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)

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.
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PMID:Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia. 1820 61

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

Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 is a multifunctional anti-inflammatory and anti-apoptotic neuropeptide widely distributed in the nervous system. The objective of this study is to determine whether PACAP38 is neuroprotective against sodium nitroprusside (SNP) and thrombin, two mechanistically distinct neurotoxic agents. Treatment of primary cortical neuronal cultures with 1 mM SNP for 4 h causes neuronal cell death that is significantly reduced by 100 nM PACAP38. PACAP38 down-regulates SNP-induced cell cycle protein (cyclin E) expression and up-regulates p57(KIP2), a cyclin-dependent kinase inhibitor as well as the anti-apoptotic protein Bcl-2. Similarly, neuronal death induced by 100 nM thrombin or the thrombin receptor activating peptide (TRAP 6) is reduced by PACAP38 treatment. Thrombin-stimulated cell cycle protein (cdk4) expression is decreased by PACAP38 while PACAP38 inhibits thrombin-mediated reduction of p57(KIP2). However, the decrease in Bcl-2 evoked by thrombin is not affected by PACAP38. Finally, both SNP and thrombin (or TRAP) increase caspase 3 activity, an effect that is decreased by PACAP38. These data show that PACAP38 supports neuronal survival in vitro suppressing cell cycle progression and enhancing anti-apoptotic proteins. Our results support the possibility that PACAP could be a useful therapeutic agent for reducing neuronal cell death in neurodegenerative diseases.
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PMID:PACAP38 protects rat cortical neurons against the neurotoxicity evoked by sodium nitroprusside and thrombin. 1868 63

N(6)-isopentenyladenosine (i6A) is a modified nucleoside with a pentaatomic isopentenyl derived from mevalonate that induces inhibition of tumor cell proliferation and apoptosis in several tumor cell lines. In this study, we reported that N(6)-isopentenyladenosine inhibited the proliferation and promotes apoptosis in DLD1 human colon cancer cells. It suppressed the proliferation of cells through inhibition of DNA synthesis, causing a cell cycle arrest that correlated with a decrease in the levels of cyclin E, cyclin A and cyclin D1 and with a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21waf and p27kip1. Moreover, it induced apoptosis through an increase in the number of annexin V-positive cells, a downregulation of antiapoptotic products and caspase-3 activation. The apoptotic effects of N(6)-isopentenyladenosine were accompanied by sustained phosphorylation and activation of c-jun N-terminal kinase (JNK) that induced phosphorylation of c-jun. Overall, our data show that JNK, could play an important role in i6A-mediated apoptosis in DLD1 human colon cancer cells.
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PMID:N6-isopentenyladenosine inhibits cell proliferation and induces apoptosis in a human colon cancer cell line DLD1. 1905 78

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

Pseudolaric acid B (PLAB, 1), a natural diterpenoid compound, was isolated from Pseudolarix kaempferi Gordon. It has shown antifungal, antifertility, and antiangiogenic properties in previous studies. Recently, increasing evidence has confirmed that 1 exhibits antitumor effects in several tumor cell lines, but the underlying mechanism has not been fully elucidated. The aim of this study was to investigate the mechanism of PLAB-induced cell apoptosis in MGC803 cells. The results showed that 1 significantly inhibited the proliferation of MGC803 cells at 0.01-10 microM and the IC(50) value was 0.91 microM for 48 h. PLAB-induced apoptosis in MGC803 cells was confirmed by DNA fragmentation assay and Hoechst33342/PI staining. PLAB-treated MGC803 cells were arrested at G(2) phase, which was associated with a marked increment of the expression of cyclin-dependent kinase inhibitor p21. The induction of p21 appeared to be transcriptionally up-regulated and was p53-dependent. In addition, PLAB induced Fas/APO-1 and caspase-3 expressions that were also correlated with apoptosis. Meanwhile, 1 decreased the mRNA expression of bcl-2, which is an antiapoptosis factor. In conclusion, 1 induced apoptosis through p53-dependent pathway in human gastric carcinoma cells. These findings suggest that 1 may be a novel promising agent for treating human gastric carcinoma.
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PMID:Pseudolaric acid B-induced apoptosis through p53-dependent pathway in human gastric carcinoma cells. 1921 27

Eosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide staining, morphological analysis by light microscopy, transmission electron microscopy and Western immunoblotting for caspase-3 cleavage. We further dissect these observations by demonstrating that eosinophils treated with R-roscovitine lose mitochondrial membrane potential and the key survival protein Mcl-1 is down-regulated. This novel finding of efficacious induction of eosinophil apoptosis by CDKi drugs has potential as a strategy for driving resolution of eosinophilic inflammation.
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PMID:The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1. 1961 48

p27 is a cyclin-dependent kinase inhibitor that regulates the progression of cells from G(1) to S phase of the cell cycle. Loss of p27 has been associated with disease progression and with an unfavourable outcome in prostate cancer. In this study, we investigated whether exogenous p27 expression in the human androgen-independent prostate cancer PC3 cell line had any effect on cell growth, and we studied the molecular mechanisms involved. p27 expression was restored in PC3 cells by plasmid delivery. Cell proliferation and apoptosis were assessed in PC3 cells transfected with p27. We also investigated the effects of p27 on the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in PC3 cells. By restoring p27 expression in PC3 cells, we observed that p27 reduced proliferation and induced arrest in G(0)/G(1) phase. Moreover, p27-transfected PC3 cells underwent apoptosis, as shown by flow cytometric analysis and western blotting analysis of Bcl-2, Bax, Bad, caspase-3 and poly(ADP-ribose)polymerase expression. Furthermore, the p27-induced anti-tumour action correlated with inhibition of the EGFR/PI3K/Akt signalling pathway, as confirmed by western blotting analysis and densitometry of EGFR, PI3K (p85), Akt and p-Akt(S473) expression. Our results suggest that exogenous expression of p27 inhibits the proliferation of PC3 cells through induction of G(1) arrest and apoptosis, and this process correlates with inhibition of the EGFR/PI3K/Akt signalling pathway.
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PMID:Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells. 1973 35

p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK+ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip(S/L), and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK+ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK+ ALCL patients.
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PMID:The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53. 1974 26

Propyl gallate (PG) as a synthetic antioxidant exerts a variety of effects on tissue and cell functions. Here, we evaluated the effects of PG on the growth of HeLa cells in relation to apoptosis and the cell cycle. PG dose-dependently inhibited the growth of HeLa cells with an IC50 of approximately 800 microM at 24 h. DNA flow cytometric analysis indicated that PG significantly induced a G1 phase arrest of the cell cycle along with an increase in the cyclin-dependent kinase inhibitor (CDKI) p27. In addition, PG induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim), activation of caspase-3 and caspase-8 and PARP cleavage. All the tested caspase inhibitors (pan-caspase, caspase-3, -8 or -9 inhibitor) significantly rescued HeLa cells from PG-induced cell death. However, none of the caspase inhibitors prevented the loss of MMP (DeltaPsim) induced by PG. In conclusion, PG inhibited the growth of HeLa cells via caspase-dependent apoptosis as well as a G1 phase arrest of the cell cycle.
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PMID:Propyl gallate inhibits the growth of HeLa cells via caspase-dependent apoptosis as well as a G1 phase arrest of the cell cycle. 2020 4


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