Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cip/Kip family protein p21, a cyclin-dependent kinase (CDK) inhibitor, is directly transactivated by retinoic acid receptor alpha (RARalpha) upon retinoic acid (RA):RARalpha binding. Yet the role of p21 upregulation by RA in lymphoma cells remains unknown. Here, we show that, in human pre-B lymphoma Nalm6 cells, RA-induced proliferation inhibition results from massive cell death characterized by apoptosis. Upregulated p21 by RA accompanies caspase-3 activation and precedes the occurrence of apoptosis. p21 induction leads to increased p21 complex formation with cyclin E/CDK2, which occurs when cyclin E and CDK2 levels remain constant. CDK2 can alternatively promote apoptosis, but the mechanisms remain unknown. Data presented here suggest a novel RA-signaling, by which RA-induced p21 induction and complex formation with cyclin E/CDK2 diverts CDK2 function from normally driving proliferation to alternatively promoting apoptosis.
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PMID:Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid-induced pre-B lymphoma cell apoptosis. 1676 49

The role of Ca2+ on the effects of capsaicin on human leukemia HL-60 cells in vitro and the molecular mechanisms of capsaicin-induced apoptosis were investigated. The flow cytometric analysis indicated that capsaicin decreased the percentage of viable HL-60 cells, via the induction of G0/G1-phase cell cycle arrest and apoptosis. Capsaicin-induced G0/G1-phase arrest involved the suppression of CDK2 and the cyclin E complex, which are check-point enzymes for cells moving from G0/G1- to S-phase. Capsaicin-induced apoptosis was associated with the elevation of intracellular reactive oxygen species and Ca2+ production, decreased the levels of mitochondrial membrane potential, promoted cytochrome c release and increased the activation of caspase-3. An intracellular Ca2+ chelator (BAPTA) significantly inhibited capsaicin-induced apoptosis. Capsaicin-induced apoptosis was time-and dose-dependent. These results suggest that the capsaicin-induced apoptosis of HL-60 cells may result from the activation of caspase-3 and the intracellular Ca2+ release pathway.
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PMID:Involvement of Bax, Bcl-2, Ca2+ and caspase-3 in capsaicin-induced apoptosis of human leukemia HL-60 cells. 1682 31

Capsaicin (N-vanillyl-8-methyl-1-nonenamide) is found in pungent fruits, especially in red pepper. Many studies have focused on the anticarcinogenic, antimutagenic or chemopreventive activities of capsaicin. However, the effects of capsaicin on human esophagus epidermoid carcinoma cells have never been investigated. In this study, we investigated the effects of capsaicin on esophagus epidermoid carcinoma cells in vitro and further examined the molecular mechanisms of capsaicin-induced apoptosis in esophagus epidermoid carcinoma cells. Capsaicin decreased the percentage of viable cells of CE 81T/VGH cells, via induction of G0-G1 phase cell cycle arrest and apoptosis. Capsaicin induced G0-G1 phase arrest underwent the promotion of p53 and p21, which is an inhibitor of Cdk2 and cyclin E complex before leading to the inhibitions of both compounds. Capsaicin induced apoptosis in time-dependent manners. Capsaicin-induced apoptosis was in association with the elevation of intracellular reactive oxygen species and Ca2+ productions and BAPTA, an intracellular Ca2+ chelator, which significantly inhibited capsaicin-induced apoptosis. Collectively, these results suggest that the capsaicin-induced apoptosis in the CE 81T/VGH cells may result from the activation of caspase-3 and intracellular Ca2+ release pathway, and it is further suggested that capsaicin has potential as a novel therapeutic agent for the treatment of esophagus epidermoid carcinoma cells.
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PMID:Capsaicin induced cell cycle arrest and apoptosis in human esophagus epidermoid carcinoma CE 81T/VGH cells through the elevation of intracellular reactive oxygen species and Ca2+ productions and caspase-3 activation. 1694 82

In this study, we first report the chemopreventive effect of rugosin E in human breast cancer cell line, MDA-MB-231. Treatment with rugosin E decreased the cell proliferation of MDA-MB-231 cells in a dose-dependent manner. Rugosin E treatment arrested MDA-MB-231 cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin D2, cyclin E, cdk2, cdk4, and cdk6, and increase of p21/WAF1. In addition, rugosin E also induced apoptotic cell death. Rugosin E increased in the expression of Bax, Bak, and Bcl-Xs, but decreased the levels of Bcl-2 and Bcl-X(L), and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c, activation of caspase-9, and caspase-3). In addition, pre-treatment of cells with caspase-9 inhibitor blocked rugosin E-induced cell proliferation and apoptosis, indicating caspase-9 activation was involved in rugosin E-mediated MDA-MB-231 cells apoptosis. Rugosin E inhibited the constitutively activated and inducible NF-kappaB in both its DNA-binding activity and transcriptional activity. Furthermore, rugosin E also inhibited the TNF-alpha-activated NF-kappaB-dependent reporter gene expression of cyclin D1, c-Myc, XIAP, Bcl-2, and Bcl-X(L) were all downregulated by rugosin E. Our results indicated that rugosin E inhibits the activation of NF-kappaB, and this may provide a molecular basis for drug development in the prevention and treatment of cancer by rugosin E.
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PMID:Rugosin E, an ellagitannin, inhibits MDA-MB-231 human breast cancer cell proliferation and induces apoptosis by inhibiting nuclear factor-kappaB signaling pathway. 1696 81

(Z)-2-(6-(Thieanisyl-2-yl)hexa-3-en-1,5-diynyl)benzenamine (THDB), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent with broad spectrum of antitumor activities against many human cancer cells. THDB was found to inhibit the growth of HL-60 cells in a time-and dose-dependent manner. Cell cycle analysis showed G2/M phase arrest in HL-60 cells following 48 h exposure to THDB. Analysis of the cell cycle regulatory proteins demonstrated that THDB did not change the steady-state levels of cyclin B1, cyclin E, Cdk1 and Cdc25C, but decreased the protein levels of Cdk2 and cyclin A. THDB also caused a marked increase in apoptosis, as characterized by DNA fragmentation (DNA ladder and sub G1 formation), and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Moreover, the THDB-induced apoptosis was significantly attenuated in the presence of specific inhibitors of caspase-3, -8 and -9. These molecular alterations provide an insight into THDB-caused growth inhibition, G2/M arrest and apoptotic death of HL-60 cells.
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PMID:Induction of G2/M phase arrest and apoptosis by a novel enediyne derivative, THDB, in chronic myeloid leukemia (HL-60) cells. 1706 74

Cardiotoxin III (CTX III) is a basic polypeptide of 60-amino acid residues isolated from Naja naja atra venom, exerts its anti-proliferative activity in human leukemia K562 cells. In the present study, the expression of mRNAs and proteins related to cell cycle and apoptosis in human leukemia K562 cells induced by CTX III was investigated by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Flow cytometric analysis revealed that CTX III resulted in G2/M phase arrest in the cell cycle progression, which was associated with a marked decrease in the mRNA and protein expressions of cyclin A, cyclin B1, and Cdk 2, with no detectable changes in the levels of Cdk 1, cyclin D1, and cyclin E. Moreover, the increase in apoptosis was associated with the Bax gene and protein levels significantly increased as treatment durations of CTX III increased, while the Bcl-2 mRNA and protein levels exhibited no changes. We also observed that caspase-9 and caspase-3 genes remained unchanged up to 12 h with 2 microg/ml CTX III. These molecular alterations provide an insight into CTX III-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells.
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PMID:Effects of cardiotoxin III on expression of genes and proteins related to G2/M arrest and apoptosis in K562 cells. 1714 43

MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. Little is known, however, about the effects of cellular and molecular mechanisms on human leukemic U937 cells. In the present study, we found that treatment with PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Thus, our results imply that PD98059-induced apoptosis is significantly involved in down-regulation of Bcl-2, caspase-3 activity, the Akt pathway, and some of the biological functions in U937 cells.
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PMID:PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. 1716 15

Curcumin (diferuloylmethane), is a natural product derived from the root of the plant Curcuma longa. For centuries, it has been used as a spice and as a herbal medicine in Chinese populations. Curcumin has been shown to inhibit cell proliferation, cell cycle arrest, cyclooxygenase (COX)-1 and -2 expression and apoptosis in several human cancer cell lines. The aim of this investigation was to clarify the mechanisms by which curcumin induced cytotoxicity and apoptosis in human leukemia HL-60 cells. The effects of curcumin on the levels of reactive oxygen species (ROS), Ca+2 production, cyclin E, cdc25c, wee1, Bcl-2, Bax, the changes of mitochondrial membrane potential (MMP), cytochrome c release and the activation of caspase-3 were also investigated in the HL-60 cells. Results of flow cytometry and DAPI staining assays indicated that curcumin induced cytotoxicity and apoptosis in the examined cells. The results from flow cytometry assay indicated that curcumin induced ROS and Ca+2 productions, decreased the levels of MMP and increased the activity of caspase-3, leading to cell apoptosis. Western blot assay also revealed that curcumin increased the levels of Bax and the release of cytochrome c, and decreased the levels of Bcl-2 in the examined cells. The inhibition of caspase-3 activation by z-VAD-fmk (broad-spectrum caspase inhibitor) completely blocked curcumin-induced apoptosis in HL-60 cells.
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PMID:Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation. 1720 Nov 56

The effect of surfactin on the proliferation of LoVo cells, a human colon carcinoma cell line, was examined. Surfactin strongly blocked the proliferation of LoVo cells by inducing pro-apoptotic activity and arresting the cell cycle, according to several lines of evidence on DNA fragmentation, Annexin V staining, and altered levels of poly (ADP-ribose) polymerase, caspase-3, p21(WAF1/Cip1), p53, CDK2 and cyclin E. The anti-proliferative activity of surfactin was mediated by inhibiting extracellular-related protein kinase and phosphoinositide 3-kinase/Akt activation, as assessed by phosphorylation levels. Therefore, our data suggest that surfactin may have anti-cancer properties as a result of its ability to downregulate the cell cycle and suppress its survival.
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PMID:Surfactin from Bacillus subtilis displays anti-proliferative effect via apoptosis induction, cell cycle arrest and survival signaling suppression. 1729 58

We investigated whether the snake venom toxin (SVT) from Vipera lebetina turanica inhibits cell growth of human prostate cancer cells by inducing apoptosis and also studied possible signaling pathways involved in this cell death. SVT inhibited growth of PC-3 and DU145 cells, androgen-independent prostate cancer cells, but not LNCaP cells, a human androgen-dependent prostate cancer cell. Cells were arrested in the G(2)-M phase by SVT with a concomitant decrease in the expression of the G(2)-M phase regulatory protein cyclin B1 and were also arrested in the G(1)-S phase with decreasing expression of cyclin-dependent kinase 4, cyclin D1 and cyclin E. In addition to the growth-inhibitory effect, SVT increased the induction of apoptotic cell death. Untreated PC-3 cells show high DNA binding activity of nuclear factor kappaB (NF-kappaB), an antiapoptotic transcriptional factor, but this was inhibited by SVT and accompanied by a significant inhibition of p50 translocation into the nucleus, as well as phosphorylation of inhibitory kappaB. Consistent with the induction of apoptosis and inhibition of NF-kappaB, this toxin increased the expression of proapoptotic proteins such as p53, Bax, caspase-3, and caspase-9, but down-regulated antiapoptotic protein Bcl-2. However, SVT did not show an inhibitory effect on cell growth and caspase-3 activity in cells carrying mutant p50 and inhibitory kappaB kinase plasmids. Confocal microscopy analysis showed that SVT is taken up into the nucleus of the cells. These findings suggest that a nanogram concentration range of SVT from V. lebetina turanica could inhibit hormone-refractory human prostate cancer cell growth, and the effect may be related to NF-kappaB signal-mediated induction of apoptosis.
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PMID:Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor kappaB. 1730 63


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