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)

Magnolol has been reported to have anticancer activity. In this study we found that treatment with 100 microm magnolol induced apoptosis in cultured human hepatoma (Hep G2) and colon cancer (COLO 205) cell lines but not in human untransformed gingival fibroblasts and human umbilical vein endothelial cells. Our investigation of apoptosis in Hep G2 cells showed a sequence of associated intracellular events that included (a) increased cytosolic free Ca(2+); (b) increased translocation of cytochrome c (Cyto c) from mitochondria to cytosol; (c) activation of caspase 3, caspase 8, and caspase 9; and (d) downregulation of bcl-2 protein. Pretreatment of the cells with the phospholipase C inhibitor 1-[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U73122) or the intracellular chelator of Ca(2+) 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM) inhibited the subsequent magnolol augmentation of [Ca(2+)](i) and also the activation of caspase-8 and caspase-9, so that the occurrence of apoptosis in those cells was greatly reduced. Pretreatment of the cells with ZB4 (which disrupts the Fas response mechanism) also decreased the subsequent magnolol-induced caspase-8 activation and reduced the occurrence of apoptosis. We interpreted these findings to indicate that the above-listed sequence of intracellular events led to the apoptosis seen in Hep G2 cells and that [Ca(2+)](i), Cyto c, and Fas function as intracellular signals to coordinate those events.
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PMID:Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. 1174 19

p21(WAF1) appears to be a major determinant of the cell fate in response to anticancer therapy. It was shown previously that HCT116 human colon cancer cells growing in vitro enter a stable arrest upon DNA damage, whereas cells with a defective p21(WAF1) response undergo apoptosis. Here we report that the enhanced sensitivity of HCT116/p21(-/-) cells to chemotherapeutic drug-induced apoptosis correlates with an increased expression of p53 and a modification of their Bax/Bcl-2 ratio in favor of the pro-apoptotic protein Bax. Treatment of HCT116/p21(-/-) cells with daunomycin resulted in a reduction of the mitochondrial membrane potential and in activation of caspase-9, whereas no such changes were observed in HCT116/p21(+/+) cells, providing evidence that p21(WAF1) exerts an antagonistic effect on the mitochondrial pathway of apoptosis. Moreover, the role of p53 in activation of this pathway was demonstrated by the fact that inhibition of p53 activity by pifithrin-alpha reduced the sensitivity of HCT116/p21(-/-) cells to daunomycin-induced apoptosis and restored a Bax/Bcl-2 ratio similar to that observed in HCT116p21(+/+) cells. Enhancement of p53 expression after disruption of p21(WAF1) resulted from a stabilization of p53, which correlated with an increased expression of the tumor suppressor p14(ARF), an inhibitor of the ubiquitin ligase activity of Mdm2. In accordance with the role of p14(ARF) in p53 stabilization, overexpression of p14(ARF) in HCT116/p21(+/+) cells resulted in a strong increase in p53 activity. Our results identify a novel mechanism for the anti-apoptotic effect of p21(WAF1) consisting in maintenance of mitochondrial homeostasis that occurs in consequence of a negative control of p14(ARF) expression.
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PMID:Inactivation of p21WAF1 sensitizes cells to apoptosis via an increase of both p14ARF and p53 levels and an alteration of the Bax/Bcl-2 ratio. 1215 95

The nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to mediate their anticancer effects by inducing apoptosis but the molecular mechanisms of their apoptotic effects remain largely unknown. Here we report that two different NSAIDs, sulindac sulfide and SC-'236 engage the death receptor 5 (DR5) and mitochondrial pathways to mediate apoptosis in human colon cancer cells. We show that sulindac sulfide and SC-'236-induced apoptosis is coupled with upregulation of DR5, caspase 8 activation and Bid cleavage. Thus, a cross talk appears to exist between the DR5 and mitochondrial pathways during apoptosis induced by these NSAIDs. We further show that sulindac sulfide and SC-'236-induced DR5 upregulation occurs independent of the COX inhibitory effects of these NSAIDs. Using Bax-proficient (Bax+/-) and Bax-deficient (Bax-/-) HCT116 human colon cancer cells, we further demonstrate that Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac sulfide and SC-'236. For example, sulindac sulfide upregulates DR5 in both Bax-deficient and proficient cells, but Apo2L/TRAIL efficiently potentiates sulindac sulfide-induced apoptosis as well as activation of caspase-8, -9 and -3 only in Bax-proficient cells. SC-'236 also upregulates DR5 in both Bax-proficient and Bax-deficient cells but Apo2L/TRAIL potentiates SC-'236-mediated apoptosis and caspases-8 and -3 activation in both Bax-proficient and Bax-deficient cells. Further, in Bax-deficient cells, neither sulindac sulfide nor SC-'236 in combination with Apo2L/TRAIL effectively promotes the release of cytochrome c from mitochondria into cytosol and caspase-9 activation. Collectively, our results suggest that unlike sulindac sulfide, SC-'236 in combination with Apo2L/TRAIL can overcome Bax deficiency to induce apoptosis. These results have important clinical implications in that the tumors harboring Bax mutations are likely to develop resistance to sulindac but not to SC-'236-like NSAIDs. In conclusion, the data presented herein form the basis of future in-depth studies to further explore the utility of Apo2L/TRAIL and NSAIDs, in combination, as a novel cancer preventive/therapeutic strategy.
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PMID:Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a COX-2 selective non-steroidal anti-inflammatory agent in Bax-deficient cells. 1220 15

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis,is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.
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PMID:Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. 1220 39

Type I cells have been defined to be independent of mitochondria for the induction of Fas death receptor-mediated apoptosis, whereas Type II cells are mitochondria-dependent. Knock-out studies in mice show that thymocytes are Type I and liver cells are Type II. We have previously shown that primary human hepatocytes and HCT116 human colon carcinoma cells behave like Type II cells because TRAIL-induced apoptosis can be blocked by the caspase 9 inhibitor, Z-LEHD-FMK. On the other hand, caspase 9 inhibition does not allow survival of TRAIL-treated SW480 colon cancer cells, which is predicted for Type I cells. Investigating the differences in TRAIL-induced apoptotic pathways in HCT116 and SW480 cells revealed that although FADD, BID, and procaspase 3 protein levels are higher in SW480 cells, and although procaspase 8 and FLIP processing is more efficient at the TRAIL-DISC of SW480 cells, BID, procaspase 3, XIAP, and PARP cleavages occur more rapidly in HCT116, despite the higher levels of BCL-2 and HSP70. Cytochrome c release from the mitochondria to the cytoplasm is more efficient in HCT116 cells. These results suggest BID cleavage as a possible limiting factor in the involvement of mitochondria in TRAIL-induced cell death. Thus, regulation of BID cleavage may define if a cell is mitochondria-dependent or -independent in response to TRAIL death receptor-induced apoptosis.
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PMID:Defining characteristics of Types I and II apoptotic cells in response to TRAIL. 1240 50

Heat shock proteins have been shown to protect cells from a variety of stressful conditions, including hyperthermia, oxidative and DNA damage, serum withdrawal, and a variety of chemicals. HSP27, HSP70, and HSP90 have been shown to downregulate different aspects of apoptosome assembly. TRAIL is a member of the TNF family of ligands and is a promising anti-cancer agent. It has been shown to be nontoxic to most normal cell types, while it is a potent killer of many different cancer cells. TRAIL engages both the receptor-mediated (extrinsic) and the mitochondria-initiated (intrinsic) cascades. We tested whether heat shock affects TRAIL-induced apoptosis in different cancer cells. TRAIL treatment does not induce HSP27, HSP70, or HSP90 levels. Nonetheless, when treated with TRAIL for 3 h after release from heat shock, the human colon cancer cell line HCT116 is protected from apoptosis whereas the human colon cancer cell line SW480 is not. This pattern is consistent with the previously observed behavior of HCT116 as Type II cells that depend on mitochondrial signaling and SW480 as Type I, whose TRAIL-induced death is not sensitive to inhibition of caspase 9. Moreover, the failure of heat shock to protect SW480 cells is not due to a lack of HSP70 or HSP90 upregulation. HSP70 and HSP90 are induced 3 h after release from heat shock, whereas HSP27 is induced much later. Thus, the observed protective effect against TRAIL is probably due to the anti-apoptotic effects of HSP70 and HSP90. These results further illustrate interactions between TRAIL receptor signaling and the intrinsic cell death pathway and have practical implications for the potential use of TRAIL and hyperthermia in cancer therapy.
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PMID:Heat shock protects HCT116 and H460 cells from TRAIL-induced apoptosis. 1246 Jun 47

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

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.
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PMID:Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. 1264 85

Thapsigargin (TG), by inducing perturbations in cellular Ca(2+) homeostasis, can induce apoptosis, but the molecular mechanisms remain to be fully elucidated. We have recently reported that TG-induced apoptosis appears to involve the DR5-dependent apoptotic pathway that cross talks with the mitochondrial pathway via TG-induced Bid cleavage. In this study, we have utilized Bax-proficient and -deficient HCT116 human colon cancer cells to investigate the effect of Bax deficiency on TG-induced apoptosis and TG regulation of the DR5 and mitochondrial pathways. Our results indicate that Bax-deficient cells are less sensitive to undergo apoptosis following TG treatment. Our results further demonstrate that TG-induced apoptosis is coupled with DR5 upregulation and caspases 8 and 3 activation, as well as Bid cleavage in both Bax-proficient and -deficient cells, although caspase 3 activation was reduced in Bax-deficient cells. TG also promoted the release of cytochrome c into cytosol and caspase 9 activation in Bax-proficient cells but not in Bax-deficient cells. These findings suggest that although Bax is not absolutely required for death receptor (DR)-dependent signals, it appears to be a key molecule in TG-regulated mitochondrial events. Bax-deficient cells were relatively more resistant to Apo2L/TRAIL than the Bax-proficient counterparts. However, the combination of Apo2L/TRAIL and TG was more effective in mediating apoptosis in both Bax-proficient and -deficient cells and that was coupled with activation of caspases 8 and 3. Although both agents in combination also induced cytochrome c release into cytosol and caspase 9 activation in Bax-proficient cells, these events were abrogated in Bax-deficient cells. Our results thus suggest that the combination of Apo2L/TRAIL and TG appears to bypass the Bax deficiency-induced defects in the mitochondrial (intrinsic) pathway by engaging the DR5-dependent apoptotic signals (extrinsic pathway).
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PMID:Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis. 1273 Jun 81

Twenty resveratrol (3,5,4'-trihydroxystilbene) (Res) derivatives, which were isolated from stem bark of Vatica rassak (Dipterocarpaceae), were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Among them, seven compounds displayed marked cytotoxicity. Vaticanol C (Vat C) as a major component induced a considerable cytotoxicity in all cell lines tested and exhibited growth suppression in colon cancer cell lines at low dose. Vat C caused two cell lines (SW480 and HL60) to induce cell death at four to seven times lower concentrations, compared with Res. The growth suppression by Vat C was found to be due to apoptosis, which was assessed by morphological findings (nuclear condensation and fragmentation) and DNA ladder formation in the colon cancer cell lines. The apoptosis in SW480 colon cancer cells was executed by the activation of caspase-3, which was shown by western blot and apoptosis inhibition assay. Furthermore, the mitochondrial membrane potential of apoptotic SW480 cells after 12 h treatment with Vat C was significantly lost, and concurrently the cytochrome c release and activation of caspase-9 were also detected by western blot analysis. Over-expression of Bcl-2 protein in SW480 cells significantly prevented the cell death induced by Vat C. Taken together, the findings presented here indicate that Vat C induced marked apoptosis in malignant cells mainly by affecting mitochondrial membrane potential.
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PMID:Antitumor effect of resveratrol oligomers against human cancer cell lines and the molecular mechanism of apoptosis induced by vaticanol C. 1284 81


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