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

TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-X(L) and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.
 ...
PMID:The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. 1455 32

Apoptosis of vascular smooth muscle cells (VSMCs) is of importance in the development of diabetic angiopathy. Our aim was to evaluate the effect of insulin and IGF-I on apoptosis in VSMCs. Rat aortic VSMCs were used and apoptosis was induced by serum starvation. As apoptotic markers we measured caspase-3 activity, histone-associated DNA fragments by ELISA and nuclear morphology by DAPI (4',6-diamidino-2-phenylindole) staining. Phosphorylation of IGF-I receptors was evaluated by Western blot. Serum starvation had increased caspase-3 activity even after 3 h. The highest activity was found after 3-12 h. IGF-I 10(-9 )M inhibited serum starvation-induced caspase-3 activity with a maximal effect after 12 h. When studied after starvation for 12 h, significant inhibitory effects on caspase-3 were found at IGF-I concentrations of 10(-8)-10(-7) M (P<0.01) and at an insulin concentration of 10(-6 )M (P<0.01). DNA fragmentation was detected by ELISA after 24 h and chromatin condensation and nuclear fragmentation by DAPI staining after 24 and 48 h respectively. IGF-I dose-dependently reduced apoptosis evaluated by ELISA, reaching a maximal effect at 10(-9) M. Insulin reduced apoptosis but the effect was weaker and a higher concentration was needed. IGF-I (10(-8 )M) and insulin at a very high concentration (10(-6) M) phosphorylated IGF-I receptors. Taken together, IGF-I and insulin have antiapoptotic effects on VSMCs but the effect of insulin is only found at high unphysiological concentration.
 ...
PMID:IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells. 1459 78

Pathogenesis of prostate cancer is paralleled by aberrant transcriptional regulation which involves gene silencing by histone deacetylases. In cancer cells, inhibitors of histone deacetylases such as valproic acid can act as differentiation agents which relieve pro-apoptotic factors from transcriptional repression. We investigated the potential of the well-tolerated anticonvulsant valproic acid in prostate cancer cell line LNCaP and analyzed the activation of pro-apoptotic factors and resulting apoptosis. We used real time RT-PCR to quantify the mRNA expression of prostate-specific antigen, prostate-derived Ets transcription factor, tissue inhibitor of matrix metalloproteinase-3 and insulin-like growth factor binding protein-3. An automated sandwich-ELISA was used to measure secretion of prostate-specific antigen in conditioned cell culture media of LNCaP prostate cancer cells. Apoptotic cells were detected cytochemically and by applying immunocytochemistry. Activity of histone deacetylases in nuclear extracts was measured with a colorimetric assay kit. Valproic acid treatment caused a marked inhibition of histone deacetylases activity. Expression of prostate-derived Ets transcription factor and consequently prostate-specific antigen were down-regulated to basal levels in LNCaP cells. Pro-apoptotic factor caspase-3, tissue inhibitor of matrix metalloproteinase-3 and insulin-like growth factor binding protein-3 were up-regulated resulting in apoptosis of tumor cells. Valproic acid mediates marked effects on the expression of genes relevant in proliferation and apoptosis. Our study provides strong evidence that prostate cancer may benefit particularly from anti-proliferative stimuli from this well established drug.
 ...
PMID:Expressional changes after histone deacetylase inhibition by valproic acid in LNCaP human prostate cancer cells. 1465 37

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the dietary carcinogens. At the initial step in the carcinogenic process, its exocyclic amino group is metabolically activated to the hydroxyamino derivative by the cytochrome P450 (CYP) 1A and 1B subfamily and then form DNA adducts, which are considered to be the main cause of DNA damage during the carcinogenic process. On the other hand, our previous study has shown that Trp-P-1 exhibits cytotoxicity to primary cultured rat hepatocytes, via induction of caspase-9-dependent apoptosis without being metabolized by CYP 1A1. In the present study, we investigated what type of DNA damage would be involved in the induction of apoptosis induced by Trp-P-1. When RL-34 cells derived from normal rat liver were treated with a high (30 microM) concentration of Trp-P-1, apoptotic events such as the loss of cell viability, nuclear condensation and the activation of caspase-3 were observed. In these apoptotic cells, intracellular topoisomerase I activity was inhibited and histone H2AX phosphorylation, which occurs after introduction of DNA double-strand breaks (DSBs), was observed in the early phase of the apoptosis. On the other hand, treatment with a non-apoptotic concentration (1 microM) of Trp-P-1 increased the formation of 8-hydroxy-2'-deoxyguanosine. The formation of DNA adducts was detected at almost the same level in both cells exposed to the apoptotic and non-apoptotic concentrations of Trp-P-1. These results indicate that Trp-P-1-induced apoptosis was triggered by DNA DSBs through the inhibition of topoisomerase I but not the formation of DNA adducts.
 ...
PMID:3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) triggers apoptosis by DNA double-strand breaks caused by inhibition of topoisomerase I. 1497 28

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.
 ...
PMID:Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. 1505 15

HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA-damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR-induced cell death, DNA fragmentation and caspase-3/-8 activation. In contrast, 5-FU did not clearly augment IR-induced cell death and caspase-3 activation. FK228 increased expression of proapoptotic BH3-only Bim proteins, and gene transfer-mediated overexpression of Bimalpha radiosensitized DLD1 cells. These data suggest that the FK228-mediated increase of Bim expression may at least partially contribute to its augmentation of radiation-induced apoptosis. However, FK228 did not distinctly affect IR-induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR-induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR-induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells.
 ...
PMID:Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. 1506 98

Apoptosis has been associated with several events in solid organ transplantation, including ischemia/reperfusion (IR) injury and acute rejection. To determine whether apoptosis-profiles may distinguish these two conditions, we analyzed apoptosis rates in a rat orthotopic small bowel transplant (SBT) model. SBT was performed in Lewis rats with either freshly harvested or preserved (4 h, in UW at 4 degrees C) syngeneic and allogeneic (Brown-Norway) grafts. Bowel samples were collected 2 h after reperfusion and on small bowel transplant postoperative days (POD) 1, 4, and 7. Apoptosis was detected by measuring levels of histone-associated DNA fragments and caspase 3 expression, and by determining apoptotic body counts. All markers measured 2 h after reperfusion increased profoundly in association with preservation. After a significant decrease on POD 1, apoptosis rates rose again between POD 4 and 7 only in allogeneic grafts. This distinct second increase in apoptosis may be an early and specific sign of acute rejection.
 ...
PMID:Increased apoptosis is specific for acute rejection in rat small bowel transplant. 1512 82

Acetylation and deacetylation of histones, catalysed by histone acetyl transferases and histone deacetylases (HDAC), respectively, are known to be involved in gene expression regulation. Here, the effect on the activity and expression of several apoptosis-related proteins of trichostatin A (TSA), a well-known HDAC inhibitor, were studied in short-term (conventional monolayer) and long-term cultured (collagen I gel sandwich cultures and co-cultures) adult rat hepatocytes. No significant effects of TSA on the caspase-3-like activity were seen in rat hepatocytes cultured in a sandwich configuration or in a co-culture with rat liver epithelial cells of primitive biliary origin. In both culture models, the basal level of apoptosis was found to be much lower than in control monolayer cultures. In the latter system, it was found that, after 4 days of culture, TSA decreased the levels of caspase-3 (both proform and p17 fragment) and of the pro-apoptotic protein Bid. No effect of TSA was found on the expression of Bax. As expected, a TSA-mediated increase of acetylated histones H3 and H4 was observed in all culture systems examined. In addition, in the presence of TSA, increased albumin secretion and cytochrome P450 1A1/2 and 2B1-dependent enzyme activities were found in conventional cultures after 7 days. In conclusion, TSA delayed the occurrence of apoptosis and loss of liver specific functions in conventional hepatocyte monolayers. In contrast, in hepatocyte culture models in which spontaneous apoptosis is already minimised through the addition of either extracellular matrix components (sandwich cultures) or non-parenchymal liver cells (co-cultures), TSA did not have any additional anti-apoptotic effect.
 ...
PMID:Effect of the histone deacetylase inhibitor trichostatin A on spontaneous apoptosis in various types of adult rat hepatocyte cultures. 1527 83

A null mutation in the SOST gene is associated with sclerosteosis, an inherited disorder characterized by a high bone mass phenotype. The protein product of the SOST gene, sclerostin, is a bone morphogenetic protein (BMP) antagonist that decreases osteoblast activity and reduces the differentiation of osteoprogenitors. We sought to delineate the mechanism by which sclerostin modulated osteoblastic function by examining the effects of the protein on differentiating cultures of human mesenchymal stem cells (hMSC). Sclerostin significantly decreased alkaline phosphatase (ALP) activity and the proliferation of hMSC cells. In addition, hMSC cells treated with sclerostin displayed a marked increase in caspase activity. Elevated levels of fragmented histone-associated DNA in these cells were detected by ELISA and by TUNEL staining. Other BMP antagonists including noggin, Chordin, Gremlin, and Twisted gastrulation did not affect caspase activity. The sclerostin-mediated increase in caspase activity was blocked by caspase-1 and caspase-3 inhibitors. Sclerostin-induced changes in ALP activity and the survival of hMSC cells were partially restored by BMP-6, suggesting the involvement of additional growth factors. These findings show that sclerostin selectively controls the apoptosis of bone cells. The ability of sclerostin to interact with important growth factors such as BMPs likely serves as the basis by which it modulates the survival of osteoblasts. By making these growth factors unavailable for cell function, sclerostin promotes the apoptosis of bone cells, providing a novel level of control in the regulation of bone formation.
 ...
PMID:Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. 1545 89

Although inhibition of histone deacetylase has been demonstrated to induce apoptosis of various cancer cells, there is no report on its effect on mast cell demise to date. Here we studied whether a histone deacetylase inhibitor Trichostatin A (TSA) produces apoptosis in p815 mastocytoma cells. TSA prominently increased the amount of acetylated histones, H3, H4, H2A and H2B, in p815 mastocytoma cells. TSA reduced the viability of p815 mastocytoma cells, and many apoptotic manifestations such as generation of DNA fragmentation, activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and increase of DNA hypoploidy proved that the reduction of viability resulted from apoptosis. Whereas TSA treatment increased the expression level of Bad, it decreased the level of Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. The reduction of mitochondrial membrane potential, the release of cytochrome c and Smac/DIABLO to cytosol, and mitochondrial localization of Bad were also shown. Taken together, TSA induces apoptosis on p815 mastocytoma cells in histone acetylation- and mitochondria-dependent fashion. Our data therefore provide the possibility that TSA could be considered as a novel therapeutic strategy for mastocytoma from its apoptosis-inducing activity.
 ...
PMID:Trichostatin A induces apoptosis of p815 mastocytoma cells in histone acetylation- and mitochondria-dependent fashion. 1549 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>