Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 is considered the guardian of the genome and has a number of biological functions, including cell cycle arrest, DNA repair, and apoptosis. In a recent study by Foster and colleagues, the pharmacological compound CP-31398 was found to stabilize wild-type p53 to enhance its transcriptional activity and inhibit tumor growth in mice. We hypothesize that CP-31398 induces apoptosis by stabilizing the p53 protein and activating the mitochondrial-mediated pathway. Using the wild-type p53 HCT116+/+ and the p53-deficient HCT116-/- colon carcinoma cell lines, we demonstrate here that CP-31398 induces apoptosis in a dose-, time-, and p53-dependent manner. CP-31398 dramatically elevated p53 and p21(Waf1) protein levels in HCT116+/+, while a smaller p53-independent p21(Waf1) induction by CP-31398 in HCT116-/- cells was also observed. Moreover, we also found that CP-31398 increased Bax expression, altered mitochondrial membrane potential causing the release of cytochrome c, and induced the cleavage of caspases-9 and -3. Taken together, our results indicate that CP-31398 induces p53-dependent apoptosis by activating the Bax/mitochondrial/caspase-9 pathway. Elucidating the mechanism by which CP-31398 induces cell death may establish it as an anticancer agent.
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PMID:The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. 1202 51

Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.
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PMID:Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. 1471 90

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anticarcinogenic effects of celecoxib is still not fully understood. To investigate the extent to which the anticarcinogenic effect of celecoxib depends on COX-2 expression, we transfected human colon carcinoma cells (Caco-2) with the human COX-2 cDNA, in both sense and in antisense orientation, to generate cells which either overexpress COX-2 (human COX-2-sense, hCOX-2-s), express no COX-2 (human COX-2-antisense, hCOX-2-as) or express only very small amounts of COX-2 (control cells). Treatment of these cells with celecoxib dose-dependently (0-100microM) reduced cell survival which was accompanied by an induction of a G(0)/G(1) phase block and apoptosis. The effect of celecoxib treatment on both, cell survival and induction of apoptosis in hCOX-2-as cells was less marked than in the COX-2-expressing cells. Apoptosis was accompanied by an activation of caspase-3 and caspase-9 and cytochrome c release. In contrast, we observed no difference in sensitivity with regard to the induction of a cell cycle block between the different cell clones. The G(0)/G(1) phase block caused by celecoxib correlated with a decrease in expression levels of cyclin A and cyclin B1 and an increase in the expression of the cell cycle inhibitory proteins p21(Waf1) and p27(Kip1) irrespective of the type of cell used. These data indicate that apoptosis-inducing effects of celecoxib partly depend on COX-2 expression of the cells, whereas induction of a cell cycle block occurred COX-2 independently. Thus, the anticarinogenic effects of celecoxib can be explained by both COX-2-dependent and -independent mechanisms.
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PMID:Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. 1504 64

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have also shown that atiprimod treatment reduced production of IL-6, VEGF and inhibited activation of Stat3, a constitutively activated protein in majority of human cancers. Together these findings suggest that atiprimod acts on several molecules that are essential for tumor growth, invasion and metastasis.
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PMID:Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis. 1584 57

The effects of reactive oxygen species (ROS) on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in solid cancers have yet to be clearly defined. In this study, we found that the classic uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a reduction in DeltaPsim and generation of ROS. This uncoupling effect enhanced TRAIL-induced apoptosis in TRAIL-resistant human colon carcinoma cell lines (RKO, HT29, and HCT8). Sensitization was inhibited by benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone, indicating the requirement for caspase activation. CCCP per se did not induce apoptosis or release of proapoptotic factors from mitochondria. Generation of ROS by CCCP was responsible for TRAIL-induced Bax and caspase activation because scavenging ROS completely abrogated apical caspase-8 activation and further downstream events leading to cell death. Overexpression of Bcl-2 did not prevent the initial loss of DeltaPsim and ROS generation following CCCP treatment, but did prevent cell death following TRAIL and CCCP exposure. Uncoupling of mitochondria also facilitated TRAIL-induced release of proapoptotic factors. X-linked inhibitor of apoptosis overexpression abrogated TRAIL-induced apoptosis in the presence of CCCP and decreased initiator procaspase-8 processing, indicating that additional processing of caspase-8 required initiation of a mitochondrial amplification loop via effector caspases. Of interest, depletion of caspase-9 in RKO cells did not protect cells from TRAIL/CCCP-induced apoptosis, indicating that apoptosis occurred via a caspase-9-independent pathway. Data suggest that in the presence of mitochondrial-derived ROS, TRAIL induced mitochondrial release of Smac/DIABLO and inactivation of X-linked inhibitor of apoptosis through caspase-9-independent activation of caspase 3.
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PMID:Reactive oxygen species regulate caspase activation in tumor necrosis factor-related apoptosis-inducing ligand-resistant human colon carcinoma cell lines. 1610 97

Photodynamic therapy (PDT) typically involves systemic or topical administration of a tumor-localizing photosensitizer or prodrug and its subsequent activation by visible light. This results primarily in singlet oxygen-induced photodamage to the tumor. 5-Aminolevulinic acid (ALA) and its derivatives have recently been widely used for PDT due to their selective induction in tumor of endogenous protoporphyrin IX (PpIX), a potent photosensitizer. Although ALA-PDT has achieved successful results in the treatment of several clinical oncological and nononcological diseases, the mechanisms of this modality are still not fully elucidated. In the present study, the human colon carcinoma cell line 320DM was treated in vitro with PDT using hexaminolevulinate (HAL), a hexylester of ALA known to be 50 to 100 times more efficient at producing PpIX formation than ALA itself. PpIX production increased with increasing HAL concentrations in the cells and phototoxicity of the cells was enhanced with increasing light (450 nm) doses. HAL-PDT induced apoptotic cell death, as measured by nuclear staining of Hoechst 33342 for fluorescence microscopy, DNA electrophoresis and TdT staining for flow cytometry. PDT with 5 muM of HAL and a light dose of 640 mJ/cm2 produced a 75% apoptotic cell population 40 hr after the treatment. Furthermore, the loss of mitochondrial membrane potential coincident with the release of cytochrome c from the mitochondria into the cytosol led to a rapid activation of caspase-9 and caspase-3 (an executioner), indicating that the selective damage to the mitochondria by HAL-PDT can induce a cytochrome-c-mediated apoptotic response in the 320DM cells.
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PMID:Induction of apoptosis by hexaminolevulinate-mediated photodynamic therapy in human colon carcinoma cell line 320DM. 1656 15

The role of the cyclin-dependent kinase (CDK) inhibitor p21 as a mediator of p53-induced growth arrest is well established. In addition, recent data provide strong evidence for new emerging functions of p21, including a role as a modulator of apoptosis. The mechanisms, however, by which p21 interferes with the death machinery, especially following ionizing radiation (IR), are largely unknown. Here, we report that IR induced caspase-9 and caspase-3 activation and subsequent apoptosis only in p21-deficient colon carcinoma cells, whereas similar treated wild-type cells were permanently arrested in the G(2)-M phase, correlating with the induction of cellular senescence. Interestingly, activation of the mitochondrial pathway, including caspase-2 processing, depolarization of the outer mitochondrial membrane, and cytochrome c release, was achieved by IR in both cell lines, indicating that p21 inhibits an event downstream of mitochondria but preceding caspase-9 activation. IR-induced p21 protein expression was restricted to the nucleus, and no evidence for a mitochondrial or cytoplasmic association was found. In addition, p21 did neither interact with caspase-3 or caspase-9, suggesting that these events are not required for the observed protection. Consistent with this assumption, we found that CDK inhibitors potently abrogated IR-induced caspase processing and activation without affecting mitochondrial events. In addition, in vitro caspase activation assays yielded higher caspase-3 activities in extracts of irradiated p21-deficient cells compared with extracts of similar treated wild-type cells. Thus, our results strongly indicate that p21 protects cells from IR-induced apoptosis by suppression of CDK activity that seems to be required for activation of the caspase cascade downstream of the mitochondria.
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PMID:p21 blocks irradiation-induced apoptosis downstream of mitochondria by inhibition of cyclin-dependent kinase-mediated caspase-9 activation. 1714 70

There is high current interest in the chemopreventive potential of Brassica vegetables (cruciferae), particularly due to their content in glucosinolates (GL), which upon myrosinase hydrolysis release the corresponding isythiocyanates (ITC). Some ITCs, such as sulforaphane (SFN) from broccoli ( Brassica oleacea italica), have been found to possess anticancer activity through induction of apoptosis in selected cell lines, as well as indirect antioxidant activity through induction of phase II detoxifying enzymes. Japanese daikon ( Raphanus sativus L.) is possibly the vegetable with the highest per capita consumption within the Brassicaceae family. Thanks to a recently improved gram scale production process, it was possible to prepare sufficient amounts of the GL glucoraphasatin (GRH) as well as the corresponding ITC 4-methylthio-3-butenyl isothiocyanate (GRH-ITC) from its sprouts. This paper reports a study on the cytotoxic and apoptotic activities of GRH-ITC compared with the oxidized counterpart 4-methylsulfinyl-3-butenyl isothiocyanate (GRE-ITC) on three human colon carcinoma cell lines (LoVo, HCT-116, and HT-29) together with a detailed kinetic investigation of the direct antioxidant/radical scavenging ability of GRH and GRH-ITC. Both GRH-ITC and GRE-ITC reduced cell proliferation in a dose-dependent manner and induced apoptosis in the three cancer cell lines. The compounds significantly ( p < 0.05) increased Bax and decreased Bcl2 protein expression, as well as producing caspase-9 and PARP-1 cleavage after 3 days of exposure in the three cancer cell lines. GRH-ITC treatment was shown to have no toxicity with regard to normal human lymphocytes (-15 +/- 5%) in comparison with SFN (complete growth inhibition). GRH and GRH-ITC were able to quench the 2,2-diphenyl-1-picrylhydrazyl radical, with second-order rate constants of 14.0 +/- 2.8 and 43.1 +/- 9.5 M(-1) s(-1), respectively (at 298 K in methanol), whereas the corresponding value measured here for the reference antioxidant alpha-tocopherol was 425 +/- 40 M (-1) s (-1). GRH reacted with H2O2 and tert-butyl hydroperoxide in water (pH 7.4) at 37 degrees C, with rate constants of 1.9 +/- 0.3 x 10(-2) and 9.5 +/- 0.3 x 10(-4) M(-1) s (-1) (paralleling recently developed synthetic antioxidants) being quantitatively (>97%) converted to GRE. It is demonstrated that GRH-ITC has interesting antioxidant/radical scavenging properties, associated with a selective cytotoxic/apoptotic activity toward three human colon carcinoma cell lines, and very limited toxicity on normal human T-lymphocytes.
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PMID:Cytotoxic and antioxidant activity of 4-methylthio-3-butenyl isothiocyanate from Raphanus sativus L. (Kaiware Daikon) sprouts. 1818 52

A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.
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PMID:A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma. 1856 Mar 53


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