colorectal cancer. Sulindac and selective cyclooxygenase (COX)-2 inhibitors cause regression of colonic polyps in familial polyposis patients. Sulindac induces apoptotic cell death in cancer cells in vitro and in vivo. In tumor cells, activation of extracellular-regulated kinase (ERK) 1/2 results in phosphorylation of several ERK1/2 effectors, including the proapoptotic protein Bad. Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis. Sulindac metabolites and other nonsteroidal anti-inflammatory drugs selectively inhibit ERK1/2 phosphorylation in human colon cancer cells. In this study we show that epidermal growth factor (EGF) strongly induces phosphorylation of ERK1/2 and Bad in HT29 colon cancer cells. EGF-stimulated phosphorylation of ERK and Bad is blocked by pretreatment with U0126, a selective MAP kinase kinase (MKK)1/2 inhibitor. Similarly, pretreatment with sulindac sulfide blocks the ability of EGF to induce ERK1/2 and Bad phosphorylation, but also down-regulates total Bad but not ERK1/2 protein levels. The ability of sulindac to block ERK1/2 signaling by the EGF receptor may account for at least part of its potent growth-inhibitory effects against cancer cells.
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PMID:Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells. 1256 4

Sulindac and other NSAIDs have been widely studied as potential chemopreventive agents for colon cancer. Short-term studies have shown adenomatous polyps to regress in patients with familial adenomatous polyposis (FAP). In this study the effect of sulindac on cancer as an endpoint was evaluated in ApcMin mice, a preclinical model of FAP with an Apc mutation in codon 850 that leads to gastrointestinal adenomas and carcinomas. Three groups of mice were studied all of which were fed AIN-76A diet: one group was fed AIN-76A diet alone, a second group received sulindac 200 p.p.m. premixed in the diet and a third group received sulindac 180 p.p.m. added in drinking water. ApcMin mice were killed 9 weeks after feeding was initiated. Mice receiving sulindac developed fewer tumors in the intestine overall; the major decrease in tumor development after sulindac was seen in the small intestine regardless of route of administration. In the large intestine, however, sulindac significantly increased the incidence, multiplicity and volume of tumors in the colon of ApcMin mice, a regional response to sulindac differing from previous reports. Quantitative measurements of apoptosis, Bax and Bcl-xL protein expression in the ApcMin mice revealed the ratio of Bax/Bcl-xL expression and apoptosis increased in the small intestine but decreased in the cecum, consistent with the regional tumorigenesis observed after sulindac. These findings thus suggest involvement of Bax and apoptosis in tumors developing after sulindac treatment in this mouse model.
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PMID:Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations. 1266 24

Sulindac and other nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to anti-inflammatory properties, express preventive activity against colon cancer. This antineoplastic effect may result from the suppression of polyp development in patients with familial adenomatous polyposis. However, despite intense investigations the exact mechanism for sulindac protective effect is not fully elucidated. Angiogenesis, the process of new blood vessel formation, is required to support tumor growth and may be partially involved in the transformation of polyps into tumor. Therefore, we tested the hypothesis whether sulindac might inhibit angiogenesis. The effects of sulindac metabolites, sulindac sulfide and sulindac sulfone, on vascular development were evaluated using the chick embryo chorioallantoic membrane (CAM) assay in vivo. The angiogenic response was quantitated by several methods including direct stereomicroscopic observation, measurements of hemoglobin content and DNA synthesis whereas quantitation of apoptosis was based on determinations of caspase-3 activity, caspase-3 and bax protein expression, and nuclear DNA fragmentation. Our results indicated that both sulindac metabolites were equally effective in inhibition of new blood vessel formation in CAM during chick embryo development. Moreover, both metabolites of sulindac induced the process of apoptosis parallelly to the inhibition of angiogenesis.
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PMID:Anti-angiogenic and apoptotic effects of metabolites of sulindac on chick embryo chorioallantoic membrane. 1271 91


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