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)

Differentiation inducers act through polyamine-dependent and independent pathways. Sodium butyrate (NaB) inhibits proliferation and induces terminal differentiation in human and murine cancer cell lines. An effect of this agent on polyamine biosynthesis has not been demonstrated previously. In the present study, we examined the effects of NaB on polyamine biosynthesis in mouse colon cancer (MC-26) cells. All studies were performed on exponentially growing cells, and ODC and polyamine transport measurements were performed as described previously. NaB inhibited the growth of MC-26 cells in a dose-dependent manner. Cell shape was significantly altered by treatment with NaB (development of dendritic-like processes and flattening and spreading out of cells on culture dishes). NaB stimulated ODC activity in a dose-dependent manner. The activity was elevated by 8 h after treatment, and at 48 h there was a ten-fold increase in activity (compared with control activity). The increase in ODC activity led to an increase in polyamine biosynthesis; putrescine, spermidine, and spermine levels in MC-26 cells were significantly elevated by 24 h after treatment with NaB. Polyamine uptake was similar in control cells and cells treated with NaB alone. Our finding of significant stimulation of polyamine uptake by NaB after inhibition of endogenous synthesis (by an ODC-dependent pathway) in DFMO-treated cells suggests that cellular requirements are increased for polyamines in NaB-treated cells. We conclude that polyamine-dependent processes are important in the mechanism of action of NaB in colon cancer cells.
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PMID:Sodium butyrate stimulates polyamine biosynthesis in colon cancer cells. 134 Dec 66

Cytoplasmic alkalinization induced by activation of the Na+/H+ antiport plays an essential role in the initiation of cell proliferation. In the present study we examined the effects of amiloride, a specific and reversible inhibitor of Na+/H+ antiporter, on the growth of human colon cancer cells (HT-29). Amiloride (50-800 microM) inhibited the growth of HT-29 cells in a dose-dependent fashion. Forty-three percent inhibition of growth was found at an amiloride concentration of 400 microM after 4 days of treatment. The inhibitory effect of amiloride on growth of HT-29 cells was reversible since removal of amiloride by a media change after 48 h treatment lead to rapid regrowth to control levels. The reversibility of growth inhibition suggests that amiloride is not a non-specific cytotoxin for HT-29 cells. We examined the possible mechanisms for the inhibitory effects of amiloride. Amiloride (400 microM) completely abolished serum-stimulated ODC activity and inhibited difluoromethylornithine (DMFO)-stimulated putrescine uptake by 56%. We conclude that amiloride inhibits the in vitro growth of human colon cancer cells; since ODC-activity and polyamine transport were both inhibited, the inhibitory effects may be mediated in part by polyamine-dependent processes. Amiloride may be a useful agent in the treatment of colon cancer.
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PMID:Amiloride inhibits the growth of human colon cancer cells in vitro. 134 Dec 75

Our previous work on protein kinase C (PKC) and colon cancer has shown altered levels of PKC activity in human colon tumors, as well as activation of PKC by colon tumor promoters such as bile acids. To understand further the role of PKC in colon carcinogenesis, we analyzed the expression of phorbin, a gene induced by PKC activation, in a series of different stages of human colon tumors. As shown by northern blot analyses of poly (A)+ RNA, higher levels of phorbin RNA were seen in 26 colon tumor samples than in their adjacent normal colonic mucosa. There also appeared to be a correlation between the abundance of phorbin RNA in the tumors and the extent of invasion (tumor-to-normal tissue phorbin RNA ratio = 4.2, 8.0, and 11.9 for Dukes' A, B, and C, respectively). Phorbin RNA was also abundant in a human colon cancer line (HT29). We also examined the expression of other mitogen-responsive genes (c-myc, ODC, and beta-actin) in a set of 19 colon tumor samples. All tumors displayed significant (mean 3.8-fold) increases in the level of c-myc RNA compared with their adjacent normal colonic mucosa. About 47% and 16% of these tumor samples also showed increased levels of ODC (mean 3.1-fold) and beta-actin (mean 1.6-fold) RNA, respectively. The increased levels of c-myc, ODC, and beta-actin RNA did not correlate with the extent of tumor invasion. Taken together, these results demonstrate that human colon tumors usually display increased levels of both phorbin and c-myc RNAs. The marked increases in phorbin RNA suggest that this could serve as a useful biomarker in studies on human colon cancer.
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PMID:Increased levels of phorbin, c-myc, and ornithine decarboxylase RNAs in human colon cancer. 169 76

Proliferation of both mouse and human breast cancer cells was inhibited by chlorpheniramine (CPA) in a dose-response manner. At the beginning of the exponential phase of growth (two days after seeding), 250 microM CPA was able to reduce cell proliferation by 75% (in Ehrlich cell cultures) and 30% (in MCF-7 cultures). The antiproliferative effect of CPA was also tested on a poorly-differentiated and hormone-insensitive human breast cancer cell line (MDA-MB231) and on a highly proliferative human colon cancer cell line (clone 3). CPA was cytotoxic for MDA-MB231 cells at concentrations higher than 50 microM, and it was also cytotoxic for the colon cancer cell clone 3 at 250 microM CPA. Nevertheless, colon cancer cells were slightly stimulated at CPA concentrations less than 100 microM. CPA reduced (by 50-70%) the ornithine decarboxylase induction occurring early after culture seeding of experimental mammary tumors (Ehrlich carcinoma cells) and human breast cancer cells (MCF-7). The presented data suggest that in addition to ODC inhibition, CPA presents other still unknown cytotoxic effects.
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PMID:Chlorpheniramine inhibits the synthesis of ornithine decarboxylase and the proliferation of human breast cancer cell lines. 764 40

Inhibitory effects of OK-432 administered orally on DMH-induced colon tumors in rats were examined. As for the immunological parameter, NK activity was measured. ODC activity and nuclear DNA ploidy pattern of the tumor involved areas were evaluated and the histological examination was done in the process of the occurrence of tumors. Rats were divided into four groups as follows; control group, OK-432 group, DMH group and DMH+OH-432 group. As for the appearance of DMH induced colon tumors, the average numbers of tumors per rat in the DMH+OK-432 group were inhibited significantly compared with those in the DMH group, and the rate of cancer in situ in the DMH+OK-432 group significantly increased compared with that in the DMH group. NK activity of lymphocytes in the spleen and lymph nodes in the colon was increased after the oral administration of OK-432, but it was decreased following the peak activity, and it was lower level than that of the control group. An appropriate oral administration of OK-432 may be effective against chemically induced carcinoma of the colon.
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PMID:[Inhibitory effects of OK-432 administered orally on colon carcinoma induced by DMH in rats]. 783 6

The effect of difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase activity, was evaluated in vivo and in vitro on the growth of a gastrin-sensitive human colon carcinoma (WiDr). In vivo, mice bearing the tumor treated with pentagastrin had larger tumors with higher ornithine decarboxylase activity and polyamine content (P < 0.05) than mice not treated with pentagastrin. Difluoromethylornithine treatment significantly decreased ornithine decarboxylase in both the pentagastrin-treated and the untreated animals; however, DFMO had no effect on tumor volume, weight, protein, or DNA content. In cell culture, gastrin treatment increased WiDr cell number and [3H]thymidine incorporation in the presence or absence of serum. In serum-free conditions, however, gastrin stimulated cell growth without concomitantly increasing ODC activity. DFMO, on the other hand, decreased both ODC activity and growth. These studies suggest that the trophic effect of gastrin on WiDr human colon cancer is independent of ODC activity. Since gastrin treatment increased ODC activity in vivo, gastrin may interact in vitro with other factors present in serum that can alter ODC activity.
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PMID:Effects of gastrin and difluoromethylornithine on growth of human colon cancer. 844 85

The human colon can be described as a complex microbial ecosystem, comprising several hundred bacterial species. Some of these enteric bacteria are beneficial to the host and have been shown to exert antimutagenic and anticarcinogenic properties. We have investigated the colon tumor inhibitory activity of Bifidobacterium longum, a lactic acid-producing enterobacterium. The modifying effects of this lactic culture on colonic mucosal and/or tumor cell proliferation, ODC activity and ras-p21 oncoprotein expression in colon carcinogenesis were also analyzed. Male F344 rats were fed a modified AIN-76A diet containing 0 or 2% lyophilized cultures of B. longum and s.c. administered azoxymethane (AOM) dissolved in normal saline at a dose of 15 mg/kg body wt, once weekly for 2 weeks. Vehicle controls received an equal volume of normal saline s.c. Animals were maintained on control or experimental diets until termination of the study. Animals intended for analysis of cell proliferation were killed 20 weeks after the second AOM injection, whereas animals intended for colon tumor analysis and measurement of ODC activity and ras-p21 expression were killed 40 weeks after the last AOM injection. The data demonstrate that dietary administration of lyophilized cultures of B. longum resulted in significant suppression of colon tumor incidence and tumor multiplicity and also reduced tumor volume. Results also revealed that ingestion of B. longum significantly inhibited AOM-induced cell proliferation, ODC activity and expression of ras-p21 oncoprotein. Data suggest that oral administration of probiotic B. longum exerts strong antitumor activity, as indicated by modulation of the intermediate biomarkers of colon cancer, and consequently reduced tumor outcome.
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PMID:Bifidobacterium longum, a lactic acid-producing intestinal bacterium inhibits colon cancer and modulates the intermediate biomarkers of colon carcinogenesis. 911 Dec 22

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

Epidemiology has revealed that physical activity is an important lifestyle factor that reduces the risk of colon cancer. However, the underlying mechanisms of this protective effect have so far not been defined. The aim of this study was to identify molecular targets of physical activity in rat colon mucosa by employing our voluntary exercise model. Twenty male rats underwent a 12-week exercise program, with 9 additional rats serving as a control group. Running distances, body weights and heart weights as measures of physical adaptations were recorded, and changes in mRNA steady-state levels of marker genes involved in vascularization (VEGF, HIF-1 alpha, ODC-1), apoptosis (Bcl-2, PPAR gamma) and prostaglandin synthesis (COX-2) were determined by qRT-PCR. The four housekeeping genes GAPDH, beta-actin, 18S and ALDA served as reference genes. Recorded running distances showed great inter-individual differences resulting in three different groups of low (L-EX, < 2629 m/night; n=5), moderate (M-EX, 3003 - 7458 m/night; n=10) and high (H-EX, > 8314 m/night; n=5) physical activity. The M-EX and H-EX group revealed significant (p<0.05) adaptive changes with an increase in heart mass per kg body weight and a decrease in mean body weight. Amongst the marker genes studied by mRNA expression analysis only ODC-1 appears to be differentially expressed. Its 1.8-fold increased steady-state mRNA level in the H-EX group suggests that synthesis of polyamines may be increased by physical activity. This new finding could provide a link between extensive physical activity and its protective effects on colon cancer development.
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PMID:Exercise associated genes in rat colon mucosa: upregulation of ornithin decarboxylase-1. 1711 18

ODC (ornithine decarboxylase), a key enzyme of polyamine biosynthesis, is an inducible enzyme exhibiting high activity in tumour cells, suggesting ODC as a target for antineoplastic therapy. Among the inhibitors of polyamine-related enzymes, the ODC inactivator DFMO [2-(difluoromethyl)ornithine] became the most well-known. The drug is usually cytostatic and its effects on growth are reversed by micromolar concentrations of polyamines in the cellular environment. ODC inactivation is associated with decreased transcription of the growth-related c-myc and c-fos genes. DFMO used as a single drug has only minor effects on tumour growth. The low efficacy of the drug is due to the use of exogenous (gastrointestinal) polyamines by the mammalian organism. Although it was disappointing in most therapeutic attempts, DFMO showed potential in cancer chemoprevention based on its ability to lower polyamine levels in colorectal mucosa at low dosages with no demonstrable toxicity over long periods of use. DFMO in combination with other drugs prevents and inhibits the development of a variety of chemically induced cancers in animals with doses far lower than those administered for therapy. Low doses of several NSAIDs (non-steroidal anti-inflammatory drugs) and DFMO administered in combination have been shown to be more effective in inhibiting chemically induced colon tumours in rats than are high doses of these agents given individually. This combination has gained further interest after findings suggesting that ODC polymorphism is a genetic marker for colon cancer risk and supporting the use of DFMO and aspirin or other NSAIDs in combination as a strategy for colon cancer prevention.
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PMID:Revival of 2-(difluoromethyl)ornithine (DFMO), an inhibitor of polyamine biosynthesis, as a cancer chemopreventive agent. 1737 Dec 77


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