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)

Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1+MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg(-1) day(-1)) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg(-1) day(-1))+MS-275 (2.5 mg kg(-1) day(-1)) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1+MS-275 caused DNA damage (upregulation of gammaH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-beta, p21WAF1/CIP1, E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma.
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PMID:MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours. 1834 38

Novel dietary agents for prevention and therapy of prostate cancer (PCa) are desired. The aim of this study was to determine the effect of fisetin, a tetrahydroxyflavone, on inhibition of cell growth and induction of apoptosis in human PCa cells. Treatment of fisetin (10-60 microM, 48 h) was found to result in a decrease in the viability of LNCaP, CWR22Rupsilon1 and PC-3 cells but had only minimal effects on normal prostate epithelial cells as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide assay. Treatment of LNCaP cells with fisetin also resulted in G(1)-phase arrest that was associated with a marked decrease in the protein expression of cyclins D1, D2 and E and their activating partner cyclin-dependent kinases 2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. Fisetin treatment also resulted in induction of apoptosis, poly (ADP-ribose) polymerase (PARP) cleavage, modulation in the expressions of Bcl-2 family proteins, inhibition of phosphatidyl inositol 3-kinase and phosphorylation of Akt at Ser(473) and Thr(308). There was also induction of mitochondrial release of cytochrome c into cytosol, downregulation of X-linked inhibitor of apoptosis protein and upregulation of second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI on treatment of cells with fisetin. Treatment of cells with fisetin also resulted in significant activation of caspases-3, -8 and -9. Pretreatment of cells with caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced activation of caspases. These data provide the first evidence that fisetin could be developed as an agent against PCa.
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PMID:Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. 1835 61

Our recent study showing highly recurrent loss of function of DLC1 (deleted in liver cancer 1), a tumor suppressor gene in primary prostate carcinoma (PCA), implicates this gene in the pathogenesis of this disease. To evaluate the response of PCA to oncosuppressive activity of DLC1, we examined now the effects of adenoviral vector for human DLC1 transduction into the DLC1-deficient, androgen-independent (AI) and aggressive human PCA cell lines PC-3 and C4-2-B2. Adenovirus-mediated restoration of DLC1 expression inhibited the proliferation, invasiveness and anchorage-independent growth of PC-3 and C4-2-B2 cells in vitro as well as the tumorigenicity of PC-3 cells in nude mice. It also induced cell-cycle arrest, inhibited the activation of RhoA and the formation of actin stress fibers. DLC1 induced apoptosis in C4-2-B2 cells, whereas it did not elicit such an effect in PC-3 cells. The abundance of the antiapoptotic protein Bcl-2 was greater in PC-3 cells than in C4-2-B2 cells, and PC-3 cells were rendered sensitive to DLC1-induced apoptosis by treatment with the Bcl-2 inhibitor HA14-1. These results suggest that adenovirus-mediated DLC1 transfer, alone or together with other agents, such as inhibitors of Bcl-2 or histone deacetylase, might prove effective in the treatment of aggressive, AI-PCA.
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PMID:Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy. 1836 81

Combined treatment with quercetin and TRAIL induced cytotoxicity and enhanced annexin V staining and poly (ADP-ribose) polymerase (PARP) cleavage in human prostate cancer cell lines DU-145 and PC-3. These indicators of apoptosis resulted from the activation of caspase-8, -9, and -3. Although the expression levels of FLIPs, cIAP1, cIAP2, and the Bcl-2 family were not changed in quercetin-treated cells, significant downregulation of survivin occurred. Knockdown survivin by siRNA significantly increased TRAIL-induced apoptosis. We hypothesized that quercetin-induced activation of MAPK (ERK, p38, JNK) is responsible for downregulation of survivin gene expression. To test this hypothesis, we selectively inhibited MAPK during treatment with quercetin. Our data demonstrated that inhibitor of ERK (PD98059), but not p38 MAPK (SB203580) or JNK (SP600125), significantly maintained the intracellular level of survivin during treatment with quercetin. Interestingly, PD98059 also prevented quercetin-induced deacetylation of histone H3. Data from survivin promoter activity assay suggest that the Sp1 transcription factor binds to the survivin promoter region and quercetin inhibits its binding activity through deacetylation of histone H3. Quercetin-induced activation of the ERK-MSK1 signal transduction pathway may be responsible for deacetylation of histone H3. Taken together, our findings suggest that quercetin enhances TRAIL induced apoptosis by inhibition of survivin expression, through ERK-MSK1-mediated deacetylation of H3.
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PMID:Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. 1837 72

Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-kappaB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-kappaB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-kappaB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-kappaB/p65. BetA-mediated NF-kappaB inhibition involved decreased IKK activity and phosphorylation of IkappaBalpha at serine 32/36 followed by its degradation. Reporter assays revealed that NF-kappaB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFalpha-induced activation of NF-kappaB via the IkappaBalpha pathway, thereby sensitizing the cells to TNFalpha-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-kappaB activation and supports the rationale for targeting NF-kappaB through combination protocols with BetA in androgen-refractory prostate cancer.
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PMID:Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. 1844 50

Patients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (-)-gossypol. Overexpressing Bcl-2 or Bcl-X(L) failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3-induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC.
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PMID:WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth. 1851 99

Hormone refractory human prostate cancer cell lines are known to be radioresistant, a feature attributed to their ability to induce anti-apoptotic proteins of the Bcl-2 family when exposed to radiation. We investigated whether pro-apoptotic compounds such as methyl jasmonate, a plant stress hormone, can counteract the radiation-induced anti-apoptotic mechanism in a human prostate cancer cell line PC-3. Significant (p<0.05) increase in cytotoxicity was observed in the combined treatment groups compared to single treatments with methyl jasmonate or gamma-radiation. Treatment of irradiated PC-3 cells with methyl jasmonate resulted in suppression of anti-apoptotic Bcl-2 protein and elevation of caspase-3 activity. Our results showed increased apoptosis in the combined treatment group as compared to the irradiated group or the untreated control. In summary, methyl jasmonate suppressed the radiation-induced Bcl-2 expression and enhanced the radiation sensitivity of human prostate cancer cells.
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PMID:Inhibition of expression of anti-apoptotic protein Bcl-2 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. 1857 94

Paclitaxel, a natural product originally isolated from Taxus brevifolia, belongs to the most successful anticancer drugs. Nevertheless, its poor water solubility represents a considerable disadvantage in clinical use, and novel derivatives with improved pharmacological features are required. We isolated 7-xylosyl-10-deacetylpaclitaxel from Taxus chinensis, which reveals higher water solubility than paclitaxel. This compound induced mitotic cell cycle arrest and apoptosis as measured by flow cytometry, DNA laddering, and transmission electron microscopy. Pro-apoptotic Bax and Bad protein expression was up-regulated and anti-apoptotic Bcl-2 and Bcl-XL expression down-regulated, which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9. In turn, caspase-9 activated downstream caspases-3 and -6, but not caspase-8. Bid was also activated by caspase-3. Reversely, treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetyl-paclitaxel-triggered apoptosis. Moreover, 7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-kappaB proteins, indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells.
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PMID:Activation of the mitochondria-driven pathway of apoptosis in human PC-3 prostate cancer cells by a novel hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel. 1857 55

Development of effective agents for treatment of hormone-refractory prostate cancer (HRPC) has become a national medical priority. D-Allose is a monosaccharide (C-3 epimer of glucose) distributed rarely in nature; because of its scarcity and cost, the biological effect has hardly been studied. In the present study, we demonstrated the inhibitory action of D-allose on proliferation of human HRPC cell lines, DU145 and PC-3 in a dose- and time-dependent manner, while human normal prostate epithelial (NPE) cell line, PrEC showed no remarkable effect. In vitro treatment of D-allose resulted in the alteration of Bcl-2/Bax ratio in favor of apoptosis (programmed cell death, PCD) in both the HRPC cell lines, which was associated with the lowering of mitochondrial transmembrane potential (Deltapsi(m)) and the release of cytochrome C (cyt C), the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), and the elevation of calcium concentration in cytosol ([Ca(2+)](c)). D-Allose also induced G1 phase arrest of the cell cycle in DU145 cell line. This study for the first time suggested the antiproliferative effect of D-allose through induction of PCD in HRPC cell lines, which could be due to the modulation of mitochondria mediated intrinsic apoptotic pathway.
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PMID:Rare sugar D-allose induces programmed cell death in hormone refractory prostate cancer cells. 1862 5

Antiapoptotic members of the Bcl-2 family proteins are overexpressed in prostate cancer and are promising molecular targets for modulating chemoresistance of prostate cancer. (-)-Gossypol, a natural BH3 mimetic, is a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 currently in phase II clinical trials as an adjuvant therapy for human prostate cancer. Our objective is to examine the chemosensitization potential of (-)-gossypol in prostate cancer and its molecular mechanisms of action. (-)-Gossypol inhibited cell growth and induced apoptosis through mitochondria pathway in human prostate cancer PC-3 cells and synergistically enhanced the antitumor activity of docetaxel both in vitro and in vivo in PC-3 xenograft model in nude mouse. (-)-Gossypol blocked the interactions of Bcl-xL with Bax or Bad in cancer cells by fluorescence resonance energy transfer assay and overcame the Bcl-xL protection of FL5.12 model cells on interleukin-3 withdrawal. Western blot and real-time PCR studies showed that a dose-dependent increase of the proapoptotic BH3-only proteins Noxa and Puma contributed to the cell death induced by (-)-gossypol and to the synergistic effects of (-)-gossypol and docetaxel. The small interfering RNA knockdown studies showed that Noxa and Puma are required in the (-)-gossypol-induced cell death. Taken together, these data suggest that (-)-gossypol exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma. (-)-Gossypol significantly enhances the antitumor activity of chemotherapy in vitro and in vivo, representing a promising new regime for the treatment of human hormone-refractory prostate cancer with Bcl-2/Bcl-xL/Mcl-1 overexpression.
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PMID:Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. 1864 28


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