UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose)polymerase (PARP) has been implicated in DNA repair mechanisms and the associated activity shown to markedly increase after DNA damage in carcinogen-treated cells. A defective DNA repair has been associated to the aetiology of human cancers. In order to assess the potential role of this enzyme in cellular response to DNA damage by gamma-radiation, we studied the activity of PARP in patients with familial adenomatous polyposis (FAP). We compared poly(ADP-ribose)polymerase activity by the rate of incorporation of radioactivity from [3H]adenine-NAD+ into acid-insoluble material in permeabilized leucocytes from FAP patients and healthy volunteers. Concomitantly, the intracellular levels of NAD+--the substrate for the PARP--and the reduced counterpart NADH were determined using an enzymatic cycling assay 30 min after [60Co] gamma-ray cells irradiation. Our results demonstrate that a marked stimulation of PARP activity is produced upon radiation of the cells from healthy subjects but not in the FAP leucocytes, which concomitantly show a marked decrease in total NAD-/NADH content. Our observations point to a role of PARP in the repair of the gamma-radiation-induced DNA lesions through a mechanism that is impaired in the cells from FAP patients genetically predisposed to colon cancer. The differences observed in PARP activation by gamma-radiation in patients and healthy individuals could reflect the importance of PARP activity dependent on treatment with gamma-rays. The absence of this response in FAP patients would seem to suggest a possible defect in the role of PARP in radiation-induced DNA repair in this cancer-prone disease.
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PMID:Absence of stimulation of poly(ADP-ribose) polymerase activity in patients predisposed to colon cancer. 963 38

We have shown earlier that pre-treatment of V79 Chinese hamster cells with 6-aminonicotinamide (6-AN) or 2-deoxyglucose (2-dG) results in over-expression of the Mr 78,000 glucose-regulated stress protein (GRP78) and the subsequent development of resistance to inhibitors of topoisomerase II. These phenomena also occur in V79-derived cell lines that are deficient in poly(ADP-ribose) (p(ADPR)) metabolism. In contrast, over-expression of GRP78 under the conditions outlined above is found to be associated with hypersensitivity to several clinically-relevant DNA cross-linking agents, namely, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, and melphalan. We have also previously shown that pre-treatment with 6-AN, an inhibitor of p(ADPR) metabolism, causes an increase in the life span in BCNU-treated mice bearing L1210 tumors. These observations prompted us to examine whether 6-AN pre-treatment can result in the over-expression of GRP78 in human colon cancer cell lines and, if so, whether this increase is associated with sensitization to DNA cross-linking agents outlined above. Following treatment of three colon cancer cell lines, HCT116, SW480, and VACO-8, for 48 h with 0.1 mM 6-AN, cytosolic GRP78 levels were elevated approximately 4.2 times, 8 times, and 2.5 times for each cell line respectively, as measured by Western immunoblotting. To determine sensitivity after GRP78 up-regulation, the cells were washed and grown for 412 h in growth medium devoid of 6-AN, before being treated with DNA cross-linking agents. The 412 h time period allowed p(ADPR) metabolism to return to normal while GRP78 levels remained elevated, thus allowing us to associate GRP78 over-expression with sensitivity to those agents. After treating cells for 1 h with BCNU, cisplatin, or melphalan, cell sensitivity was determined by clonogenic survival assay or a fluorescence-based cytotoxicity assay. Based on changes in IC50 values, 6-AN caused an increase in sensitivity for HCT116, SW480, and VACO-8 cells of 1.5, 2.3, and 1.0 times, respectively, for BCNU, 4.8, 3.8, and 2.6 for cisplatin, and 6.4, 3.7, and 2.2 times for melphalan. Thus, our results show that over-expression of GRP78 in human tumor cell lines is associated with increased sensitivity to clinically useful chemotherapy agents. This sensitization occurred in three different tumor cell lines, each bearing a separate genetic defect associated with altered sensitivity.
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PMID:Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation. 1019 18

Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.
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PMID:Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP). 1046 46

Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50-60% mutations in the p53 gene and in 10-15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53(+/+),hMLH1(-)) and 2 derivative cell lines with the genotypes p53(+/+),hMLH1(+) and p53(-/-),hMLH1(-). CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53(+/+),hMLH1(+) cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1(+) cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1(+) and hMLH1(-) cells. By contrast, in the p53(-/-) cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53(+/+) cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53(+/+) cells and a short-term arrest followed by apoptosis in p53(-/-) cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.
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PMID:Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. 1220 84

Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
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PMID:Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. 1250 32

beta-sitosterol, a main dietary phytosterol found in plants, may have the potential for prevention and therapy for human cancer. The purpose of the present study was to examine the effect of beta-sitosterol on the growth of HT116 human colon cancer cells. Treatment with beta-sitosterol resulted in a dose-dependent growth inhibition coupled with the characteristic morphological features of apoptosis and with the increase of a sub-G1 cell population. Apoptosis-inducing concentrations of beta-sitosterol induced caspase-3 and caspase-9 activation accompanied by proteolytic cleavage of poly(ADP-ribose)-polymerase. In addition, beta-sitosterol-induced apoptosis in HT116 cells was associated with a decreased expression of the anti-apototic Bcl-2 protein and mRNA and a concomitant increase of the pro-apototic Bax protein and mRNA, and with release of cytochrome c from the mitochondria into the cytosol. beta-sitosterol treatment also inhibited the expression of cIAP-1 without significant changes in the level of cIAP-2. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of beta-sitosterol.
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PMID:Induction of Bax and activation of caspases during beta-sitosterol-mediated apoptosis in human colon cancer cells. 1461 38

Echinomycin, in typical DNA minor groove binder, had comparable efficacy compared to 5-FU in the phase II trail of colon cancer treatment. To improve echinomycin's drawback (hydrophobicity, toxicity), we synthesized the YK-2000 series (echinomycin analogues). Among these, YK-2000 had the best in vitro cytotoxicity on six different human solid cancer cell lines. Echinomycin and YK-2000 were enabled to induce the apoptosis on the HT-29 colorectal cancer cell line. The hypothesis that apoptosis in the HT-29 cell was triggered by echinomycin and YK-2000 were supported through DNA laddering, poly-(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. In order to explore the signaling pathway of echinomycin and YK-2000, we examined the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 MAP kinase. However, what the mechanism of cancer cell death would be induced by echinomycin and YK-2000 is unknown. Here, we present some evidence that one of the major apoptotic signaling pathways induced by echinomycin and YK-2000 is possibly the MAP kinases pathway in HT-29 human colon cancer cells.
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PMID:Echinomycin and a novel analogue induce apoptosis of HT-29 cells via the activation of MAP kinases pathway. 1517 10

The isothiocyanates sulforaphane and PEITC (beta-phenethyl isothiocyanate) as well as the indoles indole-3-carbinol and its condensation product 3,3'-diindolylmethane are known to inhibit cancer cell proliferation and induce apoptosis. In this study, we compared the cell growth inhibitory potential of the four compounds on the p53 wild type human colon cancer cell line 40-16 (p53(+/+)) and its p53 knockout derivative 379.2 (p53(-/-)) (both derived from HCT116). Using sulforhodamin B staining to assess cell proliferation, we found that the isothiocyanates were strongly cytotoxic, whereas the indoles inhibited cell growth in a cytostatic manner. Half-maximal inhibitory concentrations of all four compounds in both cell lines ranged from 5-15 microM after 24, 48 and 72 h of treatment. Apoptosis induction was analyzed by immunoblotting of poly(ADP-ribose)polymerase (PARP). Treatment with sulforaphane (15 microM), PEITC (10 microM), indole-3-carbinol (10 microM) and 3,3'-diindolylmethane (10 microM) induced PARP cleavage after 24 and 48 h in both 40-16 and the 379.2 cell lines, suggestive of a p53-independent mechanism of apoptosis induction. In cultured 40-16 cells, activation of caspase-9 and -7 detected by Western blotting indicated involvement of the mitochondrial pathway. We detected time- and concentration-dependent changes in protein expression of anti-apoptotic Bcl-x(L) as well as pro-apoptotic Bax and Bak proteins. Of note is that for sulforaphane only, ratios of pro- to anti-apoptotic Bcl-2 family protein levels directly correlated with apoptosis induction measured by PARP cleavage. Taken together, we demonstrated that the glucosinolate breakdown products investigated in this study have distinct profiles of cell growth inhibition, potential to induce p53-independent apoptosis and to modulate Bcl-2 family protein expression in human colon cancer cell lines.
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PMID:Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae. 1650 Jun 82

Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.
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PMID:Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. 1733 89

Berberine is the major constituent of Coptidis Rhizoma with multiple pharmacological activities, including anti-inflammation, promotion of apoptosis and anticancer potential effect. Mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) may contribute to the causal relationship between tumorigenesis and pro-apoptotic function. Berberine is studied for the mechanism of its action in apoptotic pathway in human colonic carcinoma cell. Treatment of SW620 cells with 50 microM berberine resulted in activation of the caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c; whereas, the expression of BID and anti-apoptosis factor c-IAP1, Bcl-2, and Bcl-(XL) were decreased markedly. Berberine-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. Furthermore, the induction of apoptosis was alleviated by inhibitors specific for JNK and p38. In addition, there was an increase in the cellular levels of phospho-c-Jun, FasL and t-BID in the berberine-induced apoptosis via the activation of JNK and p38 signaling modules. NAC administration, a scavenger of ROS, reversed berberine-induced apoptosis effects via inhibition of JNK, p38 and c-jun activation, and FasL and t-BID expression. These results leads us to speculate that berberine may play an apoptotic cascade in SW620 cells by activation of the JNK/p38 pathway and induction of ROS production, providing a new mechanism for berberine-induced cell death in human colon cancer cells.
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PMID:Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL. 1767 78

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