Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa.
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PMID:A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis. 1870 87

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, beta-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G(1) phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45alpha, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed IkappaBalpha phosphorylation and JunD expression, resulting in inactivation of nuclear factor-kappaB and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL.
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PMID:Anti-adult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinol. 1879 63

Tacrolimus (FK506) has been widely used as an immunosuppressant. We examined the effects of FK506 on expression of apoptotic signal transduction pathway proteins of Jurkat human T lymphocytes. We investigated the effects of FK506 on apoptosis, cell viability, caspase family protein activity, Western blotts of Bcl-2, Bak, Fas, Fas-L, CDK4, and cyclin D1, as well as reactive oxygen species (ROS) generation and mitochondrial membrane potential transition. Cells were cultured in the presence or absence of FK506. Flow cytometric analysis was performed after staining with propidium iodide. Viability of Jurkat cells was decreased by the addition of FK506 in dose- and time- dependent manner. FK506-induced cytotoxicity was characterized by G0/G1 phase cell cycle arrest. FK506-induced cell death was confirmed by apoptosis characterized by nuclear fragmentation and caspase-3 protease activation. FK506 induced no change in catalytic activity of caspase-6, -8, and -9 proteases. No change in expression of Bcl-2 protein was noted but we confirmed increased expression of Bak protein. No changes of expressions of Fas and Fas-L were seen. Increased expressions of CDK4 and cyclin D1 were identified. In addition, pharmacological scavenging study of ROS, including H2O2, revealed that cytotoxicity was achieved by generation of ROS, which might modulate Bak protein expression and mitochondrial dysfunction. In conclusion, FK506-induced cell death was apoptotic, characterized by nuclear fragmentation and caspase-3 activation. FK506 induced G0/G1 phase cell cycle arrest via expression of CDK4 and cyclin D1. Apoptosis was also achieved by generation of H2O2, which modulated Bak protein expression and mitochondrial dysfunction.
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PMID:Tacrolimus-induced apoptotic signal transduction pathway. 1892 48

This study examined the mechanism for the anti-cancer effects of histone deacetylase (HDAC) inhibitor trichostatin A (TsA) in H-ras-transformed human breast epithelial (MCF10A-ras) cells. The effects of TsA on anti-cancer effects of MCF10A-ras cells were determined by measuring the level of cell cycle regulator expression and apoptotic cell death using Western blotting and flow cytometry analysis, respectively. TsA induced morphological changes, apoptotic cell death and modulation of the cell cycle regulatory proteins in the MCF10A-ras cells. TsA increased the levels of acetylated histone H3 and H4 in MCF10A-ras cells. In addition, TsA markedly down-regulated the expression of cyclin D1 and CDK4, up-regulated the expression of p21WAF1 and p53 and induced cell cycle arrest at the G1 phase in MCF10A-ras cells. The levels of hyperphosphorylation of the Rb protein were lower in MCF10A-ras cells after the TsA treatment. Furthermore, the up-regulation of p53 promoted Bax expression, which led to the activation of pro-caspase-3 and eventually to apoptosis in MCF10A-ras cells. TsA significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Overall, the TsA-activated ERK pathway plays an important role in cell cycle arrest and apoptosis through the ERK-dependent induction of p21 in Ras-related human cancer cells.
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PMID:Effects of trichostatin A, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells. 1894 80

Antimycin A (AMA) inhibits mitochondrial electron transport between cytochrome b and c. We evaluated the effects of AMA on the growth of human lung cancer cell line, Calu-6. AMA inhibited the growth of Calu-6 cells. AMA induced a G1 phase arrest of the cell cycle in these cells at 72h. AMA increased a cyclin-dependent kinase inhibitor (CDKI), p27 and decreased CDK2, CDK4, and CDK6, as well as cyclin D1 and cyclin E in Calu-6 cells. AMA also induced apoptosis in Calu-6 cells. The apoptotic process in AMA-treated Calu-6 cells was accompanied by the up-regulation of Bax, the loss of mitochondrial membrane potential (DeltaPsi(m)), and the activation of caspase-3 and -8. All of the tested caspase inhibitors, especially pan-caspase inhibitor (Z-VAD), markedly rescued Calu-6 cells from AMA-induced Calu-6 cell death. Inhibitors of pan-caspase and caspase-8 also prevented the loss of mitochondrial membrane potential (DeltaPsi(m)). AMA decreased the intracellular ROS levels but increased the O(2)(*-) levels in Calu-6 cells. In conclusion, AMA as a mitochondrial electron transport inhibitor decreased the growth of lung cancer Calu-6 cell via inducing a G1 arrest of the cell cycle and apoptosis.
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PMID:Growth inhibition in antimycin A treated-lung cancer Calu-6 cells via inducing a G1 phase arrest and apoptosis. 1911 65

Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways.
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PMID:Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. 1913 78

Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) is an uncoupler of mitochondrial oxidative phosphorylation in eukaryotic cells. Here, we evaluated the in vitro effects of FCCP on the growth of Calu-6 lung cancer cells. FCCP inhibited the growth of Calu-6 cells with an IC(50) of approximately 6.64+/-1.84 microM at 72 h, as shown by MTT. DNA flow cytometric analysis indicated that FCCP induced G1 phase arrest below 20 microM of FCCP. Treatment with FCCP decreased the level of CDKs and cyclines in relation to G1 phase. In addition, FCCP not only increased the p27 level but also enhanced its binding with CDK4, which was associated with hypophosphorylation of Rb protein. While transfection of p27 siRNA inhibited G1 phase arrest in FCCP-treated cells, it did not enhance Rb phosphorylation. FCCP also efficiently induced apoptosis. The apoptotic process was accompanied with an increase in sub-G1 cells, annexin V staining cells, mitochondria membrane potential (MMP) loss and cleavage of PARP protein. All of the caspase inhibitors (caspase-3, -8, -9 and pan-caspase inhibitor) markedly rescued the Calu-6 cells from FCCP-induced cell death. However, knock down of p27 protein intensified FCCP-induced cell death. Moreover, FCCP induced the depletion of GSH content in Calu-6 cells, which was prevented by all of the caspase inhibitors. In summary, our results demonstrated that FCCP inhibits the growth of Calu-6 cells in vitro. The growth inhibitory effect of FCCP might be mediated by cell cycle arrest and apoptosis via decrease of CDKs and caspase activation, respectively. These findings now provide a better elucidation of the mechanisms involved in FCCP-induced growth inhibition in lung cancer.
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PMID:Effects of carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone on the growth inhibition in human pulmonary adenocarcinoma Calu-6 cells. 1981 88

This study was undertaken to determine the in vitro effect of lentivirus-mediated siPin1 on cell cycle and apoptosis of vascular smooth muscle cells (VSMCs). Further we sought to provide insight into the mechanisms behind these processes. Human umbilical artery smooth muscle cells (HUASMCs) were transfected with lentiviral siPin1. Real-time RT-PCR and Western blotting were used to examine Pin1 mRNA and protein expression. MTT and [(3)H]thymidine incorporation assays were employed to observe cell proliferation status. The apoptotic rate and cell cycle were analyzed by Hoechst33258 staining and flow cytometry. Finally we measured the expression of cyclin D1, beta-catenin, CDK4, cytochrome c, procaspase-3, cleaved caspase-3, procaspase-9, cleaved caspase-9, Bcl-2, Bax, STAT3, phosphorylated STAT3 and VEGF in lentiviral siPin1 infected VSMCs. Lentivirus-mediated siPin1 effectively diminished endogenous Pin1 expression in VSMCs resulting in cell cycle arrest and enhancement of apoptosis. This was accompanied by downregulation of cyclin D1, beta-catenin, CDK4, increase of Bax/Bcl-2 ratio, release of cytochrome c, and activation of caspase-3 and -9. We concluded that this effect was mediated, at least in part, via the beta-catenin/cyclin D1/CDK4 cascade, and that the mitochondrial pathway was responsible for VSMC apoptosis in the absence of Pin1. Our observations raised the possibility that Pin1 might be a potential therapeutic target to prevent stenosis.
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PMID:Inhibition of peptidyl-prolyl cis/trans isomerase Pin1 induces cell cycle arrest and apoptosis in vascular smooth muscle cells. 1990 10

We investigated the antiproliferative effects of synthetic flavanone derivatives using an MTT assay in MCF-7 and MDA-MB-453 cells. When cells were treated with synthetic flavanone derivatives in concentrations ranging from 1 to 200 microM for 48 h, cell growth decreased at concentrations >50 microM. 4'-Chloroflavanone is more potent than flavanone among the synthetic flavanone derivatives. Exposure to 4'-chloroflavanone at 50 microM for 48 h caused cell cycle arrest in both MCF-7 and MDA-MB-453 cells. In addition, when 4'-chloroflavanone caused G1/S phase arrest, a decrease in CDK4 and cyclin D, together with an increase in p21Cip1, was observed in the cells. The p21Cip1 is a downstream target of p53 that may be affected by the activation of p53 by 4'-chloroflavanone. These results indicate that activation of p53 played some role in 4'-chloroflavanone-induced cell cycle arrest of human breast cancer cells. 4'-Chloroflavanone increased cytochrome c expression and decreased the expression of caspase-3, but did not change the expression of Bcl-2 and Bax. Activation of cytochrome c and its downstream target, caspase-3, is suggested to be an important inducer of the apoptosis process by 4'-chloroflavanone. 4'-Chloroflavanone inhibits cell proliferation through G1/S phase disruption and may induce apoptosis. Based on our findings, we propose that 4'-chloro-flavanone is useful as an anticancer drug.
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PMID:Anti-carcinogenic effect of a new analogue 4'-chloroflavanone from flavanone in human breast cancer cells. 2004 41

This study is to investigate the effect of fascaplysin on human cervical cancer cells (HeLa) in order to provide insights into the mechanisms of growth suppression involved in fascaplysin-mediated apoptosis. Cytotoxic activity of fascaplysin on HeLa cells was determined using MTT assay, cell cycle analysis, and apoptosis (Annexin V-FITC and PI double staining) studies. The role of the molecules in cell cycle regulation and apoptosis was analyzed by Western blotting and flow cytometry. Fascaplysin markedly inhibited HeLa cells proliferation in a dose-dependent manner, however, did not provoke G1 phase arrest in HeLa cells with downregulation of CDK4, cyclin D1 and CDK4-specific Ser795 pRb phosphorylation. Furthermore, fascaplysin induced significantly apoptosis evidenced by sub-G1 peak and Annexin V-FITC and PI double staining. The molecular mechanism of fascaplysin-induced apoptosis was characterized with the activation of caspase-3, -8, and -9, truncation of Bid, release of cytochrome c into cytosol, and down-regulation of Bcl-2 level. Fascaplysin exhibits anti-proliferation effect towards human cervical cancer HeLa cells through induction of apoptosis via extrinsic death pathway and mitochondrial pathway, but not arresting cell cycle progression at G1 phase. All together, these data sustain our contention that fascaplysin has anticancer properties and merits further investigation as a potential therapeutic agent.
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PMID:[Anti-proliferation of human cervical cancer HeLa cell line by fascaplysin through apoptosis induction]. 2005 72


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