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)

Beta-elemene is a novel anticancer drug, which was extracted from the ginger plant. However, the mechanism of action of beta-elemene in non-small-cell lung cancer (NSCLC) remains unknown. Here we show that beta-elemene had differential inhibitory effects on cell growth between NSCLC cell lines and lung fibroblast and bronchial epithelial cell lines. In addition, beta-elemene was found to arrest NSCLC cells at G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases in the levels of p27(kip1) and phospho-Cdc2 (Tyr-15). Moreover, beta-elemene reduced the expression of Cdc25C, which dephosphorylates/activates Cdc2, but enhanced the expression of the checkpoint kinase, Chk2, which phosphorylates/ inactivates Cdc25C. These findings suggest that the effect of beta-elemene on G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism. We also demonstrate that beta-elemene triggered apoptosis in NSCLC cells. Our results clearly show that beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly(ADP-ribose) polymerase in NSCLC cells. These data indicate that the effect of beta-elemene on lung cancer cell death may be through a mitochondrial release of the cytochrome c-mediated apoptotic pathway.
 ...
PMID:Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. 1586 11

Prostate cancer is the second leading cancer diagnosed in elderly males in the Western world. Epidemiologic studies suggest that dietary modifications could be an effective approach in reducing various cancers, including prostate cancer, and accordingly cancer-preventive efficacy of dietary nutrients has gained increased attention in recent years. We have recently shown that grape seed extract (GSE) inhibits growth and induces apoptotic death of advanced human prostate cancer DU145 cells in culture and xenograft. Because prostate cancer is initially an androgen-dependent malignancy, here we used LNCaP human prostate cancer cells as a model to assess GSE efficacy and associated mechanisms. GSE treatment of cells led to their detachment within 12 hours, as occurs in anoikis, and caused a significant decrease in live cells mostly due to their apoptotic death. GSE-induced anoikis and apoptosis were accompanied by a strong decrease in focal adhesion kinase levels, but an increase in caspase-3, caspase-9, and poly(ADP-ribose) polymerase cleavage; however, GSE caused both caspase-dependent and caspase-independent apoptosis as evidenced by cytochrome c and apoptosis-inducing factor release into cytosol. Additional studies revealed that GSE causes DNA damage-induced activation of ataxia telangiectasia mutated kinase and Chk2, as well as p53 Ser(15) phosphorylation and its translocation to mitochondria, suggesting this to be an additional mechanism for apoptosis induction. GSE-induced apoptosis, cell growth inhibition, and cell death were attenuated by pretreatment with N-acetylcysteine and involved reactive oxygen species generation. Together, these results show GSE effects in LNCaP cells and suggest additional in vivo efficacy studies in prostate cancer animal models.
 ...
PMID:Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation. 1673 59

Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO(*) in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH(2)-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.
 ...
PMID:JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. 1738 1

This study first investigates the anticancer effect of kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells.
 ...
PMID:Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells. 1851 Nov 69

Emodin was isolated from Rheum palmatum L. and exhibits an anticancer effect on human cancer cell lines, however, the molecular mechanisms of emodin-mediated apoptosis in human tongue cancer cells have not been fully investigated. In this study, treatment of human tongue cancer SCC-4 cells with various concentrations of emodin led to G2/M arrest through promoted p21 and Chk2 expression but inhibited cyclin B1 and cdc2; it also induced apoptosis through the pronounced release of cytochrome c from mitochondria and activations of caspase-9 and caspase-3. These events were accompanied by the generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (delta psi(m)) and a decrease in the ratio of mitochondrial Bcl-2 and Bax content; emodin also promoted the levels of GADD153 and GRP78. The free radical scavenger N-acetylcysteine and caspase inhibitors markedly blocked emodin-induced apoptosis. Taken together, these findings suggest that emodin mediated oxidative injury (DNA damage) based on ROS production and ER stress based on the levels of GADD153 and GRP78 that acts as an early and upstream change in the cell death cascade to caspase- and mitochondria-dependent signaling pathways, triggers mitochondrial dysfunction from Bcl-2 and Bax modulation, mitochondrial cytochrome c release and caspase activation, consequently leading to apoptosis in SCC-4 cells.
 ...
PMID:Emodin induces apoptosis of human tongue squamous cancer SCC-4 cells through reactive oxygen species and mitochondria-dependent pathways. 1933 Nov 69

Diosgenin is a plant steroid which is able to induce megakaryocytic differentiation of human erythroleukemia (HEL) cells followed by apoptosis at a later stage. Apoptosis markers and phospho-kinases involved during the subsequent apoptosis of megakaryocytes after diosgenin-induced differentiation in these cells were detected using a proteomic approach. In mature megakaryocytes undergoing apoptosis, we observed increased expression of intrinsic apoptosis markers such as Bax/Bcl-2 ratio and cleaved caspase-9 as well as extrinsic apoptosis markers including cell death receptors and cleaved caspase-8. Furthermore, we demonstrated the link between both apoptotic pathways by Bid cleavage and confirmed the executive phase of apoptosis by caspase-3 cleavage. For the first time, we examined kinase activation and showed that kinases including Src, Tor, Akt, CREB, RSK and Chk2 may be implicated in signalling of subsequent apoptosis of mature megakaryocytes after diosgenin-induced differentiation of HEL cells.
 ...
PMID:A proteomic approach to the identification of molecular targets in subsequent apoptosis of HEL cells after diosgenin-induced megakaryocytic differentiation. 1941 84

This study is the first to investigate the anticancer effect of isoliquiritigenin (ISL) in human cervical carcinoma HeLa cells. The results reveal that ISL inhibits HeLa cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Blockade of cell cycle is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by ISL phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, ISL-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2, and cdc25C, and increases in the phosphorylation of Chk2, cdc25C, and cdc2. The specific ATM inhibitor caffeine significantly decreased ISL-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. ISL induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked ISL-induced apoptosis, indicating that caspase-9 activation is involved in ISL-mediated HeLa cell apoptosis. These findings suggest that ISL may be a promising chemopreventive agent against human uterine cervical cancer.
 ...
PMID:Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells. 1953 69

This study is the first to investigate the anticancer effect of tricetin in human breast adenocarcinoma MCF-7 cells. Results reveal that tricetin inhibits MCF-7 cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Cell cycle blockade is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by tricetin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, tricetin-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2 and cdc25C, and increases in the phosphorylation of Chk2, cdc25C and cdc2. The specific ATM inhibitor caffeine significantly decreased tricetin-mediated G2/M arrest by inhibiting the phosphorylation of p53 (serine 15) and Chk2. Tricetin-induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering the mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked tricetin-induced apoptosis, indicating that caspase-9 activation is involved in tricetin-mediated MCF-7 cell apoptosis. These findings suggest that tricetin may be a promising chemopreventive agent against human breast cancer.
 ...
PMID:Tricetin, a dietary flavonoid, inhibits proliferation of human breast adenocarcinoma mcf-7 cells by blocking cell cycle progression and inducing apoptosis. 1970 44

The possibility of synergism between the topoisomerase inhibition by coralyne and its DNA photonicking properties being used to kill cancer cells was explored. Compared with coralyne alone, the CUVA treatment dramatically enhanced DNA damage and apoptosis in cells. Despite causing an increased p53 expression, the CUVA treatment led to p53-independent apoptosis, causing almost similar cell death in wild-type, p53 mutant, and p53-silenced tumor cells. Expression of the p53-regulated downstream proteins like p21, and DNA-damage-dependent p53 phosphorylation at serine-15 residue also was not elicited by the CUVA treatment, at a low coralyne concentration. Instead, it led to an immediate activation of the Chk2-mediated S-phase arrest, despite activating PARP protein for DNA repair. The S-phase arrest subsequently ensures apoptosis through activation of caspases-3 and -9, the latter being reflected from the results with a specific caspase-9 inhibitor. Abrogation of Chk2 activity by shRNA or by using ATM-specific inhibitor (ATMi) led to a defective S-phase checkpoint and further augmentation in apoptosis. However, at a high coralyne concentration, the CUVA-induced apoptosis followed multiple and independent pathways, involving several caspases. The CUVA treatment may represent a novel mechanism-based protocol for increasing the efficacy of coralyne in inducing apoptosis in both p53 wild-type and mutant tumor cells.
 ...
PMID:Topoisomerase inhibitor coralyne photosensitizes DNA, leading to elicitation of Chk2-dependent S-phase checkpoint and p53-independent apoptosis in cancer cells. 1992 65

The protoapigenone analogue WYC02-9, a novel synthetic flavonoid, has been shown to act against a variety of experimental tumors. However, its effects on prostate cancer and its mechanism of action are unknown. Thus, WYC02-9 was investigated for its cytotoxicity against DU145 prostate cancer cells, as was the underlying mechanisms by which WYC02-9 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). WYC02-9 inhibited the cell growth of three prostate cancer cell lines, especially DU145 cells. In DU145 cells, WYC02-9 increased the generation of intracellular ROS, followed by induction of DNA damage and activation of the ATM-p53-H2A.X pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, WYC02-9 induced apoptotic cell death through mitochondrial membrane potential decrease and activation of caspase-9, caspase-3, and PARP. The above effects were all prevented by the ROS scavenger N-acetylcysteine. Administration of WYC02-9 in a nude mouse DU145 xenograft model further identified the anti-cancer activity of WYC02-9. These findings therefore suggest that WYC02-9-induced DNA damage and mitochondria-dependent cell apoptosis in DU145 cells are mediated via ROS generation.
 ...
PMID:A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species. 2125 11


1 2 3 Next >>