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)

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.
Carcinogenesis 2002 Jan
PMID:Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. 1175 35

[6]-paradol, a pungent phenolic substance found in ginger and other Zingiberaceae plants, has been demonstrated to be an effective inhibitor of tumor promotion in mouse skin carcinogenesis. In the present study, we found that [6]-paradol and other structurally related derivatives, [10]-paradol, [3]-dehydroparadol, [6]-dehydroparadol, and [10]-dehydroparadol, with the exception of [3]-paradol induce apoptosis in an oral squamous carcinoma cell line, KB, in a dose-dependent manner. [10]-paradol and [10]-dehydroparadol exhibited a similar extent of cytotoxicity to that of [6]-paradol. [6]-Dehydroparadol and [3]-dehydroparadol appeared to be more potent, with an IC50 less than 40 microM. Treatment of KB cells with an apoptosis-inducing concentration of [6]-dehydroparadol caused induction of proteolytic cleavage of pro-caspase-3. These results suggest that [6]-paradol and structurally related derivatives induce apoptosis through a caspase-3-dependent mechanism.
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PMID:Induction of apoptosis and caspase-3 activation by chemopreventive [6]-paradol and structurally related compounds in KB cells. 1180 29

Although gastric cancer formation with H. pylori in Mongolian gerbils was recently reported, the same inoculation procedure did not result in cancer formation in other animals such as mice. Disturbed regulation of apoptosis and cell proliferation are known to link the multistep process of carcinogenesis. The present study is designed to examine the level of gastric epithelial cell apoptosis in Mongolian gerbils colonized with the H. pylori (Sydney strain: SS1) in comparison with that in mice. Mice (C57BL/6) and Mongolian gerbils were orally inoculated with SS1 and the stomachs were examined 9 and 18 months later. MPO activity increased persistently in gerbils, but increased transiently in mice. While the levels of DNA fragmentation, caspase-3 activity, and the number of TUNEL-positive cells increased significantly in mice, such parameters were attenuated in gerbils. On the other hand, the number of PCNA-positive cells increased after SS1 inoculation only in Mongolian gerbils, suggesting the enhancement of cell turnover in H. pylori-colonized gerbils. In conclusion, the SS1-induced increase in gastric mucosal apoptosis observed in mice was attenuated significantly in Mongolian gerbils, suggesting the causative role for the higher incidence of gastric carcinogenesis in this animal.
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PMID:Attenuated apoptosis in H. pylori-colonized gastric mucosa of Mongolian gerbils in comparison with mice. 1183 40

Long-term psoralen plus ultraviolet A radiation (PUVA) therapy is associated with an increased risk of squamous cell carcinoma and malignant melanoma. Genistein (4',5,7-trihydroxyisoflavone), a major isoflavone in soybeans and a specific inhibitor of protein tyrosine kinase, has been shown to inhibit UVB induced skin carcinogenesis in hairless mice. For this study we examined the protective effects of topical genistein on PUVA-induced photodamage. In two separate experiments, genistein in a dimethyl sulfoxide/acetone (1:9) solution was applied to SKH-1 female mice 1 h post 8-methoxy-psoralen dosing and 1 h prior to UVA irradiation. Application of genistein significantly decreased PUVA-induced skin thickening, and greatly diminished cutaneous erythema and ulceration in a dose-dependent manner. Histological examination showed that PUVA treatment of mouse skin induced dramatic inflammatory changes throughout the epidermis; topical genistein prevented these changes without noticeable adverse effects. Cells containing cleaved poly(ADP-ribose) polymerase (PARP) and active caspase-3 were significantly increased in PUVA-treated skin (P < 0.05 and P < 0.0001, respectively) as compared with unexposed control skin. Topical genistein completely inhibited cleavage of PARP and caspase-3. Proliferating cell nuclear antigen (PCNA) positive cells were observed in suprabasal areas of the epidermis and were significantly decreased in PUVA-treated skin compared with both control samples and samples treated with PUVA plus topical genistein (P < 0.005). These results indicate that genistein protects the skin from PUVA-induced photodamage.
Carcinogenesis 2002 Feb
PMID:Effects of the isoflavone 4',5,7-trihydroxyisoflavone (genistein) on psoralen plus ultraviolet A radiation (PUVA)-induced photodamage. 1187 39

Evidence is accumulating that bile acids induce apoptosis in colonic cells. Therefore, it becomes important to study the underlying molecular mechanisms and the role of this phenomenon in tumor promotion. Minutes after exposure of HCT 116 and HT-29 cells to deoxycholate (DCA), DNA damage, measured using the COMET assay, was evident. Caspase-3 was rapidly activated in HCT 116 cells exposed to DCA, whereas in HT-29 cells, caspase-3 activation was delayed. Using transient transfections with reporter constructs, we showed that the transcription factors activator protein-1 (AP-1) and NF-kB were increased in HCT 116 cells, in a dose-dependent fashion, by DCA COX-2 promoter activity was also induced by DCA and using mutant COX-2 promoter plasmids, we showed that the ability of DCA to induce promoter activity was partly dependent upon a functional NF-kB and C/EBP site, and completely dependent on a functional c-AMP response element site. DNA damage thus appears to be the initiating event in DCA-induced apoptosis. In conclusion, the bile acid, DCA, has a major impact on apoptotic mechanisms in colonic cells and this may be contributing to its effect as a tumor promoter.
Carcinogenesis 2002 May
PMID:Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1. 1201 58

Red meat and fiber rich foods are the dietary factors most consistently related to colon carcinogenesis. Although several components in these dietary sources may contribute, the biochemical mechanism by which red meat and fiber affect colorectal carcinogenesis has not yet been established. Sphingomyelin metabolism is a novel signal transduction pathway that may have an impact on colonic tumorigenesis. The present study investigated the activity changes of sphingomyelinase (SMase), ceramidase and caspase-3 in colonic mucosa of rats fed on a high fat control diet, the control diet with beef and the control diet with fiber (cellulose). After a three week feeding period the colonic mucosa were scraped and homogenized and enzyme activities were determined. The fiber diet significantly increased the activities of neutral and acid SMases but had no effect on those of alkaline SMase and neutral ceramidase. The beef diet, on the other hand, significantly reduced neutral ceramidase activity, but had no effect on the activities of any SMase. In addition, the beef diet significantly reduced and the fiber diet increased caspase-3 activity in the colonic mucosa when compared with the control diet. The changes of caspase-3 activities were abolished by preincubating the samples with caspase-3 inhibitor. No significant changes of intestinal alkaline phosphatase could be found among the three dietary groups. In conclusion, fiber and red meat in the high fat diet affected in an opposite way the enzymes responsible for sphingomyelin metabolism and apoptosis in the colon. The effects may have implications in colorectal tumorigenesis.
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PMID:Effects of red meat and fiber in high fat diet on activities of sphingomyelinase, ceramidase and caspase-3 in rat colonic mucosa. 1216 63

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
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PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

To identify genes involved in cervical carcinogenesis, the mRNA differential display method was used. A 220-bp cDNA fragment called CA11 was present in normal cervical tissue but not in primary cervical cancer tissue or cervical cancer cell lines. CA11 exhibited 98% homology with the recorded human secreted frizzled-related protein (hsFRP) sequence. A dominant hsFRP mRNA transcript of approximately 4.6 kb was present in three normal cervical tissues examined. Expression of the transcript was nearly absent from three cervical cancer tissues and from five human cervical cancer-derived cell lines. Results from in situ hybridization showed that the hsFRP transcript was confined to the normal cervical epithelial layer. When hsFRP-transfected HeLa and CUMC-6 cervical cancer cells were cultured in serum-free medium, most of the cells died within 8 days. This effect is associated with the apoptotic process. The caspase-3 inhibitor 1, Ac-DEVD-CHO, blocked hsFRP-induced apoptotic cell death. Additionally, cleavage of poly (ADP-ribose) polymerase in hsFRP-transfected cells was confirmed by colorimetric assay. These results indicate that the hsFRP gene probably functions as a tumor suppressor in normal cervical epithelium and down-regulation of hsFRP contributes to development of cervical cancer.
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PMID:Human secreted frizzled-related protein is down-regulated and induces apoptosis in human cervical cancer. 1241 93

Grape seed extract (GSE), rich in the bioflavonoids commonly known as procyanidins, is one of the most commonly consumed dietary supplements in the United States because of its several health benefits. Epidemiological studies show that many prostate cancer (PCA) patients use herbal extracts as dietary supplements in addition to their prescription drugs. Accordingly, in recent years, we have focused our attention on assessing the efficacy of GSE against PCA. Our studies showed that GSE inhibits growth and induces apoptotic death of human PCA cells in culture and in nude mice. Here, we performed detailed studies to define the molecular mechanism of GSE-induced apoptosis in advanced human PCA DU145 cells. GSE treatment of cells at various doses (50-200 micro g/ml) for 12-72 h resulted in a moderate to strong apoptotic death in a dose- and time-dependent manner. In the studies assessing the apoptotic-signaling pathway induced by GSE, we observed an increase in cleaved fragments of caspases 3, 7 and 9 as well as PARP in GSE-treated cells after 48 and 72 h of treatment. Pre-treatment of cells with general caspases inhibitor, z-Val-Ala-Asp(OMe)-FMK or caspase 3-like proteases inhibitor [z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-FMK], almost completely (approximately 90%) inhibited the GSE-induced apoptotic cell death. In a later case, GSE-induced caspase-3 activity was completely inhibited. Selective caspase 9 inhibitor [z-Leu-Glu(OMe)-His-Asp(OMe)-FMK] showed only partial inhibition of GSE-induced apoptosis whereas GSE-induced protease activity of caspase 9 was completely inhibited. Upstream of caspase cascade, GSE showed disappearance of mitochondrial membrane potential and an increase in cytochrome c release in cytosol. Together, these results suggest that GSE possibly causes mitochondrial damage leading to cytochrome c release in cytosol and activation of caspases resulting in PARP cleavage and execution of apoptotic death of human PCA DU145 cells. Furthermore, GSE-caused caspase 3-mediated apoptosis also involves other pathway(s) including caspase 9 activation.
Carcinogenesis 2002 Nov
PMID:Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. 1241 35

We have shown that a combination of fish oil (high in n-3 fatty acids) with the butyrate-producing fiber pectin, upregulates apoptosis in colon cells exposed to the carcinogen azoxymethane, protecting against colon tumor development. We now hypothesize that n-3 fatty acids prime the colonocytes such that butyrate can initiate apoptosis. To test this, 30 Sprague-Dawley rats were provided with diets differing in the fatty acid composition (corn oil, fish oil or a purified fatty acid ethyl ester diet). Intact colon crypts were exposed ex vivo to butyrate, and analyzed for reactive oxygen species (ROS), mitochondrial membrane potential (MMP), translocation of cytochrome C to the cytosol, and caspase-3 activity (early events in apoptosis). The fatty acid composition of the three major mitochondrial phospholipids was also determined, and an unsaturation index calculated. The unsaturation index in cardiolipin was correlated with ROS levels (R = 0.99; P = 0.02). When colon crypts from fish oil and FAEE-fed rats were exposed to butyrate, MMP decreased (P = 0.041); and translocation of cytochrome C to the cytosol (P = 0.037) and caspase-3 activation increased (P = 0.032). The data suggest that fish oil may prime the colonocytes for butyrate-induced apoptosis by enhancing the unsaturation of mitochondrial phospholipids, especially cardiolipin, resulting in an increase in ROS and initiating apoptotic cascade.
Carcinogenesis 2002 Nov
PMID:Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes. 1241 41


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