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)

Meclizine (MEC), a histamine H1 antagonist, is used for the treatment of motion sickness and vertigo. In this study, we demonstrate that MEC dose-dependently induced apoptosis in human colon cancer cell lines (COLO 205 and HT 29 cells). Results of a DNA ladder assay revealed that DNA ladders appeared with MEC treatment in COLO 205 cells at dosage of >50 microM. In addition, the total cell number decreased dose-dependently after treatment with MEC in COLO 205 and HT 29 cells. Using flow cytometry, the percentage of COLO 205 cells arrested at G0/G1 phase increased dose-dependently. Analysis of changes in cell-cycle arrest-associated proteins with Western blotting showed that p53 and p21 were upregulated after treatment with MEC. The kinase activities of cyclin-dependent kinase 2 (CDK2) and CDK4 were suppressed in MEC-treated cells. As for apoptosis, MEC may induce upregulation of p53 and downregulation of Bcl-2, thus causing the release of cytochrome C from mitochondria and the translocation of apoptosis-inducing factor (AIF) to the nucleus. This resulted in the activation of caspase 3, 8, and 9. Our results provide the molecular basis of MEC-induced apoptosis and cell-cycle arrest in human colon cancer cells.
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PMID:Induction of apoptosis and cell-cycle arrest in human colon cancer cells by meclizine. 1722 94

The active metabolite of vitamin D(3) (1alpha,25-dihydroxyvitamin D(3), calcitriol) has potent antitumor activities in vitro and in vivo in multiple cancers. Concerns about induction of hypercalcemia by calcitriol and the desire for more potent agents have prompted development of less-calcemic vitamin D analogs. These studies demonstrate that two vitamin D analogs, 19-nor-1alpha,25-dihydroxyvitamin D(2) (paricalcitol) and 1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D(3) (QW-1624F(2)-2, QW), have anticancer effects in the calcitriol-responsive squamous cell carcinoma (SCC) cell line. Paricalcitol (GI50 = 0.7 nM) and QW (GI50 = 0.001 nM) inhibited SCC cell growth; however, QW was more potent. Paricalcitol (10 nM) and QW (10 nM) induced G0/G1 cell cycle arrest and inhibited DNA synthesis by approximately 95%. The vitamin D analogs modulated cell cycle regulators, including decreasing mRNA and protein levels of p21(Waf1/Cip1) (p21) and cyclin-dependent kinase 2 (cdk2), and increasing p27(Kip1) (p27) protein expression. Vitamin D analogs induced apoptosis, caspase-3 cleavage and increased expression of pro-apoptotic MEKK-1. Phosphorylation of Akt, MEK and ERK1/2 that promote cell growth and survival were inhibited by vitamin D analogs. The anticancer effects of paricalcitol and QW are comparable to the effect of calcitriol. These less-calcemic vitamin D analogs are as effective as calcitriol in vitro and are promising for prevention and treatment of cancer and other diseases.
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PMID:Antitumor effects of two less-calcemic vitamin D analogs (Paricalcitol and QW-1624F2-2) in squamous cell carcinoma cells. 1723 23

As S-phase checkpoints play critical roles in maintaining genomic integrity and replicating the human genome correctly, understanding the molecular mechanism by which they regulate the therapeutic response is of great interest. Previously, we reported that the cytotoxic effect of a zinc-bound form of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), which is currently evaluated in clinical trials, in combination with low-dose CPT-11, induces apoptosis of C4-2 human prostate cancer cells and tissues. Here, we show that apoptosis, induced synergistically by this combination treatment, was associated with accumulation of cells in early S phase, indicated by cell cycle analyses, increased proliferating cell nuclear antigen, and Chk2-Thr(68) phosphorylation in tumors xenografted in mice. The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases, leading to phosphorylation and decreased Cdc25A levels. Cdc25A-dependent regulation of cyclin-dependent kinase 2 (Cdk2) and changes in association of p21(WAF1/CIP1) and hSpy1 with Cdk2 resulted in inhibition of Cdk2-associated kinase activity. Knockdown of ataxia telangiectasia mutated/Chk2 and ataxia telangiectasia mutated and Rad3 related/Chk1 by small inhibitory RNAs abrogated the S-phase checkpoint and accelerated apoptosis, resulting in caspase-3 activation and poly(ADP-ribose) polymerase 1 cleavage following combination treatment. Thus, Apo2L/TRAIL + CPT-11 treatment-induced apoptosis is regulated through an S-phase checkpoint controlled by the Chk2-Cdc25A and Chk1-Cdc25A pathways and inhibition of Cdk2-associated kinase activity. Low-dose CPT-11 and aphidicolin increased the proportion of S-phase cells and sensitized cells to Apo2L/TRAIL, by inducing phosphatidylserine externalization, caspase activation, and poly(ADP-ribose) polymerase 1 cleavage. Combinations with S-phase arrest-inducing chemotherapeutic drugs may represent promising avenues for clinical development of Apo2L/TRAIL.
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PMID:S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells. 1743 Nov 15

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also induces apoptosis in various types of cancer cells. Here, the effects of pterostilbene on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that pterostilbene was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Pterostilbene-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of pterostilbene-induced apoptosis was also investigated. The results show the caspase-2, -3, -8, and -9 are all activated by pterostilbene, together with cleavage of the downstream caspase-3 target DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Moreover, the results indicate that the Bcl-family of proteins, the mitochondrial pathway, and activation of the caspase cascade are responsible for pterostilbene-induced apoptosis. Pterostilbene markedly enhanced the expression of growth arrest DNA damage-inducible gene 45 and 153 (GADD45 and GADD153) in a time-dependent manner. Flow cytometric analysis indicated that pterostilbene blocked cell cycle progression at G1 phase in a dose- and time-dependent manner. Pterostilbene increased the p53, p21, p27, and p16 proteins and decreased levels of cyclin A, cyclin E, cyclin-dependent kinase 2 (Cdk2), Cdk4, and Cdk6, but the expression of cyclin D1 was not affected. Over a 24 h exposure to pterostilbene, the degree of phosphorylation of Rb was decreased after 6 h. In summary, pterostilbene induced apoptosis in AGS cells through activating the caspase cascade via the mitochondrial and Fas/FasL pathway, GADD expression, and by modifying cell cycle progress and changes in several cycle-regulating proteins. The induction of apoptosis by pterostilbene may provide a pivotal mechanism of the antitumor effects and for treatment of human gastric cancer.
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PMID:Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells. 1769 82

Cytoskeletal alteration is a key factor in neurodegenerative processes like Alzheimer's or Parkinson's disease. Colchicine is a microtubule-disrupting agent that binds to tubuline, inhibiting microtubule assembly, and which triggers apoptosis. The present research describes the transcriptional activation of molecules related to alternative forms of apoptosis, in an acute colchicine model of apoptosis in rat cerebellar granule neurons (CGNs). Treatment with colchicine up-regulated significantly the activity of genes related to oxidative stress: glutathione peroxidase 1 and catalase; altered significantly genes related to cell cycle control (cyclin D1 and cyclin-dependent kinase 2), genes related to classical apoptosis pathway (caspase 3) and a neuronal cell-related gene (pentraxin 1). Colchicine treatment also down-regulated the gene expression of calpain 1. In conclusion, our experiments demonstrate that the cell damage caused by exposure to colchicine activates the classical apoptosis pathway, but also promotes the up-regulation of several genes related to oxidative stress and cell cycle control. Present data may help to a better understanding of the molecular mechanisms involved in cytoskeletal degradation-induced apoptosis in neurons.
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PMID:DNA low-density array analysis of colchicine neurotoxicity in rat cerebellar granular neurons. 1825 50

Cobalamin-dependent methionine synthase, with a cofactor of vitamin B12, catalyzes the reaction of 5-methyltetrahydrofolate and homocysteine to form methionine and tetrahydrofolate, which takes a core position in folate cycle, one-carbon-unit transfer, and sulfur amino acid pathways. The 'methyl folate trap' hypothesis suggests that methionine synthase is a potential target for anticancer drug development. ZL031 and ZL033 are 5-methyltetrahydrofolate-like compounds that have been newly synthesized as potential inhibitors of the enzyme. To identify the effect of these two compounds on methionine synthase activity, a spectrophotometric assay was used and the results proved that ZL031 and ZL033 inactivated methionine synthase in HL-60 cells with an IC50 dose of 10.0 and 1.4 mumol/l, respectively. Moreover, obvious inhibitory effect on proliferation of HL-60 cells was observed, leading to our further investigation of the underlying anticancer mechanism. Under the circumstances of methionine synthase deficiency and subsequent folate depletion, cell cycle was arrested in G1/S phase and apoptosis was also observed. Analysis of cell cycle regulatory proteins demonstrated that cyclin E and cyclin-dependent kinase 2 were both increased. Furthermore, reduction of caspase-3, poly (ADP-ribose) polymerase, caspase-8, and caspase-9 protein levels were observed. In all the biological experiments we have performed, ZL033 has shown a better efficacy compared with ZL031. These results suggest that ZL031 and ZL033, as novel methionine synthase inhibitors, caused G1/S phase delay and apoptosis and eventually inhibit the proliferation of HL-60 cells in vitro. ZL033, with a carboxylic acid substituent, might have a better potential for drug development than ZL031 with an ester substituent.
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PMID:Two newly synthesized 5-methyltetrahydrofolate-like compounds inhibit methionine synthase activity accompanied by cell cycle arrest in G1/S phase and apoptosis in vitro. 1859 11

Tubulin and deoxyribonucleic acid (DNA) are two potential targets for the development of cancer chemotherapeutic agents. Mana-Hox is a synthetic derivative of beta-carboline, a structure relevant to marine sponge component, manzamine. In this study, Mana-Hox induced an inhibition of cell proliferation in several types of human cancer cell lines, including androgen-independent prostate cancer PC-3 and DU-145, hepatocellular carcinoma Hep3B and HepG2, and colorectal cancer HT-29 cells. The p53-null PC-3 cells were used for to anticancer mechanisms. Mana-Hox stimulated an increase of ataxia telangiectasia mutated (ATM) phosphorylation on Ser-1981, indicating the induction of DNA double-strand breaks. It also displayed an inhibitory effect on tubulin polymerization using tubulin turbidity assay and immunofluorescence identification. However, it only showed a minor inhibition on the activity of Aurora kinase and histone deacetylase. Mana-Hox induced mitotic arrest of the cell cycle identified by downregulation of cyclin E, cyclin A, and cyclin-dependent kinase 2 (Cdk2) and an increase of MPM-2 expression. Next, it caused Bcl-2 phosphorylation on Ser-70, downregulation of Mcl-1 expression, and activation of caspase-3, leading to apoptotic cell death. Notably, Mana-Hox was not a P-glycoprotein (P-gp) substrate and showed equipotent activity against P-gp-rich cancer cells. We conclude that Mana-Hox induces dual effects on DNA damage and tubulin depolymerization, leading to mitotic arrest and activation of mitochondria-mediated apoptotic pathways. Data provide evidence that the anticancer strategy of dual-action targets could be a potential anticancer approach.
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PMID:Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress. 1866 30

Glioma still remains a major health problem in the world. Celastrol has been proved to be an effective natural proteasome inhibitor and was used for treatment of autoimmune disease, chronic inflammation and neurodegenerative disease. However, its effect on glioma is unclear. In this study, we investigated the therapeutic effects of celastrol on C6 glioma cells. The results demonstrated that celastrol inhibited cell proliferation in a time- and dose-dependent manner, suppressed proteasome chymotrypsin-like activity and induced apoptosis and cell cycle arrest at G2/M phase in C6 cells. Proapoptosis proteins bax and caspase-3 were up-regulated, as well as cell cycle G2/M-related proteins cyclin B(1), p21 and p27. Conversely, anti-apoptosis proteins bcl-2 and XIAP and cell cycle regulator cyclin-dependent kinase 2 were down-regulated. Taken together, our data suggest that celastrol can suppress proteasome activity and induce apoptosis and cell cycle arrest in C6 glioma cells, which make it be a potential drug for glioma.
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PMID:Celastrol causes apoptosis and cell cycle arrest in rat glioma cells. 1990 82

The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward ovarian cancer cells while sparing healthy cells. HO-3867 induced G(2)-M cell cycle arrest in A2780 cells by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy.
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PMID:Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. 2044 15

Cisplatin cytotoxicity is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro. A Cdk2 mutant (Cdk2-F80G) was designed in which the ATP-binding pocket was altered. When expressed in mouse kidney cells, this protein was kinase inactive, did not inhibit endogenous Cdk2, but protected from cisplatin. The mutant was localized in the cytoplasm, but when coexpressed with cyclin A, it was activated, localized to the nucleus, and no longer protected from cisplatin cytotoxicity. Cells exposed to cisplatin in the presence of the activated mutant had an apoptotic phenotype, and endonuclease G was released from mitochondria similar to that mediated by endogenous Cdk2. But unlike apoptosis mediated by wild-type Cdk2, cisplatin exposure of cells expressing the activated mutant did not cause cytochrome c release or significant caspase-3 activation. We conclude that cisplatin likely activates both caspase-dependent and -independent cell death, and Cdk2 is required for both pathways. The mutant-inactive Cdk2 protected from both death pathways, but after activation by excess cyclin A, caspase-independent cell death predominated.
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PMID:Protection of cisplatin cytotoxicity by an inactive cyclin-dependent kinase. 2044 41


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