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)

Apoptosis plays a central role in tumor development and it has been hypothesized that lack/failure of apoptosis leads to the development of tumors, including colon tumors. Thus, induction of apoptosis in tumor cells is an effective approach to the regulation of tumor growth. It has been shown by us and other investigators that various chemopreventive agents induce apoptosis and inhibit tumor growth. Identification of agents or combinations of agents that induce tumor cell apoptosis guides the development of novel agents for colon cancer treatment. Experiments were designed to assess the effectiveness of lovastatin, a 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitor, and celecoxib a cyclooxygenase-2 inhibitor, individually or in combination on the induction of apoptosis in human HT-29 colon cancer cells. In addition, we studied the modulatory effect of lovastatin and celecoxib on lamin B levels, caspase-3 activity and expression in relationship to apoptosis in colon cancer cell lines. HT-29 cells exposed to various subtoxic levels of lovastatin or celecoxib or a combination of both were analyzed for apoptosis (by DAPI method), caspase-3 expression (immunoblot analysis) and caspase-3 activity (fluorimetric method). We found that: i) pretreatment with lovastatin (5-30 microM) induces apoptosis in HT-29 cells significantly only at high concentrations (> or = 20 microM) but not at low dose levels; ii) similarly, pretreatment with celecoxib produced apoptosis in colon cancer cells at high concentrations only (> or = 75 microM); iii) caspase-3 protein expression was moderately altered by the treatment with lovastatin or celecoxib at lower concentrations; however, a significant increase (1.6 to 4-fold) in caspase-3 expression and activity was found in HT-29 cells exposed with 20-25 microM lovastatin and/or 5-125 microM celecoxib and iv) importantly, in tumor cells exposed to low doses of (5 or 10 microM) lovastatin, combined with 25-75 microM of celecoxib, apoptosis induction rose 2.5 to 10-fold, caspase-3 expression was 2.3 to 8-fold higher, and enzyme activities were 1.5 to 5.5-fold elevated. This effect was highly synergistic and dose-dependent. Lamin B levels were significantly increased in a dose-dependent manner in cells treated with lovastatin but no such effect was observed with celecoxib. These results indicate that agents with different modes of action when applied in combinations will induce apoptosis synergistically by enhancing caspase-3 activities. These findings further support the hypothesis that HMGCo-R and COX-2 activities play important roles in apoptosis and regulation of apoptosis by selective agents such as lovastatin and celecoxib would provide effective strategies for the prevention of colon cancer.
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PMID:Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens. 1189 21

A number of small GTPases are involved in cancer cell proliferation, migration and invasion. They need to be prenylated for full biological functions. We have recently reported that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which block the biosynthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate, inhibit in vitro invasion of human pancreatic cancer cells. In the present study, we examined the effects of two selective inhibitors of prenylation, a farnesyltransferase inhibitor (FTI-277) and a geranylgeranyltransferase type I inhibitor (GGTI-298), on in vitro invasion of cancer cells in a modified Boyden chamber assay. The invasion of COLO 320DM human colon cancer cells was inhibited potently by HMG-CoA reductase inhibitor lovastatin and GGTI-298 but weakly by FTI-277. The treatment of cancer cells with GGTI-298 markedly caused RhoA to decrease in the membrane fraction and accumulate in the cytosolic fraction, whereas it had almost no effect on the translocation of Ras. FTI-277 markedly inhibited membrane localization of Ras, but its inhibitory effect on cancer cell invasion occurred only at doses that affected membrane localization of RhoA. FTI-277 and GGTI-298 decreased the growth potential of COLO 320DM cells, but the inhibitory effect of GGTI-298 was rather selective toward invasion in association with changes in cell morphology and RhoA localization. These results suggest that geranylgeranylation of RhoA by geranylgeranyltransferase type I is critical for cancer cell invasion, and inhibition of geranylgeranyltransferase type I activity should offer a novel approach to the treatment of invasion and metastasis of cancer cells resistant to farnesyltransferase inhibitors.
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PMID:Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor. 1459 91

Cytochrome P450 (CYP) gene transfer sensitizes tumor xenografts to anticancer prodrugs such as cyclophosphamide (CPA) without a detectable increase in host toxicity. Optimal prodrug activation is achieved when a suitable P450 gene (e.g., human CYP2B6) is delivered in combination with NADPH-cytochrome P450 reductase (P450R), which encodes the flavoenzyme P450 reductase. We sought to improve this gene therapy by coordinated delivery and expression of P450 and P450R on a single bicistronic vector using an internal ribosomal entry site (IRES) sequence. Retrovirus encoding a CYP2B6-IRES-P450R expression cassette was shown to induce strong P450-dependent CPA cytotoxicity in a population of infected 9L gliosarcoma cells. Adeno-P450, a replication-defective, E1/E3 region-deleted adenovirus engineered to express CYP2B6-IRES-P450R, induced intracellular CPA 4-hydroxylation, and CPA cytotoxicity, in a broad range of human cancer cell lines. However, limited Adeno-P450 gene transfer and CPA chemosensitization was seen with certain human tumor cells, notably PC-3 prostate and HT-29 colon cancer cells. Remarkable improvements could be obtained by coinfecting the tumor cells with Adeno-P450 in combination with Onyx-017, an E1b-55k gene-deleted adenovirus that selectively replicates in p53 pathway-deficient cells. Substantial increases in gene expression were observed during the early stages of viral infection, reflecting an apparent coamplification of the Adeno-P450 genome, followed by enhanced viral spread at later stages, as demonstrated in cultured tumor cells, and in A549 and PC-3 solid tumor xenografts grown in scid mice. This combination of the replication-defective Adeno-P450 with a replication-conditional and tumor cell-targeted helper adenovirus dramatically improved the low gene transfer observed with some human tumor cell lines and correspondingly increased tumor cell-catalyzed CPA 4-hydroxylation, CPA cytotoxicity, and in vivo antitumor activity in a PC-3 tumor xenograft model. The use of tumor-selective, replicating adenovirus to promote the spread of replication-defective gene therapy vectors, such as Adeno-P450, substantially increases the therapeutic potential of adenoviral delivery systems, and should lead to increased activity and enhanced tumor selectivity of cytochrome P450 and other gene-directed enzyme prodrug therapies.
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PMID:Use of replication-conditional adenovirus as a helper system to enhance delivery of P450 prodrug-activation genes for cancer therapy. 1472 37

5,10-Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme in folate-mediated 1-carbon metabolism. Reduced MTHFR activity has been associated with genomic DNA hypomethylation. Methylated cytosines at CpG sites are easily mutated and have been implicated in G:C-->A:T transitions in the p53 tumor suppressor gene. We investigated 2 polymorphisms in the MTHFR gene (C677T and A1298C) and their associations with colon tumor characteristics, including acquired mutations in Ki-ras and p53 genes and microsatellite instability (MSI). The study population comprised 1248 colon cancer cases and 1972 controls, who participated in a population-based case-control study and had been analyzed previously for MSI, acquired mutations in Ki-ras, p53, and germline MTHFR polymorphisms. Multivariable-adjusted odds ratios are presented. Overall, MTHFR genotypes were not associated with MSI status or the presence of any p53 or Ki-ras mutation. Individuals with homozygous variant MTHFR genotypes had a significantly reduced risk of G:C-->A:T transition mutations within the p53 gene, yet, as hypothesized, only at CpG-associated sites [677TT vs. 677CC (referent group) OR = 0.4 (95% CI: 0.1-0.8) for CpG-associated sites; OR = 1.5 (0.7-3.6) for non-CpG associated sites]. Genotypes conferring reduced MTHFR activity were associated with a decreased risk of acquired G:C-->A:T mutations within the p53 gene occurring at CpG sites. Consistent with evidence on the phenotypic effect of the MTHFR C677T variant, we hypothesize that this relation may be explained by modestly reduced genomic DNA methylation, resulting in a lower probability of spontaneous deamination of methylated cytosine to thymidine. These results suggest a novel mechanism by which MTHFR polymorphisms can affect the risk of colon cancer.
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PMID:MTHFR variants reduce the risk of G:C->A:T transition mutations within the p53 tumor suppressor gene in colon tumors. 1617 13

Thioredoxin (Trx) expression is increased in several human primary cancers associated with aggressive tumor growth and decreased patient survival, and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Various gold(III) compounds with none, one, two or three carbon-gold bonds were evaluated for their capacity to inhibit TrxR and the growth of MCF-7 cancer cells in vitro. Compounds with up to two carbon-gold bonds were often potent inhibitors of TrxR with IC50 values as low as 2 nmol/l. In the presence of Trx and insulin the inhibiting capacity was much lower. However, the inhibitory concentrations of the compounds did not correlate with the ability to kill cells. Out of the organometallics tested, only compound 8 with two carbon-gold bonds was able to inhibit colony formation by MCF-7 breast cancer cells at low micromolar concentrations (IC50=1.6 micromol/l). Unfortunately, the compound did not show any anti-tumor activity against MCF-7 breast cancer and HT-29 colon cancer xenografts in scid mice.
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PMID:Thioredoxin reductase and cancer cell growth inhibition by organogold(III) compounds. 1670 10

A growing body of experimental evidence suggests the therapeutic potential of diosgenin, a steroid [corrected] saponin against several cancers. However, precise molecular and cellular mechanisms underlying the modes of action of this compound against colon cancer remain only partially understood. In this study, we investigated if the anticancer mechanism of diosgenin in HCT-116 human colon carcinoma cells involves modulation in the expression of 3-hydroxy-3-methylglutaryl Co-enzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway. Diosgenin treatment resulted in a dose-dependent decrease in the viability and growth of HCT-116 cells. The IC(50) cytotoxic dose of diosgenin in HCT-116 was approximately 35 microM after 24h, while concentrations of approximately 32 microM or greater decreased the percent viable cells by 50%. Higher doses of diosgenin (30-40 microM) effectively inhibited recovery of cells for up to 24h post-treatments. At sub-cytotoxic doses, diosgenin induced a dose-dependent increase in apoptotic demise. In part, the apoptotic mechanism was through the cleavage of the 116 kDa poly (ADP-ribose) polymerase protein to the 85kDa fragment. The expression of HMG-CoA reductase at both mRNA and protein levels was significantly lowered by increasing concentrations of diosgenin. This was accompanied by a concomitant dose-dependent decrease in the expression of p21 ras and beta-catenin. In conclusion, our data demonstrates that the food saponin, diosgenin is a potent inhibitor of HCT-116 human colon carcinoma cells by growth inhibition and induction of apoptosis. Importantly, our result identifies that the growth suppressive or apoptotic activity of diosgenin may involve cholesterol homeostasis.
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PMID:Diosgenin, a naturally occurring steroid [corrected] saponin suppresses 3-hydroxy-3-methylglutaryl CoA reductase expression and induces apoptosis in HCT-116 human colon carcinoma cells. 1755 73

The antiproliferative and proapoptotic properties of melatonin in human colon cancer cells in culture were recently reported. To address the mechanisms involved in these actions, HT-29 human colon cancer cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum at 37 degrees C. Cell proliferation was assessed by the incorporation of [(3)H]-thymidine into DNA. Cyclic nucleotide levels, nitrite concentration, glutathione peroxidase and reductase activities, and glutathione levels were assessed after the incubation of these cells with the following drugs: melatonin membrane receptor agonists 2-iodo-melatonin, 2-iodo-N-butanoyl-5-methoxytryptamine, 5-methoxycarbonylamino-N-acetyltryptamine (GR-135,531), and the antagonists luzindole, 4-phenyl-2-propionamidotetralin, and prazosin; the melatonin nuclear receptor agonist CGP 52608, and four synthetic kynurenines analogs to melatonin 2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid, 2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid, 2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid and 2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid. The results show that the membrane receptors are not necessary for the antiproliferative effect of melatonin and the participation of the nuclear receptor in this effect is suggested. Moreover, the antioxidative and anti-inflammatory actions of melatonin, counteracting the oxidative status and reducing the production of nitric oxide by cultured HT-29 cells seem to be directly involved in the oncostatic properties of melatonin. Some of the synthetic kynurenines exert higher antiproliferative effects than melatonin. The results reinforce the clinical interest of melatonin due to the different mechanisms involved in its oncostatic role, and suggest a new synthetic pathway to obtain melatonin agonists with clinical applications to oncology.
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PMID:Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. 1764 98

Chinese red yeast rice (RYR) is a food herb made by fermenting Monascus purpureus Went yeast with white rice. RYR contains a mixture of monacolins, one of which--monacolin K (MK)--is identical to lovastatin (LV). Epidemiological studies show that individuals taking statins have a reduced risk of colon cancer. In the present study, LV decreased cellular proliferation (P<.001) and induced apoptosis (P<.05) in HCT-116 and HT-29 human colon cancer cells. RYR inhibited both tumor cell growths (P<.001) and enhanced apoptosis (P<.05) in HCT-116 cells. Inhibition of proliferation was reversed by mevalonate (MV) in LV-treated cells, since LV is a 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR) inhibitor. However, RYR with MV did not reverse the observed inhibition of growth. MK-free RYR did not reverse the observed LV-mediated inhibition of cancer cell growth. These observations suggest that other components in RYR, including other monacolins, pigments or the combined matrix effects of multiple constituents, may affect intracellular signaling pathways differently from purified crystallized LV in colon cancer cells. RYR was purified into two fractions: pigment-rich fraction of Chinese red yeast rice (PF-RYR) and monacolin-rich fraction of Chinese red yeast rice (MF-RYR). The effect of MF-RYR was similar to that of LV, while the effect of PF-RYR was similar to the effect of the whole RYR extract on the proliferation, apoptosis and mRNA level of HMGCR and sterol response element binding protein-2. These results suggest that the matrix effects of RYR beyond MK alone may be active in inhibiting colon cancer growth. RYR with or without MK may be a botanical approach to colon cancer chemoprevention worthy of further investigation.
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PMID:Anticancer effects of Chinese red yeast rice versus monacolin K alone on colon cancer cells. 1786 85

Chitosan oligosaccharide (COS, 3 kDa<MW<5 kDa) was tested for colon cancer chemoprevention by measuring the activities of quinine reductase (QR) and glutathione-S-transferase (GST), glutathione (GSH) levels, ornithine decarboxylase (ODC) activity, and cyclooxygenase (COX)-2 expression in HT-29 cells treated with COS. COS induced QR activity in a dose-dependent manner over a concentration range of 0.1-4.0 mg/ml. GST activity was also induced in HT-29 cells treated with COS. In addition, GSH levels were increased 1.3-, 1.4-, and 1.5-fold with COS at 2, 3, and 4 mg/ml, respectively. ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was inhibited by 33% and 39% with 3 and 4 mg/ml of COS, respectively. COS also inhibited the expression of TPA-induced COX-2 protein in HT-29 cells. These results suggest that COS has colon cancer chemopreventive activity by increasing QR and GST activities and GSH levels and by inhibiting ODC activity and COX-2 expression in vitro.
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PMID:Chemopreventive effect of chitosan oligosaccharide against colon carcinogenesis. 1806 35

Cancer chemopreventive activity of sulforaphane has been predominantly associated with its ability to induce phase II detoxification enzymes. In the present study, novel targets of sulforaphane were identified and characterized using a proteomics approach. Two-dimensional gel electrophoresis and mass spectrometry were used to produce protein profiles of human colon adenocarcinoma Caco-2 cells treated with 5 mumol/L sulforaphane for 48 h and control cells (0.05% DMSO). Gel comparisons showed the down-regulation to undetectable level of the serotonin receptor 5-HT(3) after sulforaphane treatment. In addition, Aldo-keto reductase and d-dopachrome decarboxylase were also differentially expressed in control and treated cell extracts. To elucidate two-dimensional gel findings, the neurotransmitter receptors 5-HT(3A), 5-HT(1A), 5-HT(2C), and the serotonin reuptake transporter were analyzed using Western blotting. Results showed a decrease of neurotransmitter receptors in a dose-dependent manner after sulforaphane treatment. Moreover, after exposure of Caco-2 cells to sulforaphane, nicotinic acetylcholine receptor protein level was increased. These findings suggested a potential effect of sulforaphane on serotonin release. Activation of neurotransmitter receptors followed by initiation of cyclic AMP signaling might be crucial events in colon carcinoma progression. Thus, the effect of sulforaphane may help to elucidate signaling pathways serotonin-mediated in colon cancer and lead to development of potential novel therapeutic agents.
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PMID:Serotonin receptors, novel targets of sulforaphane identified by proteomic analysis in Caco-2 cells. 1859 52


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