Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Naringenin (NGEN), a naturally occurring citrus flavonone, has shown cytotoxicity in various human cancer cell lines as well as inhibitory effects on tumor growth. It has been also shown to access the brain and there is an increasing interest in its therapeutic applications. The up-regulated expression of Cx43 leads to the suppression of tumorigenicity with promoted apoptotic events. In this study, we investigated the in vivo effect of NGEN in fostering apoptosis in cerebrally implanted C6 glioma cells rat model. We analysed the expression of Cx43, caspase-3, caspase-9, Cyt C, Bcl-2 and Bax in vivo by immunoblot analysis and the ultra structure of brain cells by transmission electron microscopy. Supplementation of NGEN to experimental animals modulated Bcl-2/Bax ratio and up-regulation of caspase-3 and 9. NGEN was also found to up-regulate the expression of Cx43. These findings provide evidence that NGEN's apoptotic effect, modulation of Bcl-2/Bax ratio leads to release of Cyt C from mitochondria, thereby activation of caspase-3 and caspase-9 is mediated by enhanced expression of Cx43. These observations were well supported by the transmission electron microscopic results which showed the characteristic apoptotic features. In conclusion, our findings demonstrate that NGEN promotes apoptosis in rat C6 glioma model.
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PMID:Naringenin promote apoptosis in cerebrally implanted C6 glioma cells. 2071 7

Chemoresistance is a major cause of treatment failure in ovarian cancer. Therefore, it is necessary to explore alternative therapeutic methods to overcome drug resistance for ovarian cancer treatment. We previously reported that programmed cell death 4 (PDCD4), a tumor suppressor, significantly suppresses the malignant phenotype of ovarian cancer cells and its lost or low expression in ovarian cancer is associated with unfavorable prognosis of patients. Here we show that PDCD4 improves the sensitivity of ovarian cancer cells to platinum-based chemotherapy. Overexpression of PDCD4 enhanced chemosensitivity in SKOV3 and CAOV3 cells with low levels of PDCD4, whereas knockdown of PDCD4 reduced chemosensitivity in OVCAR3 cells with high levels of PDCD4. Subsequently, the combination of enforced PDCD4 expression with cisplatin treatment significantly suppressed ovarian tumor growth in a xenograft animal model. The PDCD4 effect appears to be specific for cisplatin and carboplatin, not affecting cyclophosphamide, etoposide, or paclitaxel. Mechanistically, PDCD4 significantly increased cisplatin-induced cleavage of caspase-3 and caspase-8, but had only a slight impact on caspase-9 cleavage and the expression of Bax and Bcl-2 in vitro and in vivo. A specific caspase-8 inhibitor, Z-ITED-FMK, attenuated cisplatin-induced apoptosis in PDCD4-overexpressing ovarian cancer cells. Taken together, our results indicate that PDCD4 enhances cisplatin-induced apoptosis by mainly activating the death receptor pathway, and PDCD4 gene transfer in combination with cisplatin therapy may break the resistance of ovarian cancer cells to chemotherapy.
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PMID:Programmed cell death 4 enhances chemosensitivity of ovarian cancer cells by activating death receptor pathway in vitro and in vivo. 2073 32

We have shown that the potent phosphodiesterase-5 (PDE-5) inhibitor sildenafil (Viagra) induces a powerful effect on reduction of infarct size following ischemia/reperfusion injury and improvement of left ventricular dysfunction in the failing heart after myocardial infarction or doxorubicin (DOX) treatment. In the present study, we further investigated the potential effects of sildenafil on improving antitumor efficacy of DOX in prostate cancer. Cotreatment with sildenafil enhanced DOX-induced apoptosis in PC-3 and DU145 prostate cancer cells, which was mediated by enhanced generation of reactive oxygen species, up-regulation of caspase-3 and caspase-9 activities, reduced expression of Bcl-xL, and phosphorylation of Bad. Overexpression of Bcl-xL or dominant negative caspase 9 attenuated the synergistic effect of sildenafil and DOX on prostate cancer cell killing. Furthermore, treatment with sildenafil and DOX in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. The reduced tumor size was associated with amplified apoptotic cell death and increased expression of activated caspase 3. Doppler echocardiography showed that sildenafil treatment ameliorated DOX-induced left ventricular dysfunction. In conclusion, these results provide provocative evidence that sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer while providing concurrent cardioprotective benefit.
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PMID:Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. 2088 55

Mantle cell lymphoma (MCL) frequently relapses after therapy and new therapeutic regimens are needed. Lenalidomide (LEN), a thalidomide analogue, displays direct cytotoxicity against MCL cells. This study was undertaken to evaluate the combined therapeutic effect of LEN and dexamethasone (DEX) on MCL. LEN synergized with DEX to induce the growth inhibition and apoptosis of both established MCL cells and freshly isolated MCL cells from refractory or relapsed MCL patients. The synergy was more significant in freshly isolated patients' MCL cells than established MCL cells. Cell cycle analysis showed that LEN enhanced DEX-induced G(0)/G(1) arrest. The effect of the LEN and DEX combination on apoptotic induction was mainly through mitochondrial signaling pathways, as demonstrated by phosphorylation of bcl-2 and up-regulation of proapoptotic proteins Bax, Bad and Bim, and the subsequent activation of caspase-9, caspase-3, and cleavage of PARP. Importantly, the combination of LEN and DEX delayed the tumor growth and improved the survival of MCL-bearing mice. The results support the use of the LEN and DEX combination as a new therapeutic regimen in clinical trials of MCL.
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PMID:Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. 2104 86

The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of the ING family has potential tumor-suppressive effects. In this study, we explored the combined effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer plus chemotherapy drug cisplatin (CDDP) on SMMC-7721 human hepatocarcinoma cells in vitro and in vivo, and its underlying mechanism. We demonstrated that Ad-ING4 plus CDDP induced synergistic growth inhibition, enhanced apoptosis, and had an additive effect on upregulation of Fas, Bax, Bak, cleaved Bid, cleaved caspase-8, caspase-9, caspase-3 and cleaved PARP, and on downregulation of Bcl-2 and Bcl-X(L) in SMMC-7721 hepatocarcinoma cells. Moreover, Ad-ING4 plus CDDP synergistically suppressed in vivo SMMC-7721 hepatocarcinoma subcutaneous (s.c.) xenografted tumor growth and reduced tumor vessel CD34 expression and microvessel density (MVD) in athymic nude mice. Most importantly, Ad-ING4 plus CDDP did not have overlapping toxicities in HL-7702 normal human liver cells and normal liver tissues of mice. The in vitro and in vivo enhanced antitumor effect elicited by Ad-ING4 plus CDDP was closely associated with the cooperative regulation of extrinsic and intrinsic apoptotic pathways and synergistic inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 plus CDDP is a potential combined treatment strategy for hepatocarcinoma.
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PMID:Enhanced antitumor activity by combining an adenovirus harboring ING4 with cisplatin for hepatocarcinoma cells. 2105 98

Prostate-specific antigen (PSA), a serine protease, is a promising target for the development of prodrugs in prostate cancer treatment. In this study, we designed a novel fusion peptide, BSD352, containing three functional domains: a protein transduction domain from HIV transactivating regulatory protein (TAT) followed by the BH3 domain of the p53 upregulated modulator of apoptosis (TAT-BH3), an anti-vascular endothelial growth factor peptide (SP5.2), and an anti-basic fibroblast growth factor peptide (DG2). These different domains in BSD352 were linked together by a linker sequence corresponding to a PSA hydrolytic substrate peptide. The BSD352 fusion peptide could be selectively cleaved by PSA in PSA-producing LNCaP prostate cancer cells. Furthermore, the BSD352 fusion peptide was efficiently transduced into tumor cells both in vitro and in vivo, and the BH3 domain was found to induce tumor cell apoptosis by elevating the expression of Bax, cytochrome C release, and caspase-9 cleavage. Moreover, the SP5.2 and DG2 domains in the BSD352 fusion peptide also exhibited in-vitro endothelial cell growth inhibition and in-vivo antiangiogenic activities. Direct injection of BSD352 into an established LNCaP xenograft tumor in mice inhibited tumor growth, whereas a synergistic effect was observed with the combined use of wild-type BH3, SP5.2, and DG2 functional domains. These results suggest that BSD352 could be beneficial for the treatment of accessible prostate tumors and may provide a complementary strategy for prostate cancer therapy.
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PMID:Synergistic tumor growth-inhibitory effect of the prostate-specific antigen-activated fusion peptide BSD352 for prostate cancer therapy. 2115 Jul 73

Previous studies have established a role of vascular-disrupting agents as anti- cancer agents. Plinabulin is a novel vascular-disrupting agent that exhibits potent interruption of tumor blood flow because of the disruption of tumor vascular endothelial cells, resulting in tumor necrosis. In addition, plinabulin exerts a direct action on tumor cells, resulting in apoptosis. In the present study, we examined the anti-multiple myeloma (MM) activity of plinabulin. We show that low concentrations of plinabulin exhibit a potent antiangiogenic action on vascular endothelial cells. Importantly, plinabulin also induces apoptotic cell death in MM cell lines and tumor cells from patients with MM, associated with mitotic growth arrest. Plinabulin-induced apoptosis is mediated through activation of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase cleavage. Moreover, plinabulin triggered phosphorylation of stress response protein JNK, as a primary target, whereas blockade of JNK with a biochemical inhibitor or small interfering RNA strategy abrogated plinabulin-induced mitotic block or MM cell death. Finally, in vivo studies show that plinabulin was well tolerated and significantly inhibited tumor growth and prolonged survival in a human MM.1S plasmacytoma murine xenograft model. Our study therefore provides the rationale for clinical evaluation of plinabulin to improve patient outcome in MM.
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PMID:A novel vascular disrupting agent plinabulin triggers JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells. 2145 51

Deltonin, a steroidal saponin, isolated from Dioscorea zingiberensis Wright (DZW), has shown high-cytotoxic activity in cancer cells. However, its mechanisms and in vivo anti-cancer effects remain unknown. In the present study, we evaluated the effects and explored the anti-tumor mechanisms of deltonin on a panel of colon cancer cell lines and in a mouse model of murine colon cancer C26. Deltonin had more cytotoxic effect on C26 cells than 5-fluorouracil had, promoting dramatic G2-M phase arrest and apoptosis in C26 cells in a concentration-dependent manner; oral administration of deltonin significantly inhibited the tumor growth and prolonged survival of the tumor bearing mice. The deltonin treatment caused a noticeable apoptosis in tumor tissue, which associated with increased levels of Bax, activated caspase-3, caspase-9, and cleaved poly (ADPribose) polymerase, decreased pro-caspase-8, pro-caspase-9, Bcl-2 expression levels and extracellular signal-regulated kinase-1/2 activity; and dose-dependently inhibit angiogenesis. In conclusion, the findings in this study demonstrated that deltonin is an effective natural agent for cancer therapy, which may be mediated, in part, by induction of apoptosis, as well as involve mitogen-activated protein kinase pathways, and inhibition of angiogenesis.
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PMID:Deltonin, a steroidal saponin, inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis and antiangiogenesis. 2147 12

Bladder cancer is the ninth most common type of cancer, and its surgery is always followed by chemotherapy to prevent recurrence. Berberine is non-toxic to normal cells but has anti-cancer effects in many cancer cell lines. This study was aimed to determine whether berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87 and T24 bladder cancer cell line. The superficial bladder cancer cell line BIU-87 and invasive T24 bladder cancer cells were treated with different concentrations of berberine. MTT assay was used to determine the effects of berberine on the viability of these cells. The cell cycle arrest was detected through propidium iodide (PI) staining. The induction of apoptosis was determined through Annexin V-conjugated Alexa Fluor 488 (Alexa488) staining. Berberine inhibited the viability of BIU-87 and T24 cells in a dose- and time-dependent manner. It also promoted cell cycle arrest at G0/G1 in a dose-dependent manner and induced apoptosis. We observed that H-Ras and c-fos mRNA and protein expressionswere dose-dependently and time-dependently decreased by berberine treatment. Also, we investigated the cleaved caspase-3 and caspase-9 protein expressions increased in a dose-dependent manner. Berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87, bladder cancer cell line and T24, invasive bladder cancer cell line. Berberine can inhibit the oncogentic H-Ras and c-fos in T24 cells, and can induce the activation of the caspase-3 and caspase-9 apoptosis. Therefore, berberine has the potential to be a novel chemotherapy drug to treat the bladder cancer by suppressing tumor growth.
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PMID:Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells. 2154 98

FV-429 is a newly synthesized flavonoid with a bis(2-hydroxyethyl) amino propoxy substitution. In this study, we investigate the anticancer effect of FV-429 both in vivo and in vitro. These data have shown that FV-429 could significantly inhibit tumor growth in mice inoculated with Heps hepatoma cells without evident toxicity. After the treatment of FV-429 (40 mg/kg), the inhibitory rate of tumor weight was 52.12%. Then, we performed diamidinophenylindole staining and annexin V/propidium iodide double-staining assay to investigate the apoptosis induced by FV-429 in HepG2 cells. Further research revealed that FV-429 induced apoptosis through the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl-2 ratios, collapse of mitochondrial membrane potential, the transposition of apoptotic-inducing factor and cytochrome c, caspase-3 and caspase-9 activation, and degradation of poly (ADP-ribose) polymerase. The accumulation of reactive oxygen species induced by FV-429 in HepG2 cells was also observed. Moreover, the mitogen-activated protein kinases, the downstream effect of reactive oxygen species accumulation including c-Jun N-terminal kinase and p38 mitogen-activated protein kinases, could be activated by FV-429. Taken together, our results provided a mechanistic framework for further exploration of FV-429 as a novel chemotherapy for human tumors.
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PMID:Reactive oxygen species-mitochondria pathway involved in FV-429-induced apoptosis in human hepatocellular carcinoma HepG2 cells. 2173 Aug 22


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