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)

Chemotherapeutic drugs are usually designed to induce cancer cell death via cell cycle arrest and/or apoptosis pathways. In this study, we used the chemical drug 15,16-dihydrotanshinone I (DHTS) to inhibit breast cancer cell proliferation and tumor growth, and investigate the underlying molecular mechanisms. Human breast cancer cell lines MCF-7 and MDA-MB-231 were both used in this study, and DHTS was found to significantly decrease cell proliferation by a dose-dependent manner in both cells. Flow cytometry indicated that DHTS induced G1 phase arrest in synchronous MCF-7 and MDA-MB-231 cells. When analyzing the expression of cell cycle-related proteins, we found that DHTS reduced cyclin D1, cyclin D3, cyclin E, and CDK4 expression, and increased CDK inhibitor p27 expression in a dose-dependent manner. In addition, DHTS inhibited the kinase activities of CDK2 and CDK4 by an immunocomplex kinase assay. In addition, DHTS also induced apoptosis in both cells through mainly mitochondrial apoptosis pathways. We found that DHTS decreased the anti-apoptotic protein Bcl-xL level and increased the loss of mitochondria membrane potential and the amount of cytochrome c released. Moreover, DHTS activated caspase-9, caspase-3, and caspase-7 and caused cell apoptosis. The fact that DHTS-induced apoptosis could be blocked by pretreating cells with pan-caspase inhibitor confirmed that it is mediated through activation of the caspase-3-dependent pathway. In a nude mice xenograft experiment, DHTS significantly inhibited the tumor growth of MDA-MB-231 cells. Taken together, these results suggest that DHTS can inhibit human breast cancer cell proliferation and tumor growth, and might have potential chemotherapeutic applications.
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PMID:Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis. 1786 26

The major obstacle to successful treatment of gastric cancer is chemotherapy resistance. Our study was designed to investigate the role of phosphoinositide 3-kinase (PI3K)/Akt pathway in the development of chemoresistance in gastric cancer. In the present study, elevated Akt expression and Akt phosphorylation (Ser 473), as well as decreased PTEN expression were observed in 28 cases of gastric cancer tissues. Etoposide and doxorubicin stimulated Akt and PI3K activities in 2 gastric cancer cell lines (BGC-823 and SGC-7901), and the activities were concentration and time-dependent. Up-regulation of PTEN expression in BGC-823 cells by PEAK8-PTEN transient transfection obviously decreased the basal and anticancer drugs induced Akt activities, then sensitized BGC-823 cells to etoposide and doxorubicin. Pretreatment of BGC-823 and SGC-7901 cells with wortmannin, a PI3K inhibitor, attenuated cells's resistance to etoposide and doxorubicin. In addition, pretreatment of wortmannin blocked etoposide and doxorubicin induced IkappaB-alpha degradation, NFkappaB activation, phosphorylation of Akt, MDM-2 and forkhead transcription factors. Wortmannin pretreatment also promoted the accumulation of p27/Kip, but inhibited the Mcl-1 expression. Furthermore, wortmannin promoted etoposide and doxorubicin induced caspase-3, caspase-9 activation and poly ADP-ribose polymerase cleavage. Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the chemoresistance of gastric cancer cells. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway and then decrease the amount of resistant cells.
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PMID:Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. 1793 37

Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G(1) phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G(1) cell cycle. Future studies should focus on examining statins and other apoptosis-inducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer.
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PMID:Statin induces apoptosis and cell growth arrest in prostate cancer cells. 1819 14

Molecular mechanisms responsible for lymphoma resistance to apoptosis often involve the bcl-2 pathway. In this study, we investigated the cell signaling pathways activated in bcl-2-overexpressing human mantle cell lymphoma cell lines (JVM-2 and Z-138) that have been treated with oblimersen, a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Z-138 cells expressed higher levels of bcl-2 and were more sensitive to the effects of bcl-2 silencing, mediated by oblimersen or bcl-2 small interfering RNA, in vitro. Tumors derived following injection of Z-138 cells were sensitive to oblimersen as judged by decreases in tumor growth rate and decreases in cell proliferation (as measured by Ki-67). Immunohistochemistry and Western blot analysis of oblimersen-treated Z-138 tumors revealed a dose-dependent decrease in bcl-2 levels and an associated increase in the proapoptotic proteins caspase-3 and caspase-9. Silencing bcl-2 in Z-138 xenografts revealed an associated dose-dependent suppression of bax, a decrease in nuclear factor-kappaB and phospho-nuclear factor-kappaB, and transient loss of p53 levels. Coimmunoprecipitation studies suggest that the latter observation is mediated by an association between bcl-2 and phospho-mdm2. Bcl-2 silencing also led to p27 down-regulation and coimmunoprecipitation studies point to a role for bcl-2 in regulation of p27 localization/degradation. Bcl-2 silencing was also correlated with loss of cyclin D1a protein levels but not cyclin D1b levels. Coimmunoprecipitation studies indicate that bcl-2 may mediate its effects on cyclin D1a via interaction with p38 mitogen-activated protein kinase as well as a previously unreported interaction between bcl-2 and cyclin D1a.
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PMID:Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-kappaB, p53, bax, and p27 levels. 1837 22

Rhus verniciflua Stokes (RVS) has been used in traditional Eastern Asia medicine for the treatment of gastritis and stomach cancer, although the mechanism for its biological activity remains to be elucidated. We previously established that an ethanol extract of RVS-induced G(1)-cell cycle arrest via accumulation of p27(Kip1) controlled by Skp2 reduction and apoptosis in AGS human gastric cancer cells. Here, we showed that an ethanol extract of RVS-induced apoptosis via caspase-9 activation (mitochondrial death pathway) is mediated by the loss of mitochondrial membrane potential (MMP, Deltapsi(m)) and the release of cytochrome C from the mitochondrial intermembrane space. In addition, an ethanol extract of RVS inactivated PI3K-Akt/PKB kinase in a time-dependent manner. Moreover, combined treatment of an ethanol extract of RVS and LY294002 (a PI3K inhibitor) markedly increased apoptosis compared to treatment with an ethanol extract of RVS alone. The role of PI3K-Akt/PKB in this process was confirmed by constitutive expression of inactive mutants of this kinase in AGS cells. Finally, siRNA-mediated knockdown of Akt/PKB expression resulted in a significant reduction in AGS cell proliferation. Taken together, these results suggest that an ethanol extract of RVS induces apoptosis via a mitochondrial death pathway in human gastric cancer cells, but not in normal cells, and inhibition of the PI3K-Akt/PKB pathway enhanced the mitochondrial death pathway.
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PMID:Inhibition of the PI3K-Akt/PKB survival pathway enhanced an ethanol extract of Rhus verniciflua Stokes-induced apoptosis via a mitochondrial pathway in AGS gastric cancer cell lines. 1837 93

Gynostemma pentaphyllum Makino is known in Asia for its effect on the treatment of hepatitis and cardiovascular diseases. Gypenosides (Gyp) are the major components extracted from Gynostemma pentaphyllum Makino. However, the molecular mechanism underlying the Gyp-induced cell cycle arrest and apoptotic process is unclear. In this study, the chemopreventive role of Gyp in human lung cancer (A549) cells in vitro was evaluated by studying the regulation of the cell cycle and apoptosis. Gyp induced GO/G1 arrest and apoptosis in the human lung cancer A549 cells. Investigation of the cyclin-dependent protein kinase inhibitors by Western blotting showed that p16, p21, p27 and p53 proteins were increased with the increasing time of incubation with Gyp in the A549 cells. This increase may be the major factor by which Gyp caused GO/G1 arrest in the examined cells. Flow cytometric assay and gel electrophoresis of DNA fragmentation also confirmed that Gyp induced apoptosis in the A549 cells. Our data demonstrated that Gyp-induced apoptotic cell death was accompanied by up-regulation of Bax, caspase-3 and caspase-9, but down-regulation of the Bcl-2 levels. Taken together, Gyp appears to exert its anticancer properties by inducing GO/GI-phase arrest and apoptosis via activation of caspase-3 in human lung A549 cancer cells.
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PMID:Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. 1846 6

Our previous studies have shown that bee venom (BV) can induce apoptosis in human cervical cancer Ca Ski cells, but it can also affect human breast cancer cells, though its molecular mechanisms are not precisely known. In this study, the molecular mechanisms of apoptosis induced by BV in human breast cancer MCF7 cells were investigated. BV induced morphological changes (examined by phase-contrast microscopy) and inhibited the proliferation (examined by MTT assay) of MCF7 cells; both effects occurred in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BV induced the production of reactive oxygen species (ROS) and dysfunction of the mitochondrial membrane potential (Azm), and led to cytochrome c release, an increase in the levels of caspase-9 and Poly (ADP-ribose) polymerase (PARP) and then apoptosis. It also showed that BV induced S-phase arrest in MCF7 cells which may occur through the promotion of p53, p21, p27 and the exhibition of Cdk2. Western blotting demonstrated that BV reduced Bcl-2 and increased Bax protein levels which may have caused the changes of delta psi m. BV treatment led to ROS production up to but after treatment led to a decrease in the levels of ROS, which may be associated with the observations of BVaffecting glutathion S-transferase (GST), Zn-superoxide dismutase (Zn-SOD), Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and catalase. The Comet assay also showed that BV induced DNA damage while DAPI staining also confirmed that BV induced apoptosis in examined MCF7 cells. Our results also showed that BV increased the levels of AIF and EndoG in MCF7 cells. In conclusion, our data demonstrated that BV induced apoptosis via a mitochondria-dependent pathway based on the changes of delta psi m, AIF and EndoG release in MCF7 cells.
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PMID:The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. 1846 9

We examined the effect of (-)-syringaresinol, a furofuran-type lignan isolated from Daphne genkwa, on cell cycle regulation in HL-60 human promyelocytic leukemia cells in vitro. (-)-Syringaresinol decreased the viability of HL-60 cells by inducing G(1) arrest followed by apoptosis in a dose- and time-dependent manner. The G(0)/G(1) phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the (-)-syringaresinol-induced G(1) arrest was mediated through the increased expression of Cdki proteins (p21(cip1/waf1) and p27(kip1)) with a simultaneous decrease in cdk2, cdk4, cdk6, cyclin D(1), cyclin D(2), and cyclin E expression. The induction of apoptosis after treatment with (-)-syringaresinol for 24 h was demonstrated by morphological changes, DNA fragmentation, altered ratio of Bax/Bcl-2, cleavage of poly(ADP-ribose) polymerase and flow cytometry analysis. (-)-Syringaresinol also induced cytochrome c release and activation of caspase-3 and caspase-9. To our knowledge, this is the first time that (-)-syringaresinol has been reported to potently inhibit the proliferation of human promyelocytic HL-60 cells through G(1) arrest and induction of apoptosis. These findings suggest that (-)-syringaresinol may be a potential chemotherapeutic agent for the treatment of cancer.
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PMID:(-)-Syringaresinol inhibits proliferation of human promyelocytic HL-60 leukemia cells via G1 arrest and apoptosis. 1848 7

In this study, we investigate the anticancer effect of isoobtusilactone A (IOA), a constituent isolated from the leaves of Cinnamomum kotoense, on human non-small cell lung cancer (NSCLC) A549 cells. IOA was found to induce the arrest of G2-M phase, induce apoptosis, increase sub-G1, and inhibit the growth of these cells. Further investigation revealed that IOA's blockade of the cell cycle was associated with increased levels of p21/WAF1, p27 (kip1), and p53. In addition, IOA triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratios, resulting in a loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. We also found the generation of reactive oxygen species (ROS) to be a critical mediator in IOA-induced inhibition of A549 cell growth. In antioxidant and NO inhibitor studies, we found that by pretreating A549 cells with either N-acetylcystenine (NAC), catalase, mannitol, dexamethasone, trolox, or L-NAME we could significantly decrease IOA production of ROS. Moreover, using NAC to block ROS, we could significantly suppress IOA-induced antiproliferation, antimigration, and anti-invasion. Finally, we found that IOA inhibited the migration and invasion of A549 cell migration and invasion. Taken together, these results suggest that IOA has anticancer effects on A549 cells.
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PMID:Anticancer activity of isoobtusilactone A from Cinnamomum kotoense: involvement of apoptosis, cell-cycle dysregulation, mitochondria regulation, and reactive oxygen species. 1848 63

The effects of the crude extract of Solanum lyratum (SLE) on human colon cancer colo 205 cells were investigated. The cell viability, morphological changes of the cells, cell cycle arrest, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (deltapsi(m)) and cell cycle- and apoptosis-associated protein levels and gene expressions were examined in colo 205 cells after exposure to various concentrations of SLE for different time periods. The results indicated that SLE decreased the percentage of viable colo 205 cells accompanied by morphological changes. The most effective concentration of SLE was 300 pg/ml (SLE 300) and this concentration was used for further investigations. SLE induced S-phase arrest and apoptosis (sub-G1) in the colo 205 cells and those effects were dose- and time-dependent. DAPI staining and DNA gel electrophoresis confirmed that SLE induced apoptosis in colo 205 cells. Flow cytometric analysis also showed that SLE 300 promoted ROS production and decreased the deltapsi(m). Western blotting analysis indicated that SLE 300 increased Bax levels and decreased Bcl-2 levels, which caused the loss of deltapsi(m) followed by cytochrome c release and caspase-9 and -3 activation, finally leading to apoptosis. SLE 300 also promoted p53 and p27, but decreased the levels of cyclin B1 thus causing S-phase arrest. The gene expression associated with those proteins was also confirmed by PCR methods. The findings show that SLE might be used as a colon cancer therapeutic agent in the future.
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PMID:Crude extracts of Solanum lyratum induced cytotoxicity and apoptosis in a human colon adenocarcinoma cell line (colo 205). 1850 53


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