EC:3.4.22.62 - FACTA Search

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

We examined the mechanisms by which daidzein inhibits the growth of breast cancer cells. First, we investigated its antiproliferative effects in MCF-7 and MDA-MB-453 cells exposed to 1-100 microM daidzein for 24, 48, or 72 h. Daidzein significantly inhibited cell proliferation in a dose- and time-dependent manner (p<0.05) and resulted in significant cell cycle arrest in the G1 and G2/M phases after 72 h of treatment at concentrations over 5 and 10 microM in MCF-7 and MDA-MB-453 cells, respectively (p<0.05). In addition, daidzein caused the accumulation of cells in sub-G0 phase in a dose-dependent manner in MDA-MB-453 (p<0.05), but not MCF-7, cells. As another biomarker of apoptosis induction, caspase-9 activity was significantly increased by daidzein in both cells. To investigate the effects of daidzein on the proteins regulating cell cycle arrest, cells were treated with 100 microM daidzein for 72 h. Similar changes in the expression of regulatory proteins were detected in both cells. Daidzein treatment resulted in decreases in cyclin D, CDK2, and CDK4, whereas the expression of CDK6 and cyclin E was unchanged. The protein expression of CDK1 related to the G2/M phase decreased markedly with daidzein treatment, whereas slight expression of cyclins A and B occurred. Daidzein treatment increased the expression of the CDK inhibitors p21(Cip1) and p57(Kip2), but not that of p27(Kip1). Thus, daidzein exerts its anticancer effects in human breast cancer cells via cell cycle arrest at the G1 and G2/M phases.
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PMID:Daidzein causes cell cycle arrest at the G1 and G2/M phases in human breast cancer MCF-7 and MDA-MB-453 cells. 1854 20

Carnosic acid is a strong dietary antioxidant derived from rosemary. Here, we have demonstrated that carnosic acid decreased viability of the human promyelocytic leukaemia cell line, HL-60, in dose- and time-dependent manners, and induced G(1) arrest and apoptosis. Carnosic acid also augmented these effects when induced by a low (physiological) concentration of arsenic trioxide, which was associated with upregulation of p27 and activation of caspase-9. These effects appeared to be mediated by the induction of phosphatase and tensin homologue (PTEN) expression. These findings indicate that PTEN plays an important role in the coordinated induction of apoptosis and G(1) arrest by carnosic acid and arsenic trioxide. Carnosic acid may have potential as an adjuvant in arsenic trioxide-induced apoptosis therapy due to its anticipated safety and great potency in enhancing the apoptosis-inducing action of a low concentration of arsenic trioxide.
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PMID:Augmentation by carnosic acid of apoptosis in human leukaemia cells induced by arsenic trioxide via upregulation of the tumour suppressor PTEN. 1865 63

In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective alpha(1)-adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of alpha(1)-adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G(0)/G(1) arrest, and G(2)/M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its alpha(1)-adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and MAPKs mediated pathways.
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PMID:Inhibition of human prostate cancer cells proliferation by a selective alpha1-adrenoceptor antagonist labedipinedilol-A involves cell cycle arrest and apoptosis. 1905 58

The src homology 2 (SH2)-domain containing inositol-5-phosphatase (SHIP) is another recently identified lipid phosphatase after phosphatase and tensin homology deleted on chromosome ten gene (PTEN). It plays an important role in negatively regulating the proliferation of hematopoietic cells. The relationship between SHIP and the inhibition of tumor proliferation is rarely reported. The purpose of this study is to evaluate the apoptosis induced by SHIP gene in K562 cell line and to explore the involved signaling pathway. The K562 cells were transfected with human SHIP gene by using the lentiviral vector containing SHIP, and the transfection was verified by fluorescent quantitative PCR (FQ-PCR) and Western blot. Then the effects of SHIP protein expression on cell growth and apoptosis were measured. The levels of p-Akt, bcl-2 family, caspase and the activity of NFkappaB were assayed by Western blot and ELISA, respectively. The results are as follows: (1) Human leukemia cell line K562 was SHIP-negative; (2) Transfection with SHIP gene led to the re-expression of SHIP mRNA and protein in K562, as shown by FQ-PCR and Western blot; (3) The expression of SHIP protein inhibited cell growth and significantly increased apoptosis in K562 cells; (4) Compared to that in control group, the expression level of p-Akt-308 and p-Akt-473 in SHIP-expressing cell group decreased significantly (P<0.01); SHIP activated caspase-9, caspase-3, up-regulated protein levels of bad, p27, down-regulated expression of bcl-xL, while it had no effect on the expression of bcl-2 and bax. Furthermore, the inhibition of NF-kappaB was achieved along with the inactivation of Akt. These data suggest that SHIP gene has potential abilities to inhibit K562 leukemic cell proliferation and induce its apoptosis via inactivating PI3K/Akt pathway. The loss of SHIP might be the explanation of aberrant high-level p-Akt in human leukemia. It may be at least one of the mechanisms by which the loss of SHIP expression contributes to leukemia progression.
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PMID:[The mechanism for SHIP gene to induce the apoptosis of human leukemia cell line K562.]. 1937 26

Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and suberoylanilide hydroxamic acid is used for the treatment of cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI, CG0006, and assessed its antiproliferative effects on the NCI-60 cancer cell panel and cell lines from liver and stomach cancers that are common in Korea. Micromolar levels of CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung, melanoma, ovarian, prostatic, renal, and stomach cancer cell lines. We further analyzed cell death mechanisms activated by CG0006 in HCT116 (colon cancer) and K562 (leukemia) cells. First, to test the activity of CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression. CG0006 increased acetylation of histone 3, histone 4, and tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover, CG0006 increased the mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with CG0006. Western blot analysis showed that CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition, CG0006 activated caspase-9, caspase-3, and caspase-8. These results indicate that CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI CG0006 may be a potent anticancer drug for solid tumors and leukemia.
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PMID:A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways. 1964 55

Liverwort constituents have been reported to exert a broad spectrum of biological activities. In this study, we used a bioactivity-guided separation of an extract from the liverwort species Marchantia emarginata subsp. tosana to determine its anticancer activity. A high level of the active ingredient was isolated from this liverwort and its chemical structure was identified and characterized by various spectra. It was found to be identical to a well-known compound, marchantin A, a cyclic bisbibenzyl ether. However, no anticancer activities of this compound have previously been reported. We found that marchantin A efficiently induced cell growth inhibition in human MCF-7 breast cancer cells, with an IC(50) of 4.0microg/mL. Fluorescence microscopy and a Western blot analysis indicated that marchantin A actively induced apoptosis of MCF-7 cells. The levels of cleaved caspase-8, cleaved caspase-3, cleaved caspase-9, and cleaved poly (ADP ribose) polymerase (PARP) increased. However, the level of Bid markedly decreased in a dose- and time-dependent manner. We also evaluated the anticancer activities of marchantin A on the regulation of cell cycle regulators such as p21, p27, cyclin B1, and cyclin D1. The p21 and p27 gene expressions increased markedly while cyclin B1 and D1 gene expression decreased markedly by treatment with marchantin A. Many report demonstrated that liverwort was suggested to possess potent antioxidant activity. Our results indicate that marchantin A possesses free radical-scavenging activity (EC(50)=20microg/mL). Taken together, for the first time, the compound marchantin A from liverworts demonstrated to be a potent inducer of apoptosis in MCF-7 cells.
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PMID:Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells. 1991 53

Aloe-emodin, one of the anthraquinones, has been shown to have anticancer activity in different kinds of human cancer cell lines. Therefore, the purpose of this study was to investigate the anti-cancer effect of aloe-emodin on human tongue squamous carcinoma SCC-4 cells. The results indicated that aloe-emodin induced cell death through S-phase arrest and apoptosis in a dose- and time-dependent manner. Treatment with 30 microM of aloe-emodin led to S-phase arrest through promoted p53, p21 and p27, but inhibited cyclin A, E, thymidylate synthase and Cdc25A levels. Aloe-emodin promoted the release of apoptosis-inducing factor (AIF), endonuclease G (Endo G), pro-caspase-9 and cytochrome c from the mitochondria via a loss of the mitochondrial membrane potential (DeltaPsi(m)) which was associated with a increase in the ratio of B-cell lymphoma 2-associated X protein (Bax)/B cell lymphoma/leukemia-2 (Bcl-2) and activation of caspase-9 and -3. The free radical scavenger N-acetylcysteine (NAC) and caspase inhibitors markedly blocked aloe-emodin-induced apoptosis. Aloe-emodin thus induced apoptosis in the SCC-4 cells through the Fas/death-receptor, mitochondria and caspase cascade. Aloe-emodin could be a novel chemotherapeutic drug candidate for the treatment of human tongue squamous cancer in the future.
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PMID:Aloe-emodin induces cell death through S-phase arrest and caspase-dependent pathways in human tongue squamous cancer SCC-4 cells. 2003 98

MicroRNAs (miRNA) are noncoding RNAs that regulate multiple cellular processes, including proliferation and apoptosis. We used microarray technology to identify miRNAs that were upregulated by non-small cell lung cancer (NSCLC) A549 cells in response to cisplatin (CDDP). The corresponding synthetic miRNA precursors (pre-miRNAs) per se were not lethal when transfected into A549 cells yet affected cell death induction by CDDP, C2-ceramide, cadmium, etoposide, and mitoxantrone in an inducer-specific fashion. Whereas synthetic miRNA inhibitors (anti-miRNAs) targeting miR-181a and miR-630 failed to modulate the response of A549 to CDDP, pre-miR-181a and pre-miR-630 enhanced and reduced CDDP-triggered cell death, respectively. Pre-miR-181a and pre-miR-630 consistently modulated mitochondrial/postmitochondrial steps of the intrinsic pathway of apoptosis, including Bax oligomerization, mitochondrial transmembrane potential dissipation, and the proteolytic maturation of caspase-9 and caspase-3. In addition, pre-miR-630 blocked early manifestations of the DNA damage response, including the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and of two ATM substrates, histone H2AX and p53. Pharmacologic and genetic inhibition of p53 corroborated the hypothesis that pre-miR-630 (but not pre-miR-181a) blocks the upstream signaling pathways that are ignited by DNA damage and converge on p53 activation. Pre-miR-630 arrested A549 cells in the G0-G1 phase of the cell cycle, correlating with increased levels of the cell cycle inhibitor p27(Kip1) as well as with reduced proliferation rates and resulting in greatly diminished sensitivity of A549 cells to the late S-G2-M cell cycle arrest mediated by CDDP. Altogether, these results identify miR-181a and miR-630 as novel modulators of the CDDP response in NSCLC.
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PMID:miR-181a and miR-630 regulate cisplatin-induced cancer cell death. 2014 52

Developing a quantifiable in vitro model of steatosis is critical in understanding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and searchingfor effective therapies. Using an ORO-based colorimetric measurement, we developed a convenient assay to qualify the degree of OA-induced steatosis in HepG2 cells. We demonstrated that in the absence of exogenous inflammatory mediators, OA-induced steatosis was associated with increased production and secretion of tumor necrosis factor alpha and decreased expression of peroxisome proliferators-activated receptor alpha in HepG2 cells. OA-induced steatosis was also associated with increased lipid peroxidation, apoptosis, but decreased proliferation in these cells. The increased lipid peroxidation was related to decreased SOD-1, a free radical scavenger enzyme; while increased apoptosis was related to increased active caspase-9. The decreased proliferation mediated by OA-induced steatosis was associated with increased production of p27 with unchanged alanine transaminase (ALT) level in the culture medium, indicating OA-induced steatosis alters cell cycle progression without direct toxicity to these cells. In conclusion, the present study developed a colorimetric assay that accurately quantifies OA-induced steatosis in HepG2 cells. In the absence of exogenous inflammatory mediators, OA-induced steatosis results in a series of pathophysilogical changes in HepG2 cells, indicating direct pathogenic roles of hepatocytes in NAFLD.
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PMID:Quantification and mechanisms of oleic acid-induced steatosis in HepG2 cells. 2018 86

The mechanisms by which the strong antitumor diorganotin(IV) compound di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) (DBDCT) induces apoptosis of SGC-7901 cells were first investigated. Inhibition of proliferation of four cancer cell lines compared with normal human hepatic L-O2 cells, cancer cell apoptosis, and expression of related mRNA and protein were detected using the methyl thiazolyl tetrazolium (MTT), flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), Western blot, and DNA ladder assays, and electron microscopy and immunocytochemistry. DBDCT decreased cancer cell proliferation rates in a dose- and time-dependent manner and changed the cycle distribution of SGC-7901 cells; the proportion of cells in G(0)-G(1) phase was increased, whereas the numbers in S and G(2)-M phases were decreased. Blockade of the cell cycle was perhaps associated with increased levels of p21, p27, p53 and the decreased level of proliferating cell nuclear antigen (PCNA). Apoptosis was characterized by DNA fragmentation, chromosomal condensation, apoptotic bodies, sub-G(1) peaks, and an increased apoptotic rate, as shown using the annexin V-FITC method. Pretreatment of cells with N-acetylcysteine and caspase-9 inhibitor could reduce growth inhibition and DBDCT-induced apoptosis. The results showed that DBDCT-mediated cell-cycle arrest might occur through the induction of p21 in a p53-dependent manner and that DBDCT induction of the mitochondrial apoptotic signaling pathway is perhaps mediated by increasing Bax/Bcl-2 ratios, which result in the loss of DeltaPsi(m), release of cytochrome c into the cytoplasm, activation of caspase-3 and -9, and increased reactive oxygen species (ROS) generation.
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PMID:Mechanisms by which the antitumor compound di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) induces apoptosis and the mitochondrial-mediated signaling pathway in human cancer SGC-7901 cells. 2033 62

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