Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

This study was performed to elucidate the apoptotic pathways by thiosulfinates, major biologically active components of Allium tuberosum L., in HT-29 human colon cancer cells. Thiosulfinates significantly induced cell death in dose- and time-dependent manners in HT-29 cells, which is associated with apoptosis. Thiosulfinates activated the initiator caspase-8, and -9, and the effector caspase-3. In the present study, thiosulfinates were found to stimulate Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. Thiosulfinates down-regulated the expression of the anti-apoptotic protein Bcl-2, and up-regulated the expression of the pro-apoptotic protein Bax. We also found that thiosulfinates increased the expression of AIF, a caspase-independent mitochondrial apoptosis factor, and induced DNA fragmentation and chromatin condensation in HT-29 cells. These results indicate that thiosulfinates from A. tuberosum L. inhibited cell proliferation and activated both the caspase-dependent and caspase-independent apoptotic pathways in HT-29 cells.
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PMID:Mechanisms of thiosulfinates from Allium tuberosum L.-induced apoptosis in HT-29 human colon cancer cells. 1944 47

Ginsenoside Rg3, the main constituent isolated from Panax ginseng, has been of interest for use as a cancer preventive or therapeutic agent. We investigated here whether Rg3 can inhibit the activity of NF-kappaB, a key transcriptional factor constitutively activated in colon cancer that confers cancer cell resistance to chemotherapeutic agents. To investigate whether RG3 can suppress activation of NF-kappaB, and thus inhibit cancer cell growth, we examined the susceptibility of colon cancer cells (SW620 and HCT116) to treatment with Rg3 (25, 50, 75, 100 microM) and RG3-induced activation of NF-kappaB. RG3 dose-dependently inhibited cancer cell growth through induction of apoptosis and decreased NF-kappaB activity. In a further study of compounds in colon cancer, we used half of the IC(50) dose, values in combined treatments of Rg3 (50 microM) with conventional agents - docetaxel (5 nM), paclitaxel (10 nM) cisplatin (10 microM) and doxorubicin (2 microM). Compared to treatment with Rg3 or chemotherapy alone, combined treatment was more effective (i.e., there were synergistic effects) in the inhibition of cancer cell growth and induction of apoptosis and these effects were accompanied by significant inhibition of NF-kappaB activity. NF-kappaB target gene expression of apoptotic cell death proteins (Bax, caspase-3, caspase-9) was significantly enhanced, but the expression of anti-apoptotic genes and cell proliferation marker genes (Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), Cox-2, c-Fos, c-Jun and cyclin D1) was significantly inhibited by the combined treatment compared to Rg3 or docetaxel alone. These results indicate that ginsenoside Rg3 inhibits NF-kappaB, and enhances the susceptibility of colon cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer or adjuvant anti-cancer agent.
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PMID:Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. 1947 91

This study was performed to elucidate the anti-proliferative effects and the apoptotic mechanisms of extracts from Lethariella zahlbruckneri in HT-29 human colon cancer cells. Both the acetone extract (AEL) and methanolic extract (MEL) of L. zahlbruckneri decreased viable cell numbers in a dose- and time-dependent manner in HT-29 cells. The AEL showed stronger cytotoxicity than MEL. Cell death induced by AEL increased cell populations in the sub-G1 phase, as well as the formation of apoptotic bodies and nuclear condensation, whereas MEL did not. Therefore, the potential of AEL to induce apoptosis was examined. Apoptosis induced by AEL was associated with the activation of initiator caspases-8 and -9, as well as the effector caspase-3. AEL stimulated Bid cleavage. This indicated that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. AEL increased the expression of the pro-apoptotic protein, Bax, and decreased the expression of the anti-apoptotic protein, Bcl-2. AEL also increased the expression of the caspase-independent mitochondrial apoptosis factor, AIF, in HT-29 cells. These results indicate that AEL inhibited HT-29 cell proliferation by inducing apoptosis, which might be mediated via both caspase-dependent and -independent pathways.
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PMID:Anti-proliferative effects of Lethariella zahlbruckneri extracts in human HT-29 human colon cancer cells. 1950 Nov 27

Glycoconjugates represent a recent trend in cancer chemotherapy that adopts the concept of selective prodrug/drug targeting of tumor cells by binding to specific transmembrane glucose transporters. Following preferential uptake of sugar conjugates into cancer cells, they are presumably subject to enzymatic cleavage by specific beta-glycosidases to liberate the free active cytotoxic aglycones that act selectively on cancer cells and spare other noncancerous ones. In this sense, the role of beta-glucosidase and caspases in the bioactivation and cytotoxicity of glufosfamide has been addressed in the current study. The cytotoxicity of glufosfamide has been investigated over 24-96 h in a panel of human colon cancer cells namely, Caco-2, HT29 and T84 using a tetrazole dye; 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT assay technique. Apoptosis was assessed by fluorometric assay of caspase-3 and caspase-9 activities. Enzymatic cleavage of glufosfamide was accomplished using a host of hydrolytic enzymes and cleavage kinetics was determined using HPLC. Glufosfamide has proven cytotoxic efficacy in a concentration- and time-dependent manner. The sensitivity rank order of tumor cells towards the glycoconjugate was Caco-2>HT29>T84. This sensitivity ranking was well correlated with the enzymatic activity of beta-glucosidase assessed in these cell lines. Initiation and activation of apoptosis were increased in all colon cancer cells following exposure to glufosfamide and were well correlated with the cytotoxicity rank order of the glycoconjugate. Glufosfamide was cleaved by cytosolic and lysosomal beta-glucosidases but not by other hydrolytic enzymes such as cytosolic beta-galactosidase, pancreatic lipase or hepatic esterase. In conclusion, the current data could possibly unravel the mechanistic role of beta-glucosidase and apoptotic caspases in the bioactivation and cytotoxicity of glufosfamide within colon cancer cells.
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PMID:Possible contribution of beta-glucosidase and caspases in the cytotoxicity of glufosfamide in colon cancer cells. 1954 61

Some tumours respond favourably to tumour necrosis factor-alpha (TNF-alpha). Despite this preferential sensitivity, resistance to TNF-alpha remains a clinical problem and more interest is now being focused on finding compounds that induce apoptosis through other pathways. Sodium butyrate (NaBt) has anti-tumour effects on colon cancer cells, inhibiting cell growth and promoting differentiation and apoptosis. In this study we investigated whether NaBt induced apoptosis in the human colon cancer cell line HT-29 and examined the intracellular mechanisms involved. Pre-incubation of cells with NaBt significantly increased apoptosis as measured by fluorescence activated cell sorter analysis and mitochondrial membrane potential determination. This effect could be blocked with the caspase inhibitors, z-VAD-fmk (pan-caspase inhibitor), z-DEVD-fmk (caspase-3 inhibitor) and z-LEHD-fmk (caspase-9 inhibitor), but not with z-IETD-fmk (caspase-8 inhibitor). Enhancement of caspase-3 and caspase-9 activities suggests that NaBt induces apoptosis via mitochondrial pathways not involving TNF-alpha.
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PMID:Sodium butyrate induces human colon carcinoma HT-29 cell apoptosis through a mitochondrial pathway. 1958 63

Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and suberoylanilide hydroxamic acid is used for the treatment of cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI, CG0006, and assessed its antiproliferative effects on the NCI-60 cancer cell panel and cell lines from liver and stomach cancers that are common in Korea. Micromolar levels of CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung, melanoma, ovarian, prostatic, renal, and stomach cancer cell lines. We further analyzed cell death mechanisms activated by CG0006 in HCT116 (colon cancer) and K562 (leukemia) cells. First, to test the activity of CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression. CG0006 increased acetylation of histone 3, histone 4, and tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover, CG0006 increased the mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with CG0006. Western blot analysis showed that CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition, CG0006 activated caspase-9, caspase-3, and caspase-8. These results indicate that CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI CG0006 may be a potent anticancer drug for solid tumors and leukemia.
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PMID:A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways. 1964 55

Cancer is one of the leading causes of death in the world. The triterpenoid compound asiatic acid derived from the tropical medicinal plant Centella asiatica displays cytotoxic activity on fibroblast cells and several other kinds of cells. The present work studies asiatic acid-mediated growth inhibition of cancer cells and the underlying mechanism. Asiatic acid markedly inhibited cancer cell proliferation. Apoptosis of SW480 human colon cancer cells was induced by asiatic acid as shown by flow cytometry, DNA fragmentation and nuclear chromatin condensation experiments. Through increasing mitochondrial membrane permeability and cytochrome c release from mitochondria into cytosol, asiatic acid induced caspase-9 activity, which further activated caspase-3 and poly(ADP-ribose) polymerase cleavage resulting in irreversible apoptotic death in the tumor cells. Taken together, these results suggest that mitochondrial death apoptosis cascade plays very important roles in asiatic acid-induced cancer apoptosis.
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PMID:Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade. 1965 80

We investigated the mechanisms of inhibitory effect of growth hormone-releasing hormone (GHRH) antagonist JMR-132 on the growth of HT29, HCT-116 and HCT-15 human colon cancer cells in vitro and in vivo. High-affinity binding sites for GHRH and mRNA for GHRH and splice variant-1 (SV1) of the GHRH receptor were found in all three cell lines tested. Proliferation of HT-29, HCT-116 and HCT-15 cells was significantly inhibited in vitro by JMR-132. Time course studies revealed that the treatment of human HCT-116 colon cancer cells with 10 muM GHRH antagonist JMR-132 causes a significant DNA damage as shown by an increase in olive tail moment (OTM) and loss of inner mitochondrial membrane potential (Delta Psi m). Western blotting demonstrated a time-dependent increase in protein levels of phospho-p53 (Ser46), Bax, cleaved caspase-9, -3, cleavage of poly(ADP-ribose)polymerase (PARP) and a decrease in Bcl-2 levels. An augmentation in cell cycle checkpoint protein p21(Waf1/Cip1) was accompanied by a cell cycle arrest in S-phase. DNA fragmentation visualized by the comet assay and the number of apoptotic cells increased time dependently as determined by flow cytometric annexinV and PI staining assays. In vivo, JMR-132 decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic mice up to 75% (p < 0.05) and extended tumor doubling time (p < 0.001). Our observations suggest that GHRH antagonist JMR-132 exerts its antiproliferative effect on experimental colon cancer cells through p21(Waf1/Cip1) mediated S-phase arrest along with apoptosis involving the intrinsic pathway.
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PMID:GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells. 1975 49

The antitumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly inhibited the growth of HCT-15 cells (human colon carcinoma cells). After HCT-15 cells were treated with fucoidan, several apoptotic events such as DNA fragmentation, chromatin condensation and increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Bax protein expression levels and activation of caspases. Fucoidan decreased Bcl-2 expression, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and caspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP), a vital substrate of effector caspase, was observed. Furthermore, the induction of apoptosis was also accompanied by a strong activation of extracellular signal-regulated kinase (ERK) and p38 kinase and an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
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PMID:Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. 1980 40

Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.
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PMID:Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. 1984 53


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