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)

Genetic knockout or pharmacological inhibition of cyclooxygenase-2 decreases the number and size of adenomas in mouse models of familial adenomatous polyposis. Epidemiological and clinical studies in humans indicate that the entire class of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both COX-1 and COX-2 enzymes are promising colon cancer chemopreventive agents. We used the Apc mutant Min mouse model to test combinations of agents that might maximize preventive benefit with minimal toxicity because they act via different mechanisms. Min mice (n = 144) were exposed to low doses of the nonselective COX inhibitor piroxicam and the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO), beginning at the time they were weaned and continuing throughout the duration of the experiment. Piroxicam at 12, 25, and 50 ppm in the diet caused dose-dependent decreases in the number of tumors in the middle and distal portions of the small intestine. This decrease in tumor multiplicity was associated with a striking decrease in the size of those tumors that did grow out. In contrast, none of the doses of piroxicam alone decreased tumor multiplicity in the proximal portion of the intestine (duodenum). Exposure to DFMO (0.5 or 1.0% in water) caused a dose-dependent decrease in tumor multiplicity in the middle and distal portions of the small intestine. However, this decreased multiplicity was not associated with a striking decrease in the size of the tumors. Combined treatment of mice with piroxicam plus DFMO was much more effective than either agent alone and resulted in a significant number of mice totally free of any intestinal adenomas (P < 0.001), in contrast to the 100% incidence and high multiplicity in control Min mice. In addition to this profound effectiveness in reducing tumor number, the few residual tumors in mice treated with the combined drugs were markedly smaller in size than tumors that arose from control Min mice. These experiments suggest that selective COX-2 inhibition combined with ODC inhibition is a very promising approach for colon cancer prevention. These COX-2 and ODC inhibitor drugs were not overtly toxic at the doses used when administered to mice after weaning. However, when treatment was begun in utero, the Mendelian expected progeny ratio of 1:1 that we routinely obtained in untreated control litters was no longer observed. Apc(min)/+ progeny of pregnant dams treated with piroxicam and/or DFMO were reduced in number and their ratio to Apc+/+ progeny was decreased to approximately 0.28:1. Thus, these agents are effective against adenomas that have homozygous mutation of the APC gene and also select against fetuses bearing a heterozygous mutation in the APC gene.
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PMID:Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos. 1076 73

Deoxycholic acid (DCA) has long been implicated as tumour-promoting agent in the colon. Polyamines are necessary for cell proliferation, they are accumulated in high amounts in colon cancer cells, and their concentrations in the colonic lumen can reach millimolar levels. The aim of this study was to investigate the effects of physiological DCA concentrations on proliferation and polyamine content in human colon cancer cells (Caco-2) in culture. Over an initial 48 h in culture, DCA stimulated Caco-2 cell proliferation rate three-fold, reaching a maximum with 20 microM DCA. DCA-induced increases in ornithine decarboxylase (ODC) activity corresponded to peak proliferation rates, occurring only during the initial 48 h of cell proliferation. Treatment with low-dose DCA resulted in a two-fold increase in putrescine uptake, first noted after 2 days in culture, but persisting until the cells became confluent (day 5). Both basal and DCA-stimulated putrescine uptake in Caco-2 cells were saturable. Kinetic analysis of the uptake data showed that DCA-stimulated putrescine uptake was due to an increase in the capacity of the putative putrescine transporter, without changes in its affinity, therefore implying an increased number of putrescine transporters in the cell membrane, without change in their structure.
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PMID:Low-dose deoxycholic acid stimulates putrescine uptake in colon cancer cells (Caco-2). 1080 8

Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 microM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.
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PMID:Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. 1094 May 13

The nonsteroidal anti-inflammatory drug sulindac and the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) are both potent inhibitors of colon carcinogenesis in experimental models of this disease. The combination of these two agents is undergoing evaluation as a strategy for colon cancer chemoprevention in humans with resected colon polyps. We evaluated the effects of the major sulfide and sulfone metabolites of sulindac and DFMO alone, or in combinations, on the growth and survival of Caco-2 colon cancer-derived cells and in clones of these cells transfected with an activated K-ras oncogene. Both the sulfide and sulfone metabolites of sulindac reduced cell viability, measured by colony-forming assays, primarily by inducing apoptosis. Expression of an activated K-ras oncogene caused cells treated with either sulindac sulfide or sulfone to undergo apoptosis earlier than nontransfected controls. However, clonogenic survival, measured 2 weeks after drug treatment, was the same in both Caco-2 and ras-transfected Caco-2 cells treated with sulindac metabolites. A 24-h treatment with DFMO caused a dose-dependent decrease in the colony-forming ability of cells expressing an activated K-ras but had no effect on the viability of the parental Caco-2 cells. The DFMO-dependent decrease in colony formation in K-ras-activated cells occurred in the absence of apoptosis. Assessment of cell survival by colony-forming assays indicated that these two agents acted in an additive manner when combined. These data indicate that K-ras can influence the kinetics of apoptosis induction by sulindac metabolites and cell survival in response to DFMO. However, cytotoxicity induced by these agents occurs via unique mechanisms. These studies suggest that the combination of DFMO and sulindac may be useful in human cancer prevention strategies.
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PMID:Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine. 1109 22

In 1998 we reported that an L-peptide derived from H1 of c-Myc (Int-H1-S6A,F8A), linked to an internalization sequence from the third a-helix of Antennapedia, was endowed with an antiproliferative and proapoptotic activity toward a human mammary cancer cell line: The activity apparently depends upon the presence of the Myc motif. In the present work we have added new dimensions to our original findings. It is known that short retro-inverso (RI-) peptides can assume a 3D conformation very close to their corresponding L-forms and can be recognized by the same monoclonal antibody. We synthesized a RI-peptide form of our original L-peptide: It was much more resistant to serum peptidases than the original molecule (a half life of days rather than hours); in addition, the RI-form of the original Antennapedia internalization sequence was perfectly capable of carrying a D-peptide into human cells. We have studied three different potentially active peptides. L-peptides: Int-H1wt, Int-H1-S6A,F8A. D-peptides: RI-Int -H1-S6A,F8A. We have also studied three presumed control peptides: Int and RI-Int (no H1 motif), H1-S6A,F8A (no internalization sequence). Both 'active' and 'control' peptides have essentially confirmed our expectations, however, in cells treated with the higher concentration (10 mM) of the control peptide RI-Int, non-Myc related side effects could be detected. In order to investigate whether the antiproliferative activities displayed by some of our molecules were indeed related to an interference with the role of c-Myc (and molecules of the family), we chose an iso-amphipathic modified peptide of the H1 motif, with a proximity coefficient >50% and where the major change was at position 7 (F-->A). From a family of 73 H1 motifs belonging to (H1-Loop-H2) hu man sequences, the smallest evolutionary distance from our reference peptide was observed for the H1 of N-Myc, L-Myc, c-Myc, H1-S6A,F8A of c-Myc, and Max, in that order. Our reference peptide was therefore appropriate as a check of whether we were indeed observing activities related to Myc functions. Both Int-H1isoamph and the corresponding RI-Int-H1isoamph peptide were synthesized and studied. In terms of biological targets, we added to the human mammary cancer line of our previous work (MCF-7 cells) a colon cancer line (HCT-116 cells) and also a system of normal cells: human peripheral blood lymphocytes (PBLs) stimulated with phytohemoagglutinin (PHA). Peptides carrying an iso-amphipathic-modified H1 sequence were always very clearly (3-10 times) less active than the corresponding peptides carrying a conserved "H1 of Myc" motif. This finding was noted in five independent situations (all the cellular models considered at the present time): MCF-7 cells treated with L-peptides; MCF-7 cells treated with RI-peptides; HCT-116 cells treated with L-peptides; PBLs treated with L-peptides; PBLs treated with RI-peptides. Modulation of transcription levels of ornithine decarboxylase (ODC), p53, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in PBLs treated with our different molecules, was well compatible with an interference by our active peptides at the level of Myc transcriptional activity. We had already reported a similar observation in MCF-7 cells. On a molar basis, RI-peptides were about 5-10 times more potent and 30-35 times more stable in complete culture medium, than their corresponding L-forms. RI-Int can probably internalize longer peptido-mimetic molecules (for instance molecules mimetic of (H1-Loop-H2), or even more. These possibilities open the way to rodent studies and to more potent/selective Myc inhibitors-two steps closer to a potential drug.
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PMID:A retro-inverso peptide homologous to helix 1 of c-Myc is a potent and specific inhibitor of proliferation in different cellular systems. 1109 87

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

Using an original microcalorimetric method, we previously showed that in erythrocytes from cancer patients, the sodium pump activity was decreased and returned to normal in patient in remission. In addition we suggested that a plasma-borne factor probably secreted by cancer cells accounted for this impairment of the sodium transporter. In the present study we sought to identify this factor as well as its mechanism of action. First we determined the effect of culture media from undifferentiated and differentiated colon cancer cell lines (Caco-2 and HT29-D4) on the sodium pump activity of normal human erythrocytes. The inhibitory powers of culture media from undifferentiated cells were higher than those of differentiated cells (38.6 +/- 3.5% vs 6.9 +/- 4.6%, p<0.05 for Caco-2 and 45.8 +/- 6.2% vs 9.0 +/- 5.0%, <0.05 for HT29-D4). The use of alpha difluoro-methylomithine (2 mM) to inhibit ornithine decarboxylase, the rate-limiting enzyme for polyamine biosynthesis, dramatically reduced the sodium pump inhibition induced by the two undifferentiated cell lines (75% for Caco-2 and 89% for HT29-D4). Polyamines secreted by undifferentiated cells and then taken up by human erythrocytes thus appeared as inhibitors of sodium pump of these red blood cells. Putrescine, spermidine, and spermine (the main polyamines) exerted a similar inhibitory effect (33 +/- 2%). Tested in vitro on Na,KATPase, these polyamines (3 mM) were inhibitors (putrescine = 23 +/- 2%; spermidine= 48 +/- 3%; spermine= 55 +/- 2%) when assay condition for the ATPase reaction was suboptimal (Na+ = 10 mM; K+ = 1 mM). The inhibitory effect appeared to be related to their charge and their aliphatic chain length. The effect of spermidine and spermine on the ionic substrates and ATP-Mg showed that molecules decreased the affinity (Km) of the Na,K-ATPase for Na+ (11.24 +/- 0.49 mM for control vs 23.51 +/- 1.53 mM for spermine and 18.86 +/- 0.98 mM for spermidine), indicating that polyamines exerted their inhibitory effect in a competitive manner.
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PMID:Polyamines secreted by cancer cells possibly account for the impairment of the human erythrocyte sodium pump activity. 1135 5

The polyamines spermidine and spermine and their precursor, putrescine, are required for the growth and proliferation of eukaryotic cells. This study compares and contrasts growth arrest caused by polyamine depletion in the untransformed IEC-6 cell line with that in the p53-mutated colon cancer Caco-2 cell line. Cells were grown in the presence or absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in the synthesis of polyamines. Depletion of polyamines inhibited the growth of both cell lines equally and over the same time frame. However, whereas IEC-6 cells were arrested in the G(1) phase of the cell cycle, there was no accumulation of Caco-2 cells in any particular phase. In IEC-6 cells, growth arrest was accompanied by elevated levels of p53 and p21(Waf1/Cip1) (p21). There were no changes in p53 levels in Caco-2 cells. Levels of p21 increased in Caco-2 cells on day 2 without any effect on cell cycle progression. The amount of cyclin-dependent kinase (Cdk)2 protein was unchanged by polyamine depletion in both cell lines. However, the activity of Cdk2 was significantly inhibited by DFMO in IEC-6 cells. These data suggest that in the untransformed IEC-6 cells the regulation of Cdk2 activity and progression through the cell cycle are p53- and p21 dependent. Growth arrest in the p53-mutated Caco-2 line after polyamine depletion occurs by a different, yet unknown, mechanism.
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PMID:Polyamine depletion arrests growth of IEC-6 and Caco-2 cells by different mechanisms. 1140 53

Geraniol and other monoterpenes found in essential oils of fruits and herbs have been suggested to represent a new class of agents for cancer chemoprevention. As a first step in clarifying the mode of action of geraniol on colon carcinogenesis, we studied its effects on the growth of a human colon cancer cell line (Caco-2). Geraniol (400 microM) caused a 70% inhibition of cell growth, with cells accumulating in the S transition phase of the cell cycle, and concomitant inhibition of DNA synthesis. No signs of cytotoxicity or apoptosis were detected. Geraniol caused a 50% decrease of ornithine decarboxylase activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. This led to a 40% reduction of the intracellular pool of putrescine. Geraniol also activated the intracellular catabolism of polyamines, indicated by enhanced polyamine acetylation. These observations indicate that polyamine metabolism is presumably a target in the antiproliferative properties of geraniol.
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PMID:Geraniol, a component of plant essential oils, inhibits growth and polyamine biosynthesis in human colon cancer cells. 1140 42

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is involved in suppression of growth of several types of tumors such as liposarcoma, breast cancer, prostate cancer, and colon cancer, possibly through induction of cell cycle arrest and/or apoptosis. In this study, we demonstrated expression of PPAR-gamma mRNA and protein in human esophageal carcinoma cells. Expression of PPAR-gamma protein was higher in an adenocarcinoma cell line (TE-7 cells) than in a squamous cell carcinoma cell line (TE-1 cells). PPAR-gamma ligands such as 15-deoxy-Delta12,14-prostaglandin J2 and troglitazone significantly inhibited the growth of TE-7 cells but had less or no effect on growth of TE-1 cells. 15d-PGJ2 and troglitazone induced apoptosis in TE-7 cells but not in TE-1 cells. Troglitazone caused G1 cell cycle arrest and reduced ornithine decarboxylase activity (ODC) in TE-7 cells but not in TE-1 cells. Inhibition by PPAR-gamma ligands of growth of esophageal adenocarcinoma cells may thus be due to induction of apoptosis, G1 cell cycle arrest and reduction of ODC activity.
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PMID:PPAR-gamma ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity. 1149 23


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