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)

Weekly administrations of the potent carcinogen 1,2-dimethylhydrazine (DMH) predominantly induce carcinoma of the colon by nearly 100% after six months' treatment in rats. Polyamines, and especially the key enzyme of polyamine de novo synthesis ornithine decarboxylase (ODC) are well-known to play an important role in cell growth and tumor carcinogenesis. Male Wistar rats were s. c.-injected with a single dose of 20 mg DMH/kg b. wt. and five to eight animals were sacrificed 4, 8, 12, 24, 72, 120, 168, and 240 hours after injection of DMH or the basic solution, respectively. Additionally, seven animals were simultaneously treated with the ODC inhibitor alpha-difluoromethylornithine (DFMO) and sacrificed seven days after a single DMH injection. A single s. c.-dosage of the colon carcinogen DMH resulted in dissimilar activation patterns of polyamine metabolism in the various organs studied: in distal and less pronounced in proximal colonic mucosa ODC and putrescine are significantly increased seven days after application of DMH and DNA polymerase after ten days; in small intestinal mucosa ODC activity is significantly elevated after seven days and especially S-adenosylmethionine decarboxylase activity is significantly and prolonged increased between twelve and 72 hours after DMH injection; while spermidine/spermine N1-acetyltransferase activity is significantly elevated in liver after 168 and 240 hours, no changes compared to controls are found in the pancreas. DFMO treatment completely prevents DMH-induced activation of polyamine de novo synthesis and DNA polymerase in colon and small intestine. These data prove completely different and -interestingly-late appearing activation patterns of DMH on intracellular polyamine metabolism in various organ systems and further elucidate the complex metabolic changes following carcinogen treatment.
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PMID:Dissimilar activation patterns of the carcinogen dimethylhydrazine (DMH) on intracellular polyamine metabolism in various organs. 901 96

Polyamine synthesis (by the action of ornithine decarboxylase [ODC] and S-adenosylmethionine decarboxylase [SAMDC]) and polyamine content are high in colon cancer. In addition, colonic lumen is rich in polyamines synthesised by colonic microflora; for this reason, polyamine depletion in colon cancer may be a logical approach to impair growth of colon cancer cells. We evaluated highly specific and reportedly non-toxic hydroxylamine-containing inhibitors of ODC (1-aminooxy-3-aminopropane, APA) and SAMDC (S-(5'-deoxy-5'-adenosyl)-methylthioethyl-hydroxylamine, AMA) in human colon cancer cells (Caco-2 and HT-29) in culture. APA depleted ODC activity within 24 hr, more rapidly than did difluoromethylornithine. APA and AMA in combination (100 microM each) reduced ODC and SAMDC activities to undetectable levels within 24 hr and intracellular polyamines to 8-23% of control. The resulting growth arrest could be reversed only by twice as much spermidine as is physiologically present in the colonic lumen. In concentrations sufficient to deplete growth, APA and AMA were not toxic. Simultaneous treatment with APA, AMA, and 5-fluorouracil reduced colon cancer cell survival more potently than treatment with 5-fluorouracil alone. The hydroxylamine-containing ODC and SAMDC inhibitors APA and AMA are potent inhibitors of colon cancer cell proliferation and might be therapeutically promising in colon cancer.
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PMID:Hydroxylamine-containing inhibitors of polyamine biosynthesis and impairment of colon cancer cell growth. 1116 34

Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.
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PMID:Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization. 1294 93

Apple procyanidins have chemopreventive properties in a model of colon cancer, they affect intracellular signalling pathways, and trigger apoptosis in a human adenocarcinoma-derived metastatic cell line (SW620). In the present study we investigated relationships between procyanidin-induced alterations in polyamine metabolism and apoptotic effects. Apple procyanidins diminish the activities of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, key enzymes of polyamine biosynthesis, and they induce spermidine/spermine N(1)-acetyltransferase, which initiates retroconversion of poly-amines. As a consequence of the enzymatic changes polyamine concentrations are diminished, and N(1)-acetyl-polyamines accumulate in SW620 cells. In contrast with expectations MDL 72527, an inactivator of polyamine oxidase (PAO), improved the anti-proliferative effect of procyanidins, and caused an increase of the proportion of apoptotic cells, although it prevented the formation of hydrogen peroxide and 3-acetamidopropanal, the cytotoxic products of PAO-catalysed degradation of N(1)-acetylspermidine and N1-acetylspermine. Addition of 500 microM N1-acetylspermidine to the culture medium in the presence of procyanidins mimicked the effect of MDL 72527. Therefore we presume that the enhanced procyanidin-triggered apoptosis by MDL 72527 is mediated by the accumulation of N(1)-acetyl-polyamines. The observation that apple procyanidins enhance polyamine catabolism and reduce polyamine biosynthesis activity similar to known inducers of SSAT, without sharing their toxicity, and the potentiation of these effects by low concentrations of MDL 72527 suggests apple procyanidins for chemopreventive and therapeutic interventions.
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PMID:Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells. 1682 Aug 85

S-adenosylmethionine decarboxylase (SAMDC) is an essential enzyme for the synthesis of spermidine and spermine in the biosynthetic pathway of polyamines. The total RNA was extracted from colon cancer tissue and amplified by reverse-transcription PCR with two primers, which span the coding region of SAMDC alpha subunit. Clone vector pMD18-T-SAMDC-alpha was successfully constructed by using T-A clone technique. pMD18-T-SAMDC-alpha and pTriEx-4 were digested by NcoI and XhoI double enzymes. The purified SAMDC-alpha fragment was subcloned into the expression vector pTriEx-4 to construct the prokaryotic expression plasmid pTriEx-4-SAMDC-alpha. The recombinant plasmid pTriEx-4-SAMDC-alpha was transformed into competence E. coli JM109 (DE3). The bacterium was induced by IPTG and its lysates were loaded directly onto SDS-PAGE. An approximately 32 kDa exogenous protein was observed on the SDS-PAGE. The protein was verified by Western blot with anti His.Tag monoclonal antibody. The fusion protein including 6 x His.Tag was purified by Ni-NTA chromatographic column. Then, the purified protein can be applied for further research of the immunity of SAMDC.
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PMID:Cloning, expression and purification of human S-adenosylmethionine decarboxylase gene alpha subunit. 1759

The polyamines spermidine and spermine are synthesized in almost all organisms and are also contained in food. Polyamine synthesis decreases with aging, but no significant decrease in polyamine concentrations were found in organs, tissues, and blood of adult animals and humans. We found that healthy dietary patterns were associated with a preference for polyamine-rich foods, and first reported that increased polyamine intake extended the lifespan of mice and decreased the incidence of colon cancer induced by repeated administration of moderate amounts of a carcinogen. Recent investigations have revealed that changes in DNA methylation status play an important role in lifespan and aging-associated pathologies. The methylation of DNA is regulated by DNA methyltransferases in the presence of S-adenosylmethionine. Decarboxylated S-adenosylmethionine, converted from S-adenosylmethionine by S-adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize spermine and spermidine and acts to inhibit DNMT activity. Long-term increased polyamine intake were shown to elevate blood spermine levels in mice and humans. In vitro studies demonstrated that spermine reversed changes induced by the inhibition of ornithine decarboxylase (e.g., increased decarboxylated S-adenosylmethionine, decreased DNA methyltransferase activity, increased aberrant DNA methylation), whose activity decreases with aging. Further, aged mice fed high-polyamine chow demonstrated suppression of aberrant DNA methylation and a consequent increase in protein levels of lymphocyte function-associated antigen 1, which plays a pivotal role on inflammatory process. This review discusses the relation between polyamine metabolism and DNA methylation, as well as the biological mechanism of lifespan extension induced by increased polyamine intake.
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PMID:Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet. 3100 29