Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with alpha-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For alpha-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to alpha-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to alpha-TOS, by regulation of alpha-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with alpha-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which alpha-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.
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PMID:Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic activity: comparison with receptor-mediated pro-apoptotic signaling. 1268 Jul 82

The Ewing sarcoma is the second most common bone tumor in children and young adults. Despite the advances in therapy, the 5-year survival rate for patients with metastatic disease is poor, indicating the need for alternative treatments. Here, we report that 2-methoxy-estradiol (2-Me), a natural estrogen metabolite, induced a caspase-dependent apoptosis of Ewing sarcoma-derived cells independently of their p53 status. 2-Me-induced apoptosis occurred through the mitochondrial death pathway as evidenced by reduction of the mitochondrial transmembrane potential, cytochrome c release and caspase-9 activation. Treatment of cells with 2-Me resulted in generation of intracellular H(2)O(2), which occurred earlier than caspase-9 activation. The H(2)O(2)-reducing agent Ebselen and the lipid peroxidation inhibitor vitamin E decreased both 2-Me-induced caspase-9 activation and cell death, thus providing evidence for a role of H(2)O(2) and lipid peroxides in the initiation of this process. Rotenone, an inhibitor of the mitochondrial respiratory chain, abolished both apoptosis and H(2)O(2) production, thereby identifying mitochondria as the source of H(2)O(2). Moreover, we observed that treatment of cells with 2-Me or H(2)O(2) induced activation of the c-Jun N-terminal kinase (JNK). Overexpression of a dominant-negative mutant of JNK1 reduced 2-Me-induced apoptosis indicating that JNK participates in this process. Altogether, our results provide evidence that 2-Me triggers apoptosis of Ewing sarcoma cells through induction of a mitochondria redox-dependent mechanism and suggest that this compound or other agents that selectively increase the level of reactive oxygen species may prove useful to the development of novel strategies for treatment of Ewing tumors.
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PMID:2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production. 1273 Jun 70

Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. 1275 Feb 70

The vitamin E family of compounds is divided into two subgroups, tocopherols and tocotrienols. However, tocotrienols display more potent apoptotic activity in mammary cancer cells. Although the mechanism(s) mediating tocotrienol-induced apoptosis is presently unknown, apoptosis is carried out by activation of initiator caspases (caspase-8 or -9) that subsequently activate effector caspases (caspase-3, -6, or -7). Studies were conducted to determine whether tocotrienol-induced apoptosis is mediated by activation of the caspase-8 and/or caspase-9 pathway. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained on serum-free media. Treatment with tocotrienol-rich-fraction of palm oil (TRF) and g-tocotrienol, but not a-tocopherol, induced a dose-dependent decrease in +SA cell viability. TRF- and g-tocotrienol-induced cell death resulted from apoptosis, as determined by DNA fragmentation and positive TUNEL assay staining. Additional studies showed that treatment with 50 mM TRF or 20 mM g-tocotrienol increased intracellular activity and levels of processed caspase-8 and -3 but not caspase-9. Furthermore, treatment with specific caspase-8 or -3 inhibitors, but not caspase-9 inhibitor, completely blocked the tocotrienol-induced apoptosis in +SA cells. These findings demonstrate that tocotrienol-induced apoptosis in +SA mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation.
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PMID:Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. 1288 Oct 19

The ongoing Selenium and Vitamin E Chemoprevention Trial is designed to evaluate the efficacy of these two agents, either individually or in combination, in reducing the incidence of prostate cancer in healthy men over 55 years of age. Little information, however, is available on the potential synergy between vitamin E and selenium in chemoprevention. The present study was aimed at addressing this gap of knowledge with the use of the androgen-unresponsive, p53-null, PC-3 human prostate cancer cell line. The growth-inhibitory activity of vitamin E appeared to be dependent on the chemical form. In our hands, D-alpha-tocopheryl succinate (VES) was much more potent than either DL-alpha-tocopherol or D-alpha-tocopheryl acetate. Combining VES with methylseleninic acid (MSA), a selenium metabolite, produced a synergistic effect on cell growth suppression. The synergy was accounted for primarily by an augmented apoptotic response. Poly(ADP-ribose) polymerase cleavage and activation of specific caspases were confirmed by Western blot analysis. The caspases that were commonly modulated by either VES or MSA included initiator caspases-8 and -10, as well as executioner caspases-3, -6, and -7. In contrast, caspase-9 was activated only by VES, whereas caspases-1 and -12 were activated only by MSA. Based on the above information, it is proposed that the mitochondrial pathway and the endoplasmic reticulum stress/cytokine signaling pathway might be involved in apoptosis induction by VES and MSA, respectively. These two pathways may act in a cooperative manner to switch on the full force of the apoptotic machinery when cells are treated with both VES and MSA.
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PMID:Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. 1458 1

Previous studies suggest the protective potentiality of Ginkgo biloba (EGb 761) against apoptotic cell death induced by hydroxyl radicals, staurosporine, serum deprivation and beta-amyloid (betaA) peptide. We have extended these observations to cultured cortical neurons and studied the effect of EGb 761 on neuronal survival (evaluated as MTT reduction), the presence of condensed nuclei (monitored as Hoechst staining), the time-course of caspase-1, caspase-3 and caspase-9 activation (measured by cleavage of specific fluorescent substrates) and superoxide anion production (evaluated by hydroethidine staining) after the exposure to staurosporine. Results show that 200 microg/ml of EGb 761 increased cell survival and reduced the number of condensed nuclei after the exposure to 200 nM staurosporine. Vitamin E and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN) also significantly increased cell survival. In contrast, the broad-spectrum caspase inhibitors ZVAD and ZBIOT showed no protection. Similarly, selective inhibitors of caspase-1 (YVAD-CHO), caspase-2 (VDVAD-CHO), caspase-3 (DEVD-CHO) and caspase-8 (IETD-CHO) did not protect against cell damage induced by staurosporine. The protective effect of EGb 761 was not enhanced when coincubated with vitamin E or DEVD-CHO. Caspase-3 activity was maximally induced 5-8 h after staurosporine exposure. Both EGb 761 and vitamin E showed a tendency to decrease caspase-3 activity. In contrast, activation of caspase-1 and caspase-9 was not observed at any of the times studied after STS exposure. Exposure to staurosporine resulted in increased superoxide production that was maximal at 5 h. EGb 761 significantly inhibited superoxide production at short times after staurosporine exposure. Vitamin E and PBN also significantly reduced superoxide production. Results suggest that EGb 761 neuroprotective effect might be mediated by its well-known antioxidant activity, which might also influence caspase-3 activation. Inhibition of capase-3 induced by EGb 761 and vitamin E does not seem to contribute to their observed protective action.
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PMID:Effect of Ginkgo biloba (EGb 761) on staurosporine-induced neuronal death and caspase activity in cortical cultured neurons. 1498 36

Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of alpha-tocopheryl succinate (alpha-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to alpha-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or alpha-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAIL-induced apoptosis and its augmentation by alpha-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by alpha-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by alpha-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that alpha-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.
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PMID:Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells. 1508 98

We found that gamma-tocopherol, the predominant vitamin E form in diets, but not alpha-tocopherol, which is the exclusive form of vitamin E in most supplements, exhibited antiproliferation effect on prostate (PC-3, LNCaP) and lung (A549) cancer cells. gamma-Tocopherol induced apoptosis in androgen-sensitive LNCaP but not androgen-resistant PC-3 cells. Consequently, gamma-tocopherol treatment caused cytochrome c release and caspase-9, -3 and -7 activation. However, the apoptosis could not be completely reversed by an irreversible pancaspase inhibitor, indicating that an alternative caspase-independent pathway may also be involved. Our study suggests that gamma-tocopherol may be valuable in the prevention and therapy for certain types of cancer.
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PMID:Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms. 1575 80

Vitamin E (VE) analogues, epitomized by alpha-tocopheryl succinate (alpha-TOS), are potent inducers of apoptosis and anti-cancer agents. Here, we tested their effect on the highly malignant N-type neuroblastoma (Nb) cells and their differentiated, neurone-like counterparts. Nb cells were highly susceptible to several VE analogues, while differentiated Nb cells were relatively resistant to alpha-TOS. The importance of caspase-9 rather than caspase-8, as judged by specific siRNAs studies, together with the loss of the inner mitochondrial potential, suggests that alpha-TOS triggers apoptosis in Nb cells via the mitochondrial pathway. Cultured Nb cells were sensitized to alpha-TOS by pre-treatment with Bcl-2, Bcl-xL or Mcl-1 siRNAs, while the malignant cell line was more resistant to the vitamin E analogue when Bax was knocked down. In contrast, overexpression of Bcl-2 in Nb cells rendered them more resistant to alpha-TOS-induced apoptosis. The resistance of differentiated Nb cells to alpha-TOS-mediated apoptosis occurred via two modes: first, by up-regulation of the anti-apoptotic Bcl-2 family proteins and second, by accumulation of decreased levels of reactive oxygen species when challenged with alpha-TOS. We conclude that alpha-TOS is highly selective in killing malignant brain cancer cells while relatively inert toward differentiated neuronal cells, and that vitamin E analogues may be novel therapeutics for the treatment of tumours such as neuroblastomas.
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PMID:Alpha-tocopheryl succinate selectively induces apoptosis in neuroblastoma cells: potential therapy of malignancies of the nervous system? 1600 65

Tocotrienols and tocopherols represent the two subgroups that make up the vitamin E family of compounds. However, tocotrienols display significantly more potent apoptotic activity in neoplastic mammary epithelial cells than tocopherols. Studies were conducted to determine the intracellular mechanism(s) mediating tocotrienol-induced apoptosis in neoplastic +SA mouse mammary epithelial cells in vitro. An initial step in apoptosis is the activation of 'initiator' caspases (caspase-8 or -9) that subsequently activate 'effector' caspases (caspase-3, -6 and -7) and induce apoptosis. Treatment with cytotoxic doses of alpha-tocotrienol (20 microM) resulted in a time-dependent increase in caspase-8 and caspase-3 activity. Combined treatment with specific caspase-8 or caspase-3 inhibitors completely blocked alpha-tocotrienol-induced apoptosis and caspase-8 or caspase-3 activity, respectively. In contrast, alpha-tocotrienol treatment had no effect on caspase-9 activation, and combined treatment with a specific caspase-9 inhibitor did not block alpha-tocotrienol-induced apoptosis in (+)SA cells. Since caspase-8 activation is associated with the activation of death receptors, such as Fas, tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL) receptors, studies were conducted to determine the exact death receptor(s) and ligand(s) involved in mediating tocotrienol-induced caspase-8 activation and apoptosis. Treatment with Fas-ligand (FasL), Fas-activating antibody, or TRAIL failed to induce cell death in (+)SA neoplastic mammary epithelial cells, suggesting that these cells are resistant to death receptor-induced apoptosis. Moreover, treatment with cytotoxic doses of alpha-tocotrienol did not alter the intracellular levels of Fas, FasL, or Fas-associated death domain (FADD) in these cells. Western blot analysis also showed that alpha-tocotrienol did not induce FasL or FADD translocation from the cytosolic to membrane fraction in these cells. Finally, treatment with Fas-blocking antibody did not reverse the tocotrienol-induced apoptosis in (+)SA cells. These data demonstrate that tocotrienol-induced caspase-8 activation and apoptosis is not mediated through death receptor activation in malignant (+)SA mammary epithelial cells. Resistance to death receptor-induced apoptosis has been shown to be associated with increased expression of apoptosis-inhibitory proteins, such as FLICE-inhibitory protein (FLIP), and enhanced signalling of the phosphatidylinositol 3-kinase (PI3K)/PI3K-dependent kinase (PDK)/Akt mitogenic pathway. Additional studies showed that treatment with cytotoxic doses of alpha-tocotrienol decreased total, membrane, and cytosolic levels of FLIP, and reduced phosphorylated PDK-1 (active) and phosphorylated-Akt (active) levels in these cells. In summary, these findings demonstrate that tocotrienol-induced caspase-8 activation and apoptosis in malignant (+)SA mammary epithelial cells is not mediated through the activation of death receptors, but appears to result from the suppression of the PI3K/PDK/Akt mitogenic signalling pathway, and subsequent reduction in intracellular FLIP expression.
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PMID:Intracellular mechanisms mediating tocotrienol-induced apoptosis in neoplastic mammary epithelial cells. 1632 43


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