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)

The tumor-suppressor gene p16INK4/CDKN2 (p16) is a cyclin-dependent kinase (cdk) inhibitor and important cell cycle regulator. Here, we show that adenovirus-mediated gene transfer of p16 (AdCMV.p16) into colon cancer cells induces uncoupling of S phase and mitosis and subsequently apoptosis. Flow cytometric analysis revealed that cells infected with AdCMV.p16 showed an initial G2-like arrest followed by S phase without intervening mitosis (DNA >4N). Using microscopic analysis, deformed polyploid cells were detectable only in cells infected with AdCMV.p16 but not in control-infected cells. Subsequently, AdCMV.p16-infected polyploid cells underwent apoptosis, as assessed by AnnexinV staining and DNA fragmentation, suggesting that cell cycle dysregulation is upstream of the onset of apoptosis. Treatment of mice with subcutaneously transplanted tumors of colorectal cancer cells with AdCMV.p16 but not AdCMV.p53 resulted in significantly reduced tumor volume and prolonged survival. Using an orthotopic model of liver metastasis, we observed both reduced local tumor growth and secondary intrahepatic metastasis after AdCMV.p16 treatment. Importantly, induction of apoptosis in vitro and reduction of tumor growth in vivo by p16 was p53- as well as bax-independent because identical results were obtained using cancer cells, either wild type or mutant for p53 or bax. The studies suggest that an AdCMV.p16-based treatment may be especially effective in patients with bax-negative colon cancer where overexpression of p53 appears not to be of therapeutic value.
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PMID:Adenovirus-mediated gene transfer of P16INK4/CDKN2 into bax-negative colon cancer cells induces apoptosis and tumor regression in vivo. 1213 24

NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. NB1011 is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted drugs, which require inhibition of TS to be effective, because NB1011 cytotoxicity depends upon activation by TS. Here we report a dose-dependent, antitumor activity of NB1011 against established Tomudex-resistant breast cancer (MCF7TDX) xenografts in athymic mice. Against 5-fluorouracil-resistant colon carcinoma (H630R10) xenografts, NB1011 was as efficacious as irinotecan, a drug recently approved for the treatment of 5-fluorouracil-resistant colon cancer. To gain insight into the mechanisms NB1011 uses to suppress cellular growth, we analyzed the downstream molecular events in the high TS-expressing MCF7TDX and RKOTDX cell lines upon NB1011 treatment. NB1011 treatment increased the mRNA levels of p21, Bax, and GADD45. Furthermore, NB1011 induced p53, p21, and Bax proteins specifically in high TS-expressing tumor cells, whereas no induction was observed in low TS-expressing tumor cells (MCF7) or normal cells (WI38). Cell cycle analysis demonstrated that NB1011 treatment of MCF7TDX and RKOTDX cells resulted in an accumulation of cells in the G2-M phase of the cell cycle. Altogether, our data indicate that the induction of the p53 target genes p21, bax, and GADD45, with a concomitant deregulation of the cell cycle, may represent one of the mechanisms by which NB1011 exerts its growth-suppressive effects.
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PMID:Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and correlates with p53, p21, bax, and GADD45 induction. 1247 50

Recent progress in molecular biology and genetics has improved understanding of the mechanisms of carcinogenesis. However, there are few effective methods for prevention or therapies against cancer based on such elucidated molecular mechanisms of carcinogenesis. We therefore tried to develop novel methods of cancer prevention and therapy based on them. For example, the tumor-suppressor gene p53 is mutated in about 50% of human malignancies or in a cancer-prone family with Li-Fraumeni syndrome. It is known that p53 stimulates the promoter activities of p21/WAF1, gadd45 and bax genes to enhance their expression as a transcriptional factor, resulting in cell cycle arrest, DNA repair and apoptosis, respectively. Therefore, chemical compounds or food factors that can stimulate these genes might compensate for part of the p53 function. As a model of our hypothesis, we found that histone deacetylase inhibitors such as butyrate and trichostatin A dramatically stimulate the p21/WAF1 gene promoter through the Sp1 sites, resulting in cell cycle arrest. We therefore hypothesized that a strategy for up-regulating p53-target genes such as p21/WAF1, gadd45 and bax might be useful for cancer prevention or therapy, and termed this method "Gene-regulating chemoprevention" or "Gene-regulating chemotherapy" against cancer. In fact, butyrate, a short chain fatty acid, exists in colon lumen as a metabolite of dietary fiber, and is believed to be preventive against colon cancer. In conclusion, we proposed that "Gene-regulating chemoprevention" and "Gene-regulating chemotherapy" may be new promising strategies for cancer prevention or therapy, and histone deacetylase inhibitors are good candidates for these strategies. "Gene-regulating chemoprevention" is a particularly suitable model for "Molecular-targeting prevention", which we have proposed recently. We believe that "Molecular-targeting prevention" will become one of the most important concepts in the 21st century for general prevention of a variety of common hereditary or non-hereditary common diseases.
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PMID:[Gene-regulating chemoprevention against cancer--as a model for "molecular-targeting prevention" of cancer]. 1280 65

Chemotherapy of advanced stages of colorectal carcinoma is unsatisfactory. Retinoids inhibit cell growth and induce apoptosis in a variety of human malignancies. We compared the effect of the synthetic retinoid adapalene (ADA) and 9-cis-retinoic acid (CRA) on carcinoma cell lines in vitro. Colon carcinoma cell lines CC-531, HT-29 and LOVO as well as human foreskin fibroblasts were exposed to different concentrations of ADA and CRA for 3-72 hr. Proliferation was assessed by BrdU incorporation and apoptosis by FACS analysis. Breakdown of DeltaPsi(m) was determined by JC-1 staining and activity of caspases 3 and 8, by a colorimetric assay. Quantitative Western blots were performed to detect changes in bax, bcl-2 and caspase-3. Both retinoic derivatives suppressed DNA synthesis and induced apoptosis in all tested cell lines time- and dose-dependently. While the natural retinoid CRA showed moderate antiproliferative and proapoptotic effects only at the highest concentration (10(-4) M), the synthetic retinoic ADA was significantly more effective, showing remarkable effects even at 10(-5) M. ADA and CRA disrupt DeltaPsi(m) and induce caspase-3 activity in responsive tumor cells. Quantitative Western blots showed a shift of the bax:bcl-2 ratio toward proapoptotic bax in ADA-treated cells. Our results clearly indicate the superiority of ADA compared to CRA. Therefore, we suggest that ADA may be far more suitable as an adjunctive therapeutic agent for treatment of colon cancer in vivo.
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PMID:The synthetic retinoid adapalene inhibits proliferation and induces apoptosis in colorectal cancer cells in vitro. 1450 47

The mitochondrial permeability transition pore and Bax have both been proposed to be involved in the release of pro-apoptotic factors from mitochondria in the "intrinsic" pathway of apoptosis. The permeability transition pore is widely thought to be a supramolecular complex including or interacting with Bax. Given the relevance of the permeability transition in vivo, we have verified whether Bax influences the formation and/or the properties of the Ca(2+)/P(i)-induced permeability transition by using mitochondriaisolated from isogenic human colon cancer bax(+/-) and bax(-/-) HCT116 cell lines. We used mitochondria isolated from both types of cells and from Bax(+) cells exposed to apoptotic stimuli, as well as Bax-less mitochondria into which exogenous Bax had been incorporated. All exhibited the same behavior and pharmacological profile in swelling and Ca(2+)-retention experiments. Mitochondria from a bax(-)/bak(-) cell line also underwent an analogous Ca(2+)/P(i)-inducible swelling. This similarity indicates that Bax hasno major role in regulating the Ca(2+)-induced mitochondrial permeability transition.
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PMID:Bax does not directly participate in the Ca(2+)-induced permeability transition of isolated mitochondria. 1522 26

Puerarin was isolated from Pueraria radix and has beneficial effects on cardiovascular, neurological, and hyperglycemic disorders. The current study showed that puerarin also possessed anti-cancer properties. Methyl thiazolyl tetrazolium assay (MTT) assay revealed a dose-dependent reduction of HT-29 cellular growth in response to puerarin treatment. Apoptosis was observed following treatments ;with >or=25 microM puerarin, as reflected by the appearance of the subdiploid fraction and NDA fragmentations. We then investigated effects of puerarin on expression of apoptosis-associated genes and the results revealed an increase of bax and decreases of c-myc and bcl-2. Finally, puerarin treatment significantly increased the activation of caspase-3, a key executioner of apoptosis. These findings indicate that puerarin may act as a chemopreventive and/or chemotherapeutic agent in colon cancer cells by reducing cell viability and inducing apoptosis.
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PMID:Induction of apoptosis by puerarin in colon cancer HT-29 cells. 1605 62

Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 microM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50-100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC.
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PMID:Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. 1628 Mar 30

Sulforaphane (SFN) is an isothiocyanate from broccoli that induces phase 2 detoxification enzymes. We recently reported that SFN acts as a histone deacetylase (HDAC) inhibitor in human colon cancer cells in vitro, and the present study sought to extend these findings in vivo. In mice treated with a single oral dose of 10 mumol SFN, there was significant inhibition of HDAC activity in the colonic mucosa after 6 h, and immunoblots revealed a concomitant increase in acetylated histones H3 and H4, which returned to control levels by 48 h. Longer-term treatment with SFN in the diet resulted in levels of acetylated histones and p21(WAF1) in the ileum, colon, prostate, and peripheral blood mononuclear cells that were elevated compared with controls. Consistent with these findings, SFN suppressed tumor development in Apc(min) mice, and there was an increase in acetylated histones in the polyps, including acetylated histones specifically associated with the promoter region of the P21 and bax genes. These results provide the first evidence for HDAC inhibition by SFN in vivo and imply that such a mechanism might contribute to the cancer chemoprotective and therapeutic effects of SFN, alone or in combination with other HDAC inhibitors currently undergoing clinical trials.
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PMID:Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. 1640 54

Heme oxygenase-1 can play a protective role against cellular stress. In colon cancer cells, these effects would be relevant to oncogenesis and resistance to chemotherapy. The aim of the study was to examine the effects of heme oxygenase-1 induction on cell survival in a human colon cancer cell line, Caco-2. Serum deprivation induced apoptosis, reduced Akt and p38 phosphorylation, and increased p21(Cip/WAF1) levels. Heme oxygenase-1 induction by treatment with cobalt protoporphyrin IX resulted in resistance to apoptosis, activation of Akt, reduction in p21(Cip/WAF1) levels and modification of bcl2/bax ratio towards survival. Indomethacin reduced apoptosis but in contrast to heme oxygenase-1, arrested cells in G0/G1. Apoptosis was also inhibited by the heme oxygenase metabolites bilirubin and biliverdin but the CO donor tricarbonyldichlororuthenium(II) dimer did not exert significant effects. Protection against apoptosis in cells treated with cobalt protoporphyrin IX was reverted by incubation with heme oxygenase-1 small interfering RNA. This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin. Our results support an antiapoptotic role for HO-1 in these cells and provide a mechanism by which overexpression of HO-1 may promote tumor resistance to stress in conditions of limited nutrient supply. We have extended these observations by demonstrating that these effects are independent of p38 but are mediated via Akt pathway.
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PMID:Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway. 1669 92

Conjugated linolenic acids (CLN) are geometric and positional isomers of linolenic acid. Growth inhibition and apoptosis induction by alpha-eleostearic acid (c9,t11,t13-CLN), beta-eleostearic acid (t9,t11,t13-CLN), alpha-calendic acid (t8,t10,c12-CLN) and beta-calendic acid (t8,t10,t12-CLN) were compared. beta-Eleostearic acid and beta-calendic acid, which have all-trans-conjugated double bonds, exerted stronger growth inhibition and more DNA fragmentation, an indicator of apoptosis induction, in the human colon cancer cells Caco-2 than alpha-eleostearic acid and alpha-calendic acid with the cis configuration. Down-regulation of bcl-2 and up-regulation of bax mRNA by beta-eleostearic acid were also greater than by alpha-eleostearic acid. Interestingly, the cytotoxic effects of beta-eleostearic acid and beta-calendic acid were not counteracted completely by alpha-tocopherol, whereas the cytotoxic effects of alpha-eleostearic and alpha-calendic acids were lost in the presence of alpha-tocopherol. These results suggest that beta-eleostearic and beta-calendic acids have signaling pathways different from those of alpha-eleostearic and alpha-calendic acids and exhibit high potency for reducing the cell viability of Caco-2.
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PMID:Growth inhibition and apoptosis induction by all-trans-conjugated linolenic acids on human colon cancer cells. 1682 17


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