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)

Combination chemoprevention using tea polyphenols as one of the components has received growing consideration in recent years. The present study was designed to evaluate the antiproliferative and apoptosis inducing effects of bovine lactoferrin (bLF) and black tea polyphenol (Polyphenon-B: P-B) combination on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Topical application of DMBA for 14 weeks induced buccal pouch tumours that showed aberrant expression of cytokeratins, a marker for epithelial carcinomas. This was associated with increased cell proliferation and evasion of apoptosis as revealed by upregulation of proliferating cell nuclear antigen, NF-kappaB, mutant p53, Bcl-2 and downregulation of Bax, Fas and caspase 3 protein expression. Although dietary administration of bLF and Polyphenon-B alone significantly reduced tumour incidence, combined administration of bLF and Polyphenon-B was more effective in inhibiting HBP carcinogenesis by restoring normal cytokeratin expression, inhibiting cell proliferation and inducing apoptosis. These findings suggest that a "designer item" approach will be useful for human oral cancer prevention strategies.
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PMID:Antiproliferative and apoptosis inducing effect of lactoferrin and black tea polyphenol combination on hamster buccal pouch carcinogenesis. 1690 60

Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio- or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 microM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index <1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 microg/ml of the antioxidant alpha-tocopherol or 10 microM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspase-dependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.
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PMID:Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. 1690 21

Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid beta-peptide (Abeta) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic acid (TUDCA) modulates exogenous Abeta-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/DeltaE9), all exhibiting increased Abeta production and aggregation. Cell viability was decreased in APPswe and APPswe/DeltaE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3'-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family.
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PMID:Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. 1692 70

3,3'-Diindolylmethane (DIM) is the major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol, which is a promising anticancer agent present in cruciferous vegetables and has itself been reported to have anticarcinogenic properties. This study examined DIM-mediated regulation of apoptosis in the HCT116 (wild-type p53) and HT-29 (mutant p53) human colon cancer cell lines. DIM (0-30 micromol/L) substantially decreased the number of viable cells and induced apoptosis of HCT116 and HT-29 cells in a concentration-dependent manner. Western-blot analyses of total cell lysates revealed that DIM increased the activation of caspase-3, -7, -8, and -9 and enhanced poly(ADP-ribose) polymerase cleavage in both HCT116 and HT-29 cells. In addition, DIM increased the translocation of cytochrome c and Smac/Diablo from the mitochondria to the cytoplasm. In concert with the caspase-8 activation by DIM, increased levels of Fas and truncated Bid were observed. DIM did not affect the protein levels of p53, Bcl-2, Bax, or Fas ligand (FasL) in HCT116 cells. In HT-29 cells, however, DIM decreased Bcl-2 levels, although the protein levels of Bax or FasL were not affected. The caspase-8 inhibitor Z-IETD-FMK attenuated the DIM-induced apoptosis, indicating that increased activation of this enzyme contributed to the increase in p53-independent apoptosis that was observed in colon cancer cells. We have demonstrated that DIM induces apoptosis in colon cancer cells, providing insights into the mechanisms underlying its antitumorigenic activities.
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PMID:Activation of caspase-8 contributes to 3,3'-Diindolylmethane-induced apoptosis in colon cancer cells. 1718 97

We have recently shown that thymoquinone (TQ) is an antineoplastic drug that induces p53-dependent apoptosis in human colon cancer cells. This study evaluated the antiproliferative and pro-apoptotic effects of TQ in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts. Flow cytometric analysis showed that TQ induced a much greater increase in the PreG(1) (apoptotic) cell population, but no cell cycle arrest in MG63. G(2)/M arrest in MNNG/HOS cells was associated with p21(WAF1) upregulation. Using three DNA damage assays, TQ was confirmed to result in a significantly greater extent of apoptosis in p53 null MG63 cells. Although the Bax/Bcl-2 ratios were not differentially modulated in both cell lines, the mitochondrial pathway appeared to be involved in TQ-induced apoptosis in MG63 by showing the cleavage of caspases-9 and -3. Oxidative stress and mitochondrial O(2)(*-) generation in isolated rat mitochondria were enhanced by TQ as measured by the dose-dependent reduction in aconitase enzyme activity and Amplex Red oxidation respectively. TQ-induced oxidative damage, reflected by an increase in gamma-H2AX foci and increased protein expression levels of gamma-H2AX and the DNA repair enzyme, NBS1, was more pronounced in MNNG/HOS than in MG63. We suggest that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell cycle arrest and allows to repair DNA damage. Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, our data suggest the potential clinical usefulness of TQ for the treatment of these malignancies.
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PMID:Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. 1721 78

The Bcl-2 gene is positively regulated by estrogen (E2) primarily through E2-response elements in the coding region and a putative p53 negative regulatory element (NRE) containing a short upstream open reading frame (uORF). The ability of mutant p53 to repress or induce Bcl-2 expression is controversial. In this study E2-receptor positive (ER(+))/wild-type p53 MCF-7cells were transfected with p53Delta291, which lacks a nuclear localization signal or a DNA binding domain mutant, p53(173L). Both p53 mutants but especially p53Delta291 increased Bcl-2 protein expression from a CMV-NRE-Bcl-2 cDNA construct in an NRE-position/orientation independent manner as well as from a 1.7 kb Bcl-2 promoter reporter gene. Bcl-2 protein expression prevented the p53Delta291-mediated increase in Bcl-2 promoter activity although immunoprecipitation demonstrated that only a small proportion of the wild-type p53 but not p53Delta91 protein interacts with Bcl-2. Unless levels of ectopically expressed mutant p53 were extremely high, stable expression of mutant p53 in MCF-7 cells moderately increased Bcl-2 protein levels. Expression of mutant p53 did not alter E2 regulation of Bcl-2, however, mutation of the uORF prevented regulation by both mutant p53 and E2. Adenovirus-mediated overexpression of WT p53 strongly reduced Bcl-2 expression in ER(-)/mut p53 MDA-MB-231 cells. Taken together these data support the position that mutant p53 behaves in a dominant "positive" manner relieving repression by WT p53 or another Bcl-2 transcriptional inhibitor in a manner independent of nuclear translocation.
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PMID:Cytoplasmic mutant p53 increases Bcl-2 expression in estrogen receptor-positive breast cancer cells. 1725 99

Oral cancer accounts for 40 to 50% of cancers diagnosed in India. Oral cancer is preceeded in most cases by pre malignant lesions-leukoplakia, submucous fibrosis and lichen planus. Stoppage of causative agents reverts premalignant lesions in some of the cases only. Thus anti oxidant therapy is being used to revert premalignant change to normal. Few studies available, have taken clinical parameters as indicators of response to therapy. Extensive medline search failed to reveal any study at the cellular level. This study attempts to investigate for the first time the role of p53 and bcl2 as markers of prognosis following vitamin A therapy. 24 cases of pre malignant lesions of oral cavity were studied. 1 lakh IU of vitamin A were given orally twice a week for 3 months. Biopsies were done before and after therapy. Haematoxylin and Eosin stain was done to confirm diagnosis. Immunostaining for mutant p53 and bcl2 was done on paraffin sections. 500 cells were counted over an average of 5 HPF and percentage positivity was calculated. Statistical analysis was done by applying the paired t tests. In 19 cases (79.2%) of premalignant lesions mutant p53 expression was zero before therapy, and remained unchanged even after the therapy. 3 cases (12.5%) had high mutant p53 values which reduced following therapy (p = 0.037). Therapy thus proved effective in these cases. However, in 2 cases (8.3%) pre therapy values of zero showed an increase after vitamin A therapy. These were the cases which had dysplasia and were chronic smokers. In 2 cases (8.3%) pre therapy values of bcl2 were zero and remained unchanged even after therapy and these cases did not stop smoking even during the vitamin A therapy. In 12 cases (50.0%) higher pre therapy values were reduced after therapy (p < 0.0001). Vitamin A therapy was effective in these cases. However, in 10 cases (42.0%) expression of bcl2 increased subsequent to therapy. Therapy failed in these cases because of chronic heavy smoking and tobacco chewing. Thus, in the majority of cases vitamin A was effective in preventing mutation of p53 (91.7%) and expression of bcl2 (58.0%). In effect, these two oncoproteins can be used as prognostic markers and follow up for anti oxidant therapy.
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PMID:Role of p53 and bcl2 as markers of vitamin A response in premalignant lesions of the oral cavity. 1747 47

Solanum nigrum Linne (SNL) has been used in traditional Chinese medicine for centuries because of its diuretic and antipyretic effects. The present study examined the effect of the crude polysaccharides isolated from Solanum nigrum Linne (SNL-P) on tumor growth. SNL-P had a significant growth inhibition effect on cervical cancer (U14) of tumor-bearing mice. Further analysis of the tumor inhibition mechanism indicated that the number of apoptotic tumor cells increased significantly, the expression of Bax increased and the expression of Bcl-2 and mutant p53 decreased dramatically in cervical cancer sections after oral administration of SNL-P for 12 days. Moreover, SNL-P treatment decreased the level of blood serum TNF-alpha. These results indicated that the tumor growth inhibition of SNL-P administration might correlate with the reduction of TNF-alpha level of blood serum, which resulted in a massive necrosis in tumor tissues and the up-regulation of Bax and down-regulation of Bcl-2 and mutant p53 gene expression, which triggered apoptosis in tumor cells. These findings demonstrated that the SNL-P is a potential antitumor agent.
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PMID:Antitumor activity of crude polysaccharides isolated from Solanum nigrum Linne on U14 cervical carcinoma bearing mice. 1748 83

Pinus koraiensis Bark Procyanidins Extract (PKBPE) has been used in traditional Chinese medicine for thousands of years. In this study, we determined PKBPE effect on tumor weight, SOD (superoxidate dismutase) activity, the content of MDA (malondialdehyde) through colorimetric analysis antigenic, and expression of Ki-67, p53 and Bcl-2 on mice bearing U14 cervical cancer. Treatment with PKBPE (158 and 250 mg/kg body weight, p.o.) could inhibit U14 cervical carcinoma growth up to 47.68 and 58.94%. In addition, PKBPE enhance the activity of SOD (p<0.01) and decrease MDA content. Furthermore, we also observed that PKBPE treatment significantly inhibited the expression of Ki-67, mutant p53 and Bcl-2 protein (p<0.01). The results suggested that PKBPE showed antitumor activities on U14 cervical carcinoma mice. The mechanism of PKBPE antitumor activity might be associated with free radical production inhibition and regulation of the expression of Ki-67, mutant p53 and Bcl-2 protein.
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PMID:Antitumor activity of the procyanidins from Pinus koraiensis bark on mice bearing U14 cervical cancer. 1760 74

Saponin extracted from Patrinia villosa (Thunb.) Juss (SPVJ) is a Chinese medicine which is used widely by traditional medicine doctors. In this study, the antitumor effects and the possible mechanisms of SPVJ were investigated in mice bearing U14 cervical cancer. The results showed that SPVJ (50 mg/kg and 100 mg/kg) effectively reduced the weight of U14 cervical tumor (35.1% and 57.1%, respectively). Compared with the control group, SPVJ (100 mg/kg) significantly increased tumor cells in the G0/G1 phase (38.1% vs 68.5%), increased the number of cells in apoptosis (9.4% vs 28.9%) and G0/G1 phase and decreased the number of cells in S phase (41% vs 26.2%) and G2/M (20.9% vs 5.3%), inhibited proliferating cell nuclear antigen (PCNA) of tumor cell (80.6% vs 21.8%), decreased the expression of mutant p53 (66.4% vs 33.5%) and bcl-2 protein (78.2% vs 20.3%). The mechanism of the SPVJ antitumor effect might be associated with inhibition of tumor cells in G0/G1 phase, inducing apoptosis and inhibiting the expression of PCNA, mutant P53 and Bcl-2 protein.
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PMID:Antitumor effects of saponin extract from Patrinia villosa (Thunb.) Juss on mice bearing U14 cervical cancer. 1835 May 12


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