Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage polarization contributes to a number of human pathologies. This is exemplified for tumor-associated macrophages (TAMs), which display a polarized M2 phenotype, closely associated with promotion of angiogenesis and suppression of innate immune responses. We present evidence that induction of apoptosis in tumor cells and subsequent recognition of apoptotic debris by macrophages participates in the macrophage phenotype shift. During coculture of human primary macrophages with human breast cancer carcinoma cells (MCF-7) the latter ones were killed, while macrophages acquired an alternatively activated phenotype. This was characterized by decreased tumor necrosis factor (TNF)-alpha and interleukin (IL) 12-p70 production, but increased formation of IL-8 and -10. Alternative macrophage activation required tumor cell death because a coculture with apoptosis-resistant colon carcinoma cells (RKO) or Bcl-2-overexpressing MCF-7 cells failed to induce phenotype alterations. Interestingly, phenotype alterations were achieved with conditioned media from apoptotic tumor cells, arguing for a soluble factor. Knockdown of sphingosine kinase (Sphk) 2, but not Sphk1, to attenuate S1P formation in MCF-7 cells, restored classical macrophage responses during coculture. Furthermore, macrophage polarization achieved by tumor cell apoptosis or substitution of authentic S1P suppressed nuclear factor (NF)-kappaB signaling. These findings suggest that tumor cell apoptosis-derived S1P contributes to macrophage polarization.
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PMID:Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. 1765 60

The antitumor activity of extracts of Centaurea ainetensis (C. ainetensis), a plant endemic to Lebanon, was investigated in human colon carcinoma cells. At concentrations that were non-cytotoxic to normal human intestinal epithelial cells, the crude extract inhibited the proliferation of a host of colon-derived cancer cells. The crude extract effect was then investigated in HCT-116 (p53+/+) cells, most sensitive to treatment and was found to cause apoptosis, increase the Bax/Bcl-2 ratio, p53 and p21 protein levels and reduce cyclin B1 proteins. In vivo, the crude extract injected intraperitoneally before the subcutaneous injection of the carcinogen 1,2-dimethylhydrazine, drastically reduced the number of tumors and decreased the mean size of aberrant crypt foci. Further bioassay-guided fractionation of the crude extract resulted in the identification of the bioactive molecule Salograviolide A, a Sesquiterpene Lactone, to which the growth inhibition in colon cancer was linked. Salograviolide A, at non-cytotoxic concentrations to normal human intestinal cells, reduced the growth of colon cancer cell lines. Salograviolide A induced growth inhibition and resulted in an increased preG1 phase and presumably apoptosis induction which was further confirmed by TUNEL. These data support the testing of the C. ainetensis extract and its bioactive molecule, Salograviolide A, in colon cancer treatment.
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PMID:Anti-colon cancer effects of Salograviolide A isolated from Centaurea ainetensis. 1835 73

Besides its preventive action on bone resorption the third generation bisphosphonate zoledronic acid (ZOL) has been shown to display potent inhibitory action on the formation of bone metastases of various human cancers. Recent research also indicates an antitumoral effect on primary tumors and visceral metastases. Here we investigate for the first time the effect of ZOL on the human colon carcinoma cell line HCT-116. ZOL strongly inhibited the proliferation and soft agar colony formation of HCT-116 cells and caused a G1 cell cycle arrest in a population of ZOL treated cells. This cell cycle arrest was accompanied by an induction of apoptosis via a caspase dependent mechanism. Activation of Caspases 3, 7, 8 and 9, cleavage of PARP as well as the release of cytochrome C into the cytosol were detected in HCT-116 cells treated with low micromolar concentrations of ZOL. The induction of the mitochondrial pathway of apoptosis was accompanied by a translocation of Bax into the mitochondria, Bid activation and a decrease of overall Bcl-2 expression. We also detected a cytosolic increase of apoptosis inducing factor (AIF), a trigger of caspase-independent apoptosis. Taken together, our data indicate a potent antitumoral and apoptosis inducing effect of ZOL on HCT-116 colon carcinoma cells.
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PMID:The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. 1843 76

A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.
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PMID:A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma. 1856 Mar 53

Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X(L), or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program.
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PMID:Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. 1859 31

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.
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PMID:Immunosensitization with a Bcl-2 small molecule inhibitor. 1880 35

In many tumor cell types, ionizing radiation or DNA-damaging anticancer drugs enhance sensitivity to death receptor-mediated apoptosis, which is of clinical interest. APO010, a form of CD95/Fas ligand is currently in a phase I trial in patients with solid tumors. To analyze the potential of combined modality treatment with APO010, we used p53-mutant Jurkat T leukemic cells, in which the mitochondrial pathway was blocked by Bcl-2 overexpression. These cells were strongly sensitized to APO010 by pretreatment with ionizing - or UV radiation, etoposide, histone deacetylase - or proteasome inhibitors. These stimuli alone did not induce apoptosis in J16-Bcl-2 cells. Sensitization could not be explained by the overruling of mitochondrial resistance imposed by Bcl-2, upregulation of CD95 membrane levels or modulation of inhibitor of apoptosis proteins. Rather, the stimuli commonly downregulated c-FLIP(L/S) protein levels, which was causally related to the sensitization: deliberate c-FLIP(L/S) downregulation by RNA interference largely overruled the capacity of the various stimuli to sensitize Jurkat-Bcl-2 cells to apoptotic execution by APO010. In p53-mutant, Bcl-2 overexpressing HCT-15 colon carcinoma cells, c-FLIP downregulation correlated with sensitization to APO010 for some, but not all stimuli. We conclude that c-FLIP downregulation represents a mechanism by which diverse anticancer regimens can facilitate tumor cell execution by CD95/Fas through the direct pathway of caspase activation.
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PMID:Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation. 1979 6

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

Among diet components, some fatty acids are known to affect several stages of colon carcinogenesis, whereas others are probably helpful in preventing tumors. In light of this, our aim was to determine the composition of fatty acids and the possible correlation with apoptosis in human colon carcinoma specimens at different Duke's stages and to evaluate the effect of enriching human colon cancer cell line with the possible reduced fatty acid(s). Specimens of carcinoma were compared with the corresponding non-neoplastic mucosa: a significant decrease of arachidonic acid, PPARalpha, Bad, and Bax and a significant increase of COX-2, Bcl-2, and pBad were found. The importance of arachidonic acid in apoptosis was demonstrated by enriching a Caco-2 cell line with this fatty acid. It induced apoptosis in a dose- and time-dependent manner via induction of PPARalpha that, in turn, decreased COX-2. In conclusion, the reduced content of arachidonic acid is likely related to carcinogenic process decreasing the susceptibility of cancer cells to apoptosis.
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PMID:Decreased polyunsaturated Fatty Acid content contributes to increased survival in human colon cancer. 1984 81

It is well known that Phellinus linteus has a variety of biological functions, such as antitumor and immunomodulating activities. In our previous studies, we developed a P. linteus grown on germinated brown rice (PBR) and found that organic solvent extracts of PBR possessed immunomodulating activity to regulate a balance of cytokine network in mice. The components of PBR are ergosterol peroxide, gamma-aminobutyric acid (GABA) and Beta-glucan. In this study, we demonstrate that an organic solvent extract of P. linteus grown on PBR induced apoptotic cell death through the induction of G(0)/G(1) arrest of cell cycle and the apoptosis via DNA fragmentation in human colon carcinoma HT-29 cells. Cell death induced by the extract of P. linteus grown on PBR was shown to be associated with the upregulation of p21(CIP1/WAF1), the downregulation of cyclin D1, anti-apoptotic protein, Bcl-2, the release of cytochrome c, and the activation of caspase-9, caspase-3 and caspase-8. This study suggests that the ethyl acetate extract of P. linteus grown on PBR induces apoptosis accompanied by cell cycle arrest at G(0)/G(1) phase and regulates apoptosis-regulatory proteins, which may be applicable to anticancer therapy.
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PMID:The ethyl acetate extract of Phellinus linteus grown on germinated brown rice induces G0/G1 cell cycle arrest and apoptosis in human colon carcinoma HT29 cells. 1999 18


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