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: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. In the present study, we isolated Paris Saponin I (PSI), an active component of Rhizoma paridis, and evaluated its effects on a panel of human cell lines and in a mouse model of human ovarian cancer to explore the mechanisms of its activity. PSI had more potent and selective cytotoxic effects on tumor cell lines than etoposide had, promoting dramatic G(2)-M phase arrest and apoptosis in SKOV3 cells in a time- and dose-dependent manner. Furthermore, PSI treatment increased levels of Bax, cytochrome c, activated caspase-3, active caspase-9, and cleaved poly(ADP-ribose) polymerase and decreased both Bcl-2 expression levels and extracellular signal-regulated kinase-1/2 activity. We also assessed the antitumor efficacy of i.p. and p.o. PSI administration in mice bearing SKOV3 tumors; both significantly inhibited the growth of SKOV3 cells in a subcutaneous xenograft mouse model (by 66% and 52%, respectively). These results indicate that PSI mediates its effects via mitochondrial apoptosis, mitogen-activated protein kinase pathways, and G(2)-M cell cycle arrest. Most important, the efficacy of PSI in xenografts when administered p.o. or i.p. suggests its clinical potential. Thus, PSI is a potent antitumor compound and should be developed as a natural agent for cancer therapy.
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PMID:The antitumoral effect of Paris Saponin I associated with the induction of apoptosis through the mitochondrial pathway. 1943 69

Owing to its central role in multiple cellular functions, p53 is an attractive candidate for gene replacement therapy. We studied the role of adenovirus-mediated p53 gene (p53Ad) therapy on sensitivity of two ovarian cancer cell lines, OVCAR-3 (p53(mut)) and SK-OV-3 (p53(wt)), to docetaxel, CPT-11 and SN-38 exposures. Expressions of Bcl-XL, Bcl-XS, p53, Gadd45, c-fos, p21(waf1/cip1), Bax, Bcl-2 and Mcl-1 were measured after concomitant p53Ad and drug exposures. In SK-OV-3 cells containing a normal p53 gene, p53Ad alone or concomitantly with docetaxel, CPT-11 or SN-38 exposures did not have an effect on cell growth, cell cycle distribution or induction of apoptosis. In OVCAR-3 cells, p53 gene therapy inhibited the cell growth and sensitized cells to CPT-11/SN-38, but not to docetaxel. Growth inhibition and sensitization were results of G2M cell cycle arrest and increased apoptosis. In SK-OV-3 cells, but not in OVCAR-3 cells, CPT-11/SN-38 exposures alone increased p21(waf1/cip1) expression. The p53Ad therapy induced strong p21(waf1/cip1) expression in both cell lines. In addition, the expression of Bax and expression ratios Bax/Bcl-2 and Bax/Bcl-XL increased in p53Ad-infected OVCAR-3 cells, but not in SK-OV-3 cells. These expression ratios were further increased in p53Ad+CPT-11/SN-38-exposed OVCAR-3 samples. These results support the combination of p53 gene therapy with topoisomerase I inhibitors SN-38/CPT-11 when tumour cells contain mutated p53. When p53 status is normal, p53 gene therapy is not effective alone or concomitantly with CPT-11/SN-38. Increased expression ratios of Bax/Bcl-2 and Bax/Bcl-XL might serve as positive markers for effective p53 gene therapy and concomitant topoisomerase I inhibitor therapy.
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PMID:Concomitant exposure of ovarian cancer cells to docetaxel, CPT-11 or SN-38 and adenovirus-mediated p53 gene therapy. 1949 54

Inhibition of calcium/calmodulin-dependent protein kinase II (CaMKII) results in hypophosphorylation of CaMKII substrates and in some cases suppresses cell growth. We previously presented the first report of the human CaMKII inhibitory protein, hCaMKIINbeta. Here we report the functional characterization of hCaMKIINbeta in ovarian cancer cells. We showed that hCaMKIINbeta was highly expressed in normal ovarian tissues but was not detected in human ovarian adenocarcinoma, indicating that decreased expression of hCaMKIINbeta may be involved in the pathogenesis of human ovarian adenocarcinoma. As an endogenous CaMKII inhibitor, hCaMKIINbeta could significantly inhibit the growth of human ovarian cancer cells in vitro. In vivo, hCaMKIINbeta decreased the tumorigenicity and growth of HO-8910PM human ovarian cancer cells and prolonged the survival of tumor-bearing mice. hCaMKIINbeta blocked cell cycle progression and induced apoptosis of HO-8910PM cells, which was correlated with the up-regulation of p21, p53, and Bax and the down-regulation of cyclin A, cyclin D1, cyclin E, CDK2, phosphorylated retinoblastoma, and Bcl-2. We further demonstrated that hCaMKIINbeta-mediated CaMKII inhibition suppressed Akt activation, leading to the down-regulation of HDM2, which was responsible for the up-regulation of p53 and p21 in human ovarian cancer cells. The tumor-suppressive effect and the negative expression in human ovarian cancer tissues suggest that hCaMKIINbeta may play an important role in the regulation of tumor cell growth, possibly contributing to the development of new therapeutic strategies for ovarian cancer.
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PMID:Endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest and apoptosis through down-regulation of the phosphatidylinositide 3-kinase/Akt/HDM2 pathway. 3259 58

Cancer progression is associated with reduced apoptosis and increased proliferation. We hypothesized that upregulation of the Bag family of survival cochaperones and its molecular partners of the Bcl-2 and heat shock protein (HSP) families would correlate with disease progression and survival in ovarian cancer. Bag-1, Bag-4, HSP27, HSP70, Bcl-2, and Bcl-X(L) expression was immunohistochemically analyzed in effusions (188) and patient-matched solid tumors (43 primary carcinomas, 81 solid metastases). Results were analyzed for anatomic site-related differences, and association with clinicopathologic parameters and survival. Bag-1, Bag-4, and HSP70 were detected in the tumor cell nuclei and cytoplasm, whereas HSP27, Bcl-2, and Bcl-X(L) had exclusively cytoplasmic localization. Antiapoptotic protein expression in effusions differed significantly from primary tumors and metastases. Cytoplasmic Bag-1 (P=0.002), nuclear and cytoplasmic HSP70 (P<0.001), and Bcl-2 (P=0.001) expression was higher in primary carcinomas and solid metastases compared with effusions, whereas Bcl-X(L) (P=0.01), nuclear Bag-1 (P<0.001), nuclear Bag-4 (P=0.01), and cytoplasmic Bag-4 (P=0.002) were upregulated in effusions. Bcl-X(L) expression was associated with poor response to chemotherapy at diagnosis (P=0.02) and HSP27 expression was associated with high-grade tumors (P=0.01). Increased cytoplasmic HSP70 staining in effusions correlated with poor overall survival for the entire cohort (P=0.01). In primary carcinomas, higher Bcl-2 expression correlated with worse overall (P=0.04) and progression-free (P=0.02) survival. Antiapoptotic proteins are differentially expressed in effusions compared with solid tumors, whereas primary carcinomas and solid metastases have comparable expression patterns. HSP70 expression in effusions may be a prognostic marker of poor survival, with a similar role for Bcl-2 in primary carcinomas.
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PMID:Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma. 1962 Sep 38

New cytotoxic agents are urgently needed for the treatment of advanced ovarian cancer because of the poor long-term response of this disease to conventional chemotherapy. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity; however, the mechanism of curcumin-induced cytotoxicity in ovarian cancer cells remains a mystery. In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the extrinsic and intrinsic pathways of apoptosis. Bax expression was unchanged but Bcl-2, survivin, phosphorylated Akt (on serine 473), and total Akt were downregulated in curcumin-treated HEY cells. Curcumin also activated p38 mitogen-activated protein kinase (MAPK) without altering extracellular signal-regulated kinase 1/2 activity. We conclude that p53-independent curcumin-induced apoptosis in ovarian carcinoma cells involves p38 MAPK activation, ablation of prosurvival Akt signaling, and reduced expression of the antiapoptotic proteins Bcl-2 and survivin. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of ovarian cancer.
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PMID:Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling. 1967 5

Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO-8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein-activated ATM-Chk2-Cdc25 and ATR-Chk1-Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage-inducing and pro-apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO-8910 cells.
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PMID:Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. 1973 43

Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9+/-0.4 in the resistant group and 34.3+/-0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs.
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PMID:Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. 1974 65

Although cisplatin is a very effective anticancer agent against several types of cancer including ovarian cancer, the mechanisms of acquired resistance are not fully understood. By chronically exposing cisplatin to ovarian cancer cell lines, we established two cisplatin-resistant cell lines OV433 and TOV112D. Our results indicate that the mechanisms underlying their cisplatin resistance are distinct. In OV433 cells, cisplatin resistance is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). By knocking down MKP-1 expression by siRNA or inhibiting MKP-1 expression by its pharmacological inhibitor triptolide, cisplatin-resistant OV433 cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. In TOV112D cells, on the other hand, acquired cisplatin resistance is associated with increased levels of Bcl-2 protein. By inhibiting the activity of Bcl-2 protein with its pharmacological inhibitor gossypol or knocking down Bcl-2 expression by siRNA, cisplatin-resistant TOV112D cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. Therefore, our data suggest that the mechanisms of acquired cisplatin resistance vary among ovarian cancer cells, which involve upregulation of molecules associated with the cell survival pathways.
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PMID:Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells. 1985 82

Cisplatin is one of the most widely used anticancer agents, displaying activity against a wide variety of tumors. However, development of drug resistance presents a challenging barrier to successful cancer treatment by cisplatin. To understand the mechanism of cisplatin resistance, we investigated the role of damaged DNA binding protein complex subunit 2 (DDB2) in cisplatin-induced cytotoxicity and apoptosis. We show that DDB2 is not required for the repair of cisplatin-induced DNA damage, but can be induced by cisplatin treatment. DDB2-deficient noncancer cells exhibit enhanced resistance to cell growth inhibition and apoptosis induced by cisplatin than cells with fully restored DDB2 function. Moreover, DDB2 expression in cisplatin-resistant ovarian cancer cell line CP70 and MCP2 was lower than their cisplatin-sensitive parental A2780 cells. Overexpression of DDB2 sensitized CP70 cells to cisplatin-induced cytotoxicity and apoptosis via activation of the caspase pathway and downregulation of antiapoptotic Bcl-2 protein. Further analysis indicates that the overexpression of DDB2 in CP70 cells downregulates Bcl-2 expression through decreasing Bcl-2 mRNA level. These results suggest that ovarian cancer cells containing high level of DDB2 become susceptible to cisplatin by undergoing enhanced apoptosis.
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PMID:Overexpression of DDB2 enhances the sensitivity of human ovarian cancer cells to cisplatin by augmenting cellular apoptosis. 2001 2

This study examined the effects of ursolic acid (UA) on the proliferation and apoptosis of a human ovarian cancer cell line, CAOV3. The CAOV3 cells were cultured in the RPMI 1640 media and treated with different concentrations of UA (0, 10, 20, 40 micromol/L). The proliferation rate of the CAOV3 cells was determined by MTT assay. The apoptosis rate was measured by flow cytometry. ERK activity was detected by immunoprecipitation and the expressions of p-ERK1/2, MKP-1, Bax and Bcl-2 by Western blotting. The results showed that the proliferation rate was significantly decreased in the cells treated with UA as compared with that in the non-treated cells (P<0.05). The intracellular ERK activity and p-ERK1/2 expression were also reduced in the UA-treated cells, while the MKP-1 expression was elevated. Moreover, the apoptosis was found in the CAOV3 cells exposed to UA; the Bax expression was increased and the Bcl-2 expression decreased. The apoptosis rate in the UA-treated cells was much higher than that in the non-treated cells (P<0.05). It is concluded that UA can inhibit the proliferation of CAOV3 cells by suppressing the ERK activity and the expression of p-ERK1/2. And it can also induce the apoptosis of the CAOV3 cells by up-regulating the Bax expression and down-regulating the Bcl-2 expression.
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PMID:Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cells. 2003 23


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