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

The combination of irinotecan and a fluoro-pyrimidine is widely accepted as a treatment for advanced colorectal cancer. However, evaluable data on the feasibility of these combinations has not been presented, and an optimal sequence for administration has not been experimentally and clinically determined. The sequential effect of a combination of 5-FU and CPT-11 in the human colon cancer cell line LoVo was evaluated by WST-8 colorimetric assay. The cytotoxicity and cell cycle distributions of each drug were analyzed by apoptosis assay and flow cytometry. Further, the potential mechanisms of the sequence-dependent effects were investigated by a microarray technique, and confirmed by Western blot analysis. The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (p<0.05). In cell cycle distribution, 5-FU exposure for 24 h increased the S phase fraction in a dose-dependent manner; though there was no significant difference in cell cycle distribution in 24 h CPT-11 (0.01-1 microM) exposure. Microarray analysis revealed that expressions of some apoptosis related genes such as Bcl-2 changed, and were correlated with sequence-dependent cytotoxicity of the 5-FU --> CPT-11 sequence. Western blot analysis confirmed that the Bcl-2/Bax ratio was lower after 5-FU --> CPT-11 sequence than before. The sequence-dependent cytotoxic effect may depend on the sensitizing effect of 5-FU pretreatment on CPT-11 cytotoxicity. 5-FU followed by CPT-11 administration may be an optimal sequence for IFL treatment of advanced colon cancer.
 ...
PMID:in vitro synergistic antitumor activity of a combination of 5-fluorouracil and irinotecan in human colon cancer. 1639 4

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptor-mediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-kappaB (NF-kappaB). Inhibition of NF-kappaB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-kappaB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-kappaB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.
 ...
PMID:Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-kappaB and upregulation of BCL-2 and BCL-XL. 1640 26

Cardiotoxin III (CTX III) is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III in human colorectal cancer Colo205 cells. 2. Cardiotoxin III-induced Colo205 cell apoptosis was confirmed by DNA fragmentation (DNA ladder and sub-G1 formation) with an IC(50) of 4 mg/mL at 48 h. 3. Further mechanistic analysis demonstrate that CTX III induced the loss of mitochondrial membrane potential (Dym), cytochrome c release from mitochondria into the cytosol and activation of capase-9, caspase 3, as well as markedly enhancing the expression of Bax, but not Bcl-2, protein in the cells. Moreover, the CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. 4. However, CTX III did not generate the formation of reactive oxygen species and anti-oxidants, including N-acetylcysteine, and catalase could not block CTX III-induced apoptosis in the Colo205 cells. 5. Taken together, these results suggest that CTX III may induce apoptosis through a mitochondrial- and caspase-dependent mechanism and alteration of Bax/Bcl-2 ratio in human colorectal Colo205 cancer cells.
 ...
PMID:Mechanisms of cardiotoxin lll-induced apoptosis in human colorectal cancer colo205 cells. 1648 59

No published data are available about the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the role of PPARgamma in retinoblastoma protein (RB)-deficient human colorectal cancer (CRC) cells (SNU-C4 and SNU-C2A). Our aim was to investigate whether PPARgamma is expressed in SNU-C4 and SNU-C2A cells and to elucidate possible molecular mechanisms underlying the effect of pioglitazone, a synthetic ligand for PPARgamma, on cell growth in these cell lines. RT-PCR and Western blot analysis showed that both human CRC cell lines expressed PPARgamma mRNA and protein. Pioglitazone inhibited the cell growth of both cell lines through G2/M phase block and apoptosis. In addition, pioglitazone caused a down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bcl-2, and cyclooxygenase-2 (COX-2) under conditions leading to PPARgamma down-regulation. These results suggest that pioglitazone may have therapeutic relevance or significance in the treatment of human CRC, and the down-regulation of XIAP, Bcl-2, and COX-2 may contribute to pioglitazone-induced apoptosis in these and other RB-deficient cell lines and tumors.
 ...
PMID:Pioglitazone, a synthetic ligand for PPARgamma, induces apoptosis in RB-deficient human colorectal cancer cells. 1652 Aug 94

Molecular tumor markers are often studied in colorectal cancer using immunohistochemistry to determine their prognostic or predictive value. Protein expression is typically assigned a 'positive' score based on a predetermined cutoff. A semiquantitative scoring method that evaluates the percentage of positive tumor cells (0-100%) may provide a better understanding of the prognostic or predictive significance of these markers. The aim of this study was to assess and compare the interobserver agreement of immunohistochemistry scores using a percentage scoring method and three categorical scoring systems. Immunohistochemistry for p53, Bcl-2, vascular endothelial growth factor (VEGF) and apoptotic protease activating factor-1 (APAF-1) was performed on 87 tumor biopsies from patients with rectal carcinoma and scored independently by four pathologists as the percentage of positive tumor cells. Interobserver agreement was assessed by the intraclass correlation coefficient. The intraclass correlation coefficients for p53 and VEGF (>0.6) indicate substantial agreement between observers. The distribution of Bcl-2 and APAF-1 scores in addition to weaker interobserver agreement by percentage scoring suggest that this approach may not be appropriate for these proteins. In conclusion, p53 and VEGF protein expression assessed by immunohistochemistry in colorectal cancer and scored as a percentage of positive tumor cells may be a viable alternative scoring method.
 ...
PMID:Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer. 1674 23

As new improvements in the treatment of colorectal cancer have become available, it has become important to understand the benefits of new therapies or the deleterious effects stemming from the increased risk of toxicity. In particular, a more rational approach to adjuvant chemotherapy for patients with stage II/III disease should be defined by understanding which patients have a higher recurrence risk. Many studies have investigated several molecular markers, but none has been definitively associated with patient outcome. We present a review of studies that have evaluated the immunohistochemical correlation between expression of some biomarkers, such as thymidylate synthase, p53, Ki-67, Bcl-2, and microsatellite instability status expressed by Mut-L homologue 1 and Mut-S homologue 2 proteins, and the prognosis of patients with stage II/III colorectal cancer. We have evaluated studies in which > or = 100 patients were involved in an effort to ensure a representative study group. The only biomarker likely to have a prognostic value is microsatellite instability status, which correlated with a better prognosis.
Clin Colorectal Cancer 2006 May
PMID:Does biomolecular characterization of stage II/III colorectal cancer have any prognostic value? 1679 90

Resistance to anoikis, the cell death triggered by the loss of anchorage to the substratum, is an essential prerequisite in the proliferation and diffusion of colorectal cancer (CRC) cells. We examined whether 5-aminosalicylic acid (5-ASA), a drug that seems to reduce the risk of colitis-associated CRC, enhances CRC cell anoikis. To this end, Colo205 cells were treated with 5-ASA in the presence or absence of inhibitors of caspases (zVAD-fmk) and reactive oxygen species (ROS). We demonstrate that 5-ASA enhances Colo205 cell death. Although 5-ASA induces dissipation of mitochondrial transmembrane potential and caspase-3 activation, zVAD-fmk does not completely prevent the 5-ASA-induced cell death. 5-ASA also enhances the synthesis of ROS. However, inhibitors of ROS reduce the fraction of 5-ASA-induced Colo205 cell death but do not confer protection. In contrast, the 5-ASA-mediated Colo205 cell death is preventable by Bcl-2 over-expression. These data suggest a mechanism by which 5-ASA interferes with colon carcinogenesis.
 ...
PMID:5-aminosalicylic acid enhances anchorage-independent colorectal cancer cell death. 1691 8

Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr. PCI-mediated delivery of AdhCMV-TRAIL enabled an increased expression of TRAIL, induced a synergistic reduction in cell viability compared to the individual action of AdhCMV-TRAIL and photochemical treatment, and enhanced the induction of apoptosis demonstrated by an increase in cytoplasmic histone-associated DNA fragments, caspase-8 and caspase-3 activation, PARP cleavage and a decrease in the mitochondrial membrane potential. The synergistic effect could be related to the enhanced TRAIL expression in PCI-treated samples and a modest sensitization of the cancer cells to TRAIL induced apoptosis due to the photochemical treatment. Furthermore, an increased cleavage of Bid and a cell line dependent reduction in the expression levels of anti-apoptotic Bcl-2 family members were observed and could possibly contribute to the enhanced apoptotic level in samples exposed to the combined treatment. The presented results indicate that photochemically mediated delivery of AdhCMV-TRAIL allows a selective enhancement in cell killing, and suggest that PCI may be relevant and advantageous for therapeutic gene delivery in vivo.
 ...
PMID:Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines. 1720 62

The insulin-like growth factor binding protein 3 (IGFBP-3) is the major circulating IGF binding protein, its function regulated by proteolytic cleavage. The fragments generated have recently been suggested to have IGF-independent biological activity. We have previously established that IGFBP-3 can potentiate apoptosis in colorectal epithelial cells, although its use as a therapeutic reagent may be limited by the fact that it is cleaved in the circulation. Therefore the aim of these experiments was to determine whether the 16-kDa proteolytic fragment (1-95IGFBP-3) would have IGF-independent pro-apoptotic activity in human colonic carcinoma derived cells. We report that the enforced expression of 1-95IGFBP-3 increased the induction of apoptosis by the naturally occurring short chain fatty acid sodium butyrate (NaBt) in the IGF non-responsive HT29 human colorectal carcinoma cell line. Furthermore, the addition of condition medium containing the secreted 1-95IGFBP-3 was as effective as the intact IGFBP-3 protein at potentiating apoptosis. Although not associated with changes in Bcl-2, Bcl-XL, Bax, Bad or Bak expression levels, we report that the expression of the pro-apoptotic 1-95IGFBP-3 fragment is associated with the inhibition of TNFalpha-induced NF-kappaB activity, similar to that reported for the full length IGFBP-3 protein. These results suggest that the 16-kDa 1-95IGFBP-3 fragment is as effective as an intact recombinant protein when used in combination with apoptosis inducing agents, and due to its relative stability in the circulation, it may be important for use as an adjuvant in the treatment of colorectal cancer.
 ...
PMID:Induction of apoptosis by the 16-kDa amino-terminal fragment of the insulin-like growth factor binding protein 3 in human colonic carcinoma cells. 1701 62

Drug resistance to 5-fluorouracil (5-FU) is still a major limitation to its clinical use. In addition, the clinical value of p53 as a predictive marker for 5-FU-based chemotherapy remains a matter of debate. Here, we used HCT116 human colorectal cancer cells expressing wild-type p53 and investigated whether inhibition of Fas expression by interference RNA modulates 5-FU-induced apoptosis. Cells were treated with 5-FU (1, 4 or 8 microM) for 8-48 h. Cell viability was evaluated by trypan blue dye exclusion. Apoptosis was assessed by changes in nuclear morphology and caspase activity. The interference RNA technology was used to silence Fas expression. Caspase activation, p53, Fas, cytochrome c, and Bcl-2 family protein expression was evaluated by immunoblotting. 5-FU was cytotoxic in HCT116 cells (p<0.001). Nuclear fragmentation and caspase-3, -8 and -9 activities were also markedly increased in HCT116 cells after 5-FU (p<0.001). In addition, wild-type p53 and Fas expression were 25- and 4-fold increased (p<0.05). Notably, when interference RNA was used to inhibit Fas, 5-FU-mediated nuclear fragmentation and caspase activity were markedly reduced in HCT116 cells. Finally, western blot analysis of mitochondrial extracts from HCT116 cells exposed to 5-FU showed a 6-fold increase in Bax, together with a 3-fold decrease in cytochrome c (p<0.001). In conclusion, 5-FU exerts its cytotoxic effects, in part, through a p53/Fas-dependent apoptotic pathway that involves Bax translocation and mitochondrial permeabilization.
 ...
PMID:Inhibition of Fas expression by RNAi modulates 5-fluorouracil-induced apoptosis in HCT116 cells expressing wild-type p53. 1705 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>