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)

Homocysteine (Hcy) appears to exert different effects on immune functions possibly contributing to age-related pathological states, including vascular diseases, immune dysfunction, and Alzheimer's disease. However, molecular mechanisms underlying Hcy toxicity need to be better characterized. Since T cells are a suitable model to address the possible role of replicative senescence during the in vivo aging, we investigated the effects of high Hcy concentrations on mitogen-activated lymphocytes, with regard to evaluation of DNA damage and cell cycle alterations. Cultured human peripheral blood lymphocytes were stimulated with mitogenic concanavalin A (5 microg/ml) for 48 h in the presence or absence of Hcy (1 mM). Both flow cytometric analysis and caspase-3 activity assay showed an increased rate of apoptosis in Hcy-treated lymphocyte cultures compared to controls. Further, Hcy exposure caused DNA fragmentation as evaluated by single cell gel electrophoresis showing the occurrence of comets. Cytokinesis-block micronucleus assay, performed after addition of cytochalasin B (5 microg/ml) and incubation up to 72 h, revealed a significantly higher frequency of micronucleated/binucleated cells in Hcy-treated cultures compared to controls (P < 0.001). Hcy also reduced cyclin B expression in comparison to control cultures, while cyclin D levels were not significantly affected. Cell cycle alterations, such as the inability of cells to enter into mitosis, could be related with DNA damage. These findings provided a link between perturbation of lymphocyte proliferation homeostasis and commitment towards apoptosis. Our results suggest the involvement of Hcy in the altered immune function associated with age and disease pathology.
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PMID:Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence? 1696 6

Signature abnormalities in the cell cycle and apoptotic pathway have been identified in mantle cell lymphoma (MCL), affording the opportunity to develop targeted therapies. In this study, we tested a novel class of kinase inhibitors, styryl sulfones, which differ from prior cell cycle inhibitors in that they are not related to purines or pyrimidines. We observed that two closely related compounds, ON013100 and ON01370, altered the growth and cell cycle status of MCL lines and potently inhibited the expression of several important molecules, including cyclin-dependent kinase 4, p53, mouse double minute 2 (MDM2), and cyclin D as well as increased cyclin B expression. Using both terminal deoxy transferase uridine triphosphate nick end-labelling and poly ADP-ribose polymerase assays, we found that these compounds caused apoptosis in MCL cells. In addition, using molecular analyses, we observed the modulation of caspase-3 activity but not the expression of B-cell lymphoma family molecules. Next, we investigated the cytotoxicity of the MCL lines upon treatment with styryl sulfone compounds in combination with other currently used chemotherapeutic agents, such as doxorubicin (DOX) or vincristine (VCR). We found that the combination of DOX plus styryl sulfone or VCR plus styryl sulfone increased cytotoxicity by one log scale, compared with the single styryl sulfone compound. Thus, styryl sulfones alone, or in combination with chemotherapeutic agents, present attractive opportunities for new drug development in MCL.
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PMID:Evaluation of novel cell cycle inhibitors in mantle cell lymphoma. 1736 60

Sex hormone status has emerged as an important modulator of coronary physiology and cardiovascular disease risk in both males and females. Our previous studies have demonstrated that testosterone increases protein kinase C (PKC) delta expression and activity in coronary smooth muscle (CSMC). Because PKCdelta has been implicated in regulation of proliferation and apoptosis in other cell types, we sought to determine if testosterone modulates CSMC proliferation and/or apoptosis through PKCdelta. Porcine CSMC cultures (passages 2-6) from castrated males were treated with testosterone for 24 h. Testosterone (20 and 100 nM) decreased [(3)H]thymidine incorporation in proliferating CSMC to 59 +/- 5.3 and 33.1 +/- 4.5% of control. Flow cytometric analysis demonstrated that testosterone induced G(1) arrest in CSMC with a concomitant reduction in the S phase cells. Testosterone reduced protein levels of cyclins D(1) and E and phosphorylation of retinoblastoma protein while elevating levels of p21(cip1) and p27(kip1). There were no significant differences in the levels of cyclins D(3), CDK2, CDK4, or CDK6. Testosterone significantly reduced kinase activity of CDK2 and -6, but not CDK4, -7, or -1. PKCdelta small interfering RNA (siRNA) prevented testosterone-mediated G(1) arrest, p21(cip1) upregulation, and cyclin D(1) and E downregulation. Furthermore, testosterone increased CSMC apoptosis in a dose-dependent manner, which was blocked by either PKCdelta siRNA or caspase 3 inhibition. These findings demonstrate that the anti-proliferative, pro-apoptotic effects of testosterone on CSMCs are substantially mediated by PKCdelta.
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PMID:PKCdelta mediates anti-proliferative, pro-apoptic effects of testosterone on coronary smooth muscle. 1750 29

Di(2-ethylhexyl) phthalate (DEHP) is a well-known hepatic and reproductive toxicant whose toxicity may be mediated by peroxisome proliferators-activated receptor (PPAR). This study examined the effects of DEHP on the expression of PPAR-regulated genes involved in testicular cells apoptosis. Sprague-Dawley male rats were treated orally with 250, 500, or 750 mg/kg/d DEHP for 28 d, while control rats were given corn oil. The levels of cell cycle regulators (pRb, cyclins, CDKs, and p21) and apoptosis-related proteins were analyzed by Western blot analysis. The role of PPAR-gamma (PPAR-gamma), class B scavenger receptor type 1 (SR-B1), and ERK1/2 was further studied to examine the signaling pathway for DEHP-induced apoptosis. Results showed that the levels of pRB, cyclin D, CDK2, cyclin E, and CDK4 were significantly lower in rats given 500 and 750 mg/kg/d DEHP, while levels of p21 were significantly higher in rat testes. Dose-dependent increases in PPAR-gamma and RXRalpha proteins were observed in testes after DEHP exposure, while there was a significant decrease in RXRgamma protein levels. In addition to PPAR-gamma, DEHP also significantly increased SR-B1 mRNA and phosphorylated ERK1/2 protein levels. Furthermore, DEHP treatment induced pro-caspase-3 and cleavage of its substrate protein, poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner. Data suggest that DEHP exposure may induce the expression of apoptosis-related genes in testes through induction of PPAR-gamma and activation of the ERK1/2 pathway.
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PMID:Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats. 1765 47

Berberine is an isoquinoline plant alkaloid with a long history of being used for the treatment of many diseases in Chinese herbal medicine. Berberine has a wide range of biochemical and pharmacological effects, including antitumor activities, but its mechanism of action is not clearly understood. In this study, we investigated that the relationship between the antiproliferative activities of berberine and the apoptotic pathway associated with its molecular mechanism of action in human glioblastoma T98G cells. Berberine treatment of T98G cell lines inhibited cell proliferation and induced cell death in a dose (50-200 microg/ml) dependent manner with an IC50 value of 134 microg/ml, which was associated with an increase in G1 arrest. Western blot analysis showed that the berberine-induced G1 arrest was mediated through the increased expression of P27 and the decreased expression of cyclin-dependent kinase (CDK) 2, CDK4, cyclin D, and cyclin E proteins. Berberine treatment also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of the Bax/Bcl-2 proteins, the disruption of mitochondrial membrane potential, and the activation of procaspase-9, caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Berberine can inhibit T98G cell proliferation by inducing G1 arrest and apoptosis. These results demonstrate that the berberine-induced apoptosis of T98G cells is primarily mediated through the mitochondrial/caspases-dependent pathway.
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PMID:Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. 1837 40

Neochamaejasmin A ( 1), a biflavonoid isolated from the roots of a traditional Chinese medicine, Stellera chamaejasme L., was shown to inhibit cellular (3)H-thymidine incorporation (IC 50 12.5 microg/mL) and subsequent proliferation of human prostate cancer LNCaP cells. Treatment of LNCaP cells with low doses of 1 (< or =6.25 microg/mL) suppressed DNA-binding activities of the transcription factors NFkappaB and AP-1 to the promoter of cyclin D and also inhibited expression of the cell cycle regulatory proteins cyclin D, proliferating cell nuclear antigen, and nucleolin, thus arresting cells in G 1 phase of the cell cycle. A lengthy exposure with higher doses of 1 (> or =12.5 microg/mL) revealed the production of reactive oxygen species, dissipation of the mitochondrial membrane potential, up-regulation of cyclin-dependent kinase inhibitor p21, and induction of cell apoptosis. An aggregation of Fas-procaspase 8-procaspase 3 and p21-procaspase 3 proteins by coimmunoprecipitation, immunoblotting analysis, and MALDI-mass spectrometry indicated the involvement of Fas and p21 in 1-mediated cytotoxicity, and pretreatment of cells with antisense FasL oligonucleotides partially abolished apoptosis. Thus, 1 blocked cell cycle progression at the G 1 phase by activating the p21 protein and ultimately promoting the Fas-caspase 8-caspase 3 apoptotic machinery.
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PMID:Involvement of p21 and FasL in induction of cell cycle arrest and apoptosis by neochamaejasmin A in human prostate LNCaP cancer cells. 1838 Apr 77

It has been reported that tetrandrine induces cell cycle arrest and apoptosis in human cancer cells. In the present study, we investigated the role of PI3K/AKT/GSK3beta pathway in tetrandrine- induced G(1) arrest and apoptosis. In HT-29 cells, tetrandrine induced dephosphorylation of AKT, activation and nuclear translocation of GSK3beta as well as upregulation of p27(kip1). Activation of GSK3beta via AKT inhibitoion induced by tetrandrine resulted in enhanced phosphorylation and proteolysis of cyclin D(1), activation of caspase 3 and subsequent cleavage of PARP. Selective GSK3beta inhibitiors and GSK3beta siRNA attenuated tetrandrine-induced G(1) arrest and apoptosis. Similar to tetrandrine, transfection of wild-type GSK3beta led to G(1) arrest and apoptosis via downregulation of cyclin D(1) and cleavage of PARP. These findings suggest that tetrandrine induces G(1) arrest and apoptosis through PI3K/AKT/GSK3beta pathway and identify GSK3beta as an important mediator in the processes.
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PMID:Involvement of PI3K/AKT/GSK3beta pathway in tetrandrine-induced G1 arrest and apoptosis. 1869 64

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

Curcumin (diferuloylmethane) is the active ingredient of the spice plant Curcuma longa and has been shown to act anti-tumorigenic in different types of tumours. Therefore, we have studied its effect in pituitary tumour cell lines and adenomas. Proliferation of lactosomatotroph GH3 and somatotroph MtT/S rat pituitary cells as well as of corticotroph AtT20 mouse pituitary cells was inhibited by curcumin in monolayer cell culture and in colony formation assay in soft agar. Fluorescence-activated cell sorting (FACS) analysis demonstrated curcumin-induced cell cycle arrest at G2/M. Analysis of cell cycle proteins by immunoblotting showed reduction in cyclin D(1), cyclin-dependent kinase 4 and no change in p27(kip). FACS analysis with Annexin V-FITC/7-aminoactinomycin D staining demonstrated curcumin-induced early apoptosis after 3, 6, 12 and 24 h treatment and nearly no necrosis. Induction of DNA fragmentation, reduction of Bcl-2 and enhancement of cleaved caspase-3 further confirmed induction of apoptosis by curcumin. Growth of GH3 tumours in athymic nude mice was suppressed by curcumin in vivo. In endocrine pituitary tumour cell lines, GH, ACTH and prolactin production were inhibited by curcumin. Studies in 25 human pituitary adenoma cell cultures have confirmed the anti-tumorigenic and hormone-suppressive effects of curcumin. Altogether, the results described in this report suggest this natural compound as a good candidate for therapeutic use on pituitary tumours.
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PMID:Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivo. 1972 38

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


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