Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic adenocarcinoma carries an ominous prognosis and has little effective treatment. Several studies have demonstrated that the potently antiapoptotic phosphatidyl inositol 3'-kinase (PI3K)-protein kinase B/AKT pathway is active in pancreas cancer. A recent study identified an endogenous AKT antagonist, carboxyl terminal modulator protein (CTMP). CTMP inhibits the phosphorylation of AKT, preventing full activation of the kinase. We screened several cell permeable peptides from the N-terminal domain of CTMP (termed TAT-CTMP1-4) in vitro and found one that caused significant apoptosis in pancreatic adenocarcinoma cell lines. An inactive variant of this peptide was synthesized and used as a negative control. In all cell lines tested, TAT-CTMP4 induced a dose-dependent increase in apoptosis as detected by %-TUNEL positive cells and %-active caspase-3 (% active caspase-3 ranged from 31.2 to 61.9 at the highest dose tested (10 microM). A screening of various cell and tissue types revealed that the proapoptotic activity was highest in pancreatic adenocarcinoma. TAT-CTMP induced similar levels of active caspase-3 as several other known inducers of apoptosis: gemcitabine, radiation therapy, wortmannin and recombinant tumor necrosis factor (TNF)-alpha. No apoptosis was observed in donor human peripheral blood mononuclear cells (PBMC, p < 0.01). We further showed that TAT-CTMP4 could augment either gemcitabine chemotherapy or radiation therapy, standard therapies for pancreas cancer. Pancreatic adenocarcinoma xenografts treated with a single dose of TAT-CTMP4 demonstrated a marked increase in caspase-3 positive tumor cells when compared with untreated controls. Additionally, pancreatic adenocarcinoma allografts treated with intratumoral TAT-CTMP and systemic gemcitabine displayed a significantly smaller tumor burden while undergoing treatment than mice in control groups (p < 0.001). These data indicate that inhibiting AKT with CTMP may be of therapeutic benefit in the treatment of pancreatic adenocarcinoma and, when combined with established therapies, may result in an increase in tumor cell death.
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PMID:Targeting AKT with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma. 1940 18

Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E(2) (PGE(2)) production. In this study, we determined mechanisms through which PGE(2) promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE(2) promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-kappaB, and beta-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE(2) signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.
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PMID:Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. 1940 22

Inadequate maternal intake of omega-3-fatty acids (omega3 FAs) causes adverse neurodevelopmental outcome in the progeny; however, their molecular mechanism of action is obscure. Since omega3 FAs are known to inhibit neuronal apoptosis during neuro-degeneration, we investigated their possible contribution in regulating neuronal apoptosis during brain development. Using rat model of hypothyroidism-induced neuronal apoptosis, we provide evidence for anti-apoptotic role of omega3 FAs during cerebellar development. omega3 FAs were supplemented as a mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to pregnant and lactating rats, and primary hypothyroidism was induced by administering methimazole. The cerebella from postnatal day 16 (d16) pups were isolated, and studies on apoptosis were conducted. We observed that omega3 FA-supplementation significantly reduced DNA fragmentation and caspase-3 activation in developing cerebellum of hypothyroid pups. The protection provided by omega3 FAs was associated with their ability to prevent increases in the level of pro-apoptotic basal cell lymphoma protein-2 (Bcl-2)-associated X protein (Bax) in the cerebellum during thyroid hormone (TH) deficiency. omega3 FAs increased the levels of anti-apoptotic proteins like Bcl-2 and Bcl-extra large (Bcl-x(L)), known to be repressed in hypothyroidism. omega3 FAs also restored levels of cerebellar phospho (p)-AKT, phospho-extracellular regulated kinase (p-ERK) and phospho-c-Jun N-terminal kinase (p-JNK), which were altered by hypothyroid insults, without interfering with the expression of TH responsive gene, myelin basic protein (mbp). Taken together, these results supplement an insight into the molecular mechanism of action of omega3 FAs in developing brain that involves regulation of apoptotic signaling pathways under stress.
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PMID:Anti-apoptotic role of omega-3-fatty acids in developing brain: perinatal hypothyroid rat cerebellum as apoptotic model. 1946 Jun 32

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad-DeltaE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad-DeltaE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad-DeltaE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad-DeltaE1B19/55 compared with those treated with Ad-DeltaE1B55, indicating that the E1B 19 kDa present in Ad-DeltaE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad-DeltaE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad-DeltaE1B19/55 and radiation was more efficacious than the combination of Ad-DeltaE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.
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PMID:Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect. 1949 43

Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-beta and the phosphatidylinositol 3-kinase/AKT pathways. We preclinically evaluated enzastaurin alone and in combination with gemcitabine for transitional cell cancer (TCC). Immunohistochemistry (IHC) was done on 105 human samples from a microarray to show the expression of PKC-beta. The preclinical antitumor activity of enzastaurin and gemcitabine as single agents and in combination against aggressive human -lines (-SUP and 5637) and murine subcutaneous xenografts bearing 5637 cells was determined. Western Blot was done on tumor cells in vitro to detect signaling through PKC-beta, GSK-3beta, and AKT. The effect on cell migration was determined in vitro. Modulation of proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (CD31) in vivo was determined by IHC. IHC done on human TCC samples from a microarray showed the expression of PKC-beta in 33% of tumors. Enzastaurin induced significant apoptosis and inhibited proliferation in vitro at low micromolar concentrations. The in vitro inhibitory activity of combination enzastaurin and gemcitabine by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay seemed synergistic. Western Blotting revealed down-regulation of Akt, PKC-beta, and GSK-3 beta phosphorylation. Enzastaurin inhibited migration at an earlier time point independent of antiproliferative activity. Combination therapy had significantly superior antitumor activity in murine xenografts compared with untreated controls, whereas single agents did not. IHC showed reduced Ki-67 and CD31 and increased cleaved caspase-3 with combination therapy compared with controls. Enzastaurin showed preclinical antitumor activity against human TCC and enhanced the activity of gemcitabine.
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PMID:Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine. 1950 73

Histone deacetylases (HDACs) inhibitors induce cell growth arrest and apoptosis in a wide variety of tumor cells. The purpose of this study was to evaluate the effects of trichostatin A (TSA), one of the HDACs inhibitors, on proliferation and apoptosis of oral squamous cell carcinoma cells. Exposure of Tca83 cells (established from human tongue squamous cell carcinoma) to TSA resulted in cell growth inhibition and apoptosis in a dose-dependent manner as measured with MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and DAPI (4'6'diamidino-2-phenylindole dihydrochloride) staining. Western blot showed that both total PTEN and membrane-bound PTEN were induced by TSA treatment, whereas phosphorylation level (Ser 473) of AKT was correspondingly down-regulated by TSA treatment. Knock-down of PTEN expression with PTEN siRNA could sufficiently block 0.25mug/ml TSA induced inhibition of cell growth, but failed to block 0.5mug/ml TSA induced inhibition of cell growth and apoptosis. Moreover, induction of apoptosis by TSA treatment was also demonstrated by cytochrome C releasing and induction of caspase-3. Conclusively, the results suggested that PTEN/AKT pathway was involved in TSA induced cell growth inhibition and apoptosis of oral squamous cell carcinoma cells. HDACs inhibitors could be potential anticancer drugs for chemotherapy of oral squamous cell carcinoma.
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PMID:PTEN/AKT pathway involved in histone deacetylases inhibitor induced cell growth inhibition and apoptosis of oral squamous cell carcinoma cells. 1957 87

The effects of cocoa feeding against N-nitrosodiethylamine (DEN)-induced liver injury were studied in rats. Animals were divided into five groups. Groups 1 and 2 were fed with standard and cocoa-diet, respectively. Groups 3 and 4 were injected with DEN at 2 and 4 weeks, and fed with standard and cocoa-diet, respectively. Group 5 was treated with DEN, received the standard diet for 4 weeks and then it was replaced by the cocoa-diet. DEN-induced hepatic damage caused a significant increase in damage markers, as well as a decrease in the hepatic glutathione, diminished levels of p-ERK and enhanced protein carbonyl content, caspase-3 activity and values of p-AKT and p-JNK. The cocoa-rich diet prevented the reduction of hepatic glutathione concentration and catalase and GPx activities in DEN-injected rats, as well as diminished protein carbonyl content, caspase-3 activity, p-AKT and p-JNK levels, and increased GST activity. However, cocoa administration did not abrogate the DEN-induced body weight loss and the increased levels of hepatic-specific enzymes and LDH. These results suggested that cocoa-rich diet attenuates the DEN-induced liver injury.
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PMID:A diet rich in cocoa attenuates N-nitrosodiethylamine-induced liver injury in rats. 1960 30

Since the regression of the corpus luteum (CL) occurs via a tightly controlled apoptotic process, studies were designed to determine if local administration of the antiapoptotic agent sphingosine 1-phosphate (S1P) effectively blocks the luteolytic action of prostaglandin F-2alpha (PGF-2alpha). On day 19 of pregnancy, 2 hr before systemic PGF-2alpha administration, rats were injected intrabursa with either S1P or vehicle (control). The activity of four caspases, which contribute to the initial (caspase-2, -8, and -9) and final (caspase-3) events in apoptosis was measured in pooled CL from four individual ovaries at 0 and 4 hr after PGF-2alpha injection. The expression of the phosphorylated form of AKT (pAKT) and tumor necrosis factor-alpha (TNF-alpha) was analyzed by ELISA. In addition, cell death was evaluated by electronic microscopy (EM) in CL 4 and 36 hr after PGF-2alpha injection. The activity of caspase-2, -3, and -8 was significantly greater by 4 hr after PGF-2alpha, but not caspase-9 activity. In contrast, expression of pAKT and TNF-alpha decreased significantly. Administration of S1P suppressed (P < 0.05) these effects, decreasing caspase activities and increasing pAKT and TNF-alpha expression. The administration of S1P also significantly decreased the percentage of luteal apoptotic cells induced by PGF-2alpha. PGF-2alpha treatment increased the prevalence of luteal cells with advanced signs of apoptosis (i.e., multiple nuclear fragments, chromatin condensation, or apoptotic bodies). S1P treatment suppressed these changes and increased the blood vessel density. These results suggest that S1P blocks the luteolytic effect of the PGF-2alpha by decreasing caspase-2, -3, and -8 activities and increasing AKT phosphorylation and TNF-alpha expression.
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PMID:Local effects of the sphingosine 1-phosphate on prostaglandin F2alpha-induced luteolysis in the pregnant rat. 1964 54

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to promote apoptosis in cancer cells. However, the role of EGCG in endothelial cells following ischemia/reperfusion (I/R) injury remains unclear. In the present study, we investigated the mechanisms by which EGCG enhances I/R-induced cell growth inhibition and apoptosis in human umbilical vein endothelial cells (HUVECs). Our results showed that EGCG treatment caused cell proliferation inhibition during I/R injury, and this effect was associated with increased p27 and p21 levels and reduced cyclin D1 level. Moreover, treatment of cells with EGCG resulted in increase of caspase-3 and Bax and decrease of Bcl-2, enhancing I/R-induced apoptosis. Interestingly, EGCG decreased I/R-induced phosphorylation of AKT and its downstream substrates Foxo1 and Foxo3a and ERK1/2. In contrast, EGCG increased JNK1/2 and c-Jun phosphorylation. Furthermore, both wortamannin (PI3K inhibitor) and U0126 (MEK1/2 inhibitor) markedly enhanced EGCG-induced apoptosis during I/R, whereas SP600125 (JNK inhibitor) attenuated the action of EGCG. Taken together, our study for the first time suggest that EGCG is able to enhance growth arrest and apoptosis of HUVECs during I/R injury, at least in part, through inhibition of AKT and ERK1/2 and activation of JNK1/2 signaling pathways.
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PMID:Epigallocatechin-3-gallate enhances ischemia/reperfusion-induced apoptosis in human umbilical vein endothelial cells via AKT and MAPK pathways. 1966 89

Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.
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PMID:Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. 1969 Mar 88


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