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)

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.
 ...
PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

alpha-Tocopherol and its synthetic derivative, a-tocopheryl succinate (alpha-TS), are known to inhibit proliferation of cancer cells. alpha-TS is considered a more desirable anticancer agent because of the ability to induce apoptosis. It has been established previously that the whole intact alpha-TS molecule is necessary for its pro-apoptotic activity. For this reason, alpha-TS is not suitable for oral use because the ester bond linking succinate to tocopherol is subject to hydrolysis by intestinal esterases. One approach to overcome this problem is to replace the ester bond with an ether bond, since the latter is resistant to esterase-mediated hydrolysis. alpha-Tocopheryloxybutyrate (alpha-TOB) is the ether analog of alpha-TS. In this study, we compared the potency of alpha-TS and alpha-TOB using a panel of bioassays: cell growth, TUNEL labelling for apoptosis, PARP cleavage, caspase-3 and caspase-9 activation, as well as Akt and JNK phosphorylation. The experiments were carried out in two human prostate cancer cell lines: LNCaP and PC-3. Our results showed that alpha-TOB was capable of inhibiting cell growth and inducing apoptosis, although alpha-TOB was less active than alpha-TS on an equimolar basis. In general, it took twice as much alpha-TOB as alpha-TS to achieve the same response. Nonetheless, these two compounds shared the same mechanism of targeting the Akt and JNK signaling pathways, and activating the intrinsic cell death mediators of caspase-9 and caspase-3. Cellular analysis of alpha-TS and alpha-TOB showed that alpha-TOB was taken up as efficiently as alpha-TS (if not more so), suggesting that the lower activity of alpha-TOB is an inherent property of the molecule and not due to impaired uptake. Additional evidence is provided to show that beta-TS may act at the membrane level to interfere with Akt phosphorylation, although the exact nature of this disruption remains unclear. The future design of new anticancer tocopherol analogs should incorporate the ether linkage of the side chain for esterase resistance as well as other structural modifications for enhanced blocking of membrane signaling.
 ...
PMID:Cellular and molecular effects of alpha-tocopheryloxybutyrate: lessons for the design of vitamin E analog for cancer prevention. 1573 14

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III was found to inhibit the growth of K562 cells in a time-and dose-dependent manner with IC50 value of 1.7 microg/ml, and it displayed several features of apoptosis including apoptotic body formation, increase of sub G1 population, DNA fragmentation and poly (ADP-ribose) polymerase (PARP) cleavage. Investigation of the mechanism of CTXIII--induced apoptosis revealed that the treatment of K562 cells with CTX III resulted in the activation of caspase-9, caspase-3 and subsequent cleavage of its substrate PARP and that CTXIII was also associated with an early release of cytochrome c from the mitochondria. These results suggest that CTX III may induce apoptosis through a mitochondria- and caspase-dependent mechanism.
 ...
PMID:Induction of apoptosis in human leukemia K562 cells by cardiotoxin III. 1576 81

Tumor microenvironment, which is characterized by hypoxia, low-glucose concentrations, high-lactate concentrations, low-extracellular pH, can alter the therapeutic response in tumors. In this study, we investigated whether hypoxia affects TRAIL-induced apoptotic death. When human prostate adenocarcinoma DU-145 cells were treated with 50 ng/mL TRAIL or hypoxia for 4 h, the survival was 45.7 and 32.5%, respectively. The combination of TRAIL and hypoxia synergistically increased cell death. Similar results were observed in human prostate adenocarcinoma LNCaP cells. Western blot analysis showed that the hypoxia augmented TRAIL-induced PARP cleavage as well as the activation of caspase-8 and caspase-3, but not caspase-9. Unlike hypoxia, low glucose promoted caspase-9 activation during TRAIL treatment. These results suggest that hypoxia or low glucose-augmented TRAIL cytotoxicity is mediated through the mitochondria-independent pathway or -dependent pathway, respectively.
 ...
PMID:Hypoxia and low glucose differentially augments TRAIL-induced apoptotic death. 1579 57

We previously found that a change in the balance between mitochondrial pro- and anti-apoptotic proteins caused by ectopic expression of the Bax gene led to increased induction of apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To investigate whether a similar effect can be elicited by down-regulating Bcl-X(L), an anti-apoptotic protein, we tested the effects of a small interfering RNA (siRNA) specific for Bcl-X(L) in TRAIL-resistant cells. The down-regulation of Bcl-X(L) by siRNA inhibited cell proliferation and sensitized TRAIL-induced apoptosis in human cancer cells with both acquired and intrinsic TRAIL resistance. Combining the Bcl-X(L) siRNA with TRAIL protein treatment resulted in an increase in the percentage of apoptotic cells and increased cleavage of caspase-8, caspase-9, caspase-3 and PARP. Furthermore, the release of cytochrome c but not Smac from mitochondria was induced by Bcl-X(L) siRNA alone, and this release was dramatically amplified by combining the Bcl-X(L) siRNA and TRAIL protein treatment. Together, our data suggest that simultaneous triggering of the death receptor and mitochondrial apoptotic pathways leads to enhanced induction of apoptosis, which makes it potentially useful for the treatment of resistant cancers.
 ...
PMID:Enhancing TRAIL-induced apoptosis by Bcl-X(L) siRNA. 1590 90

Flaviviruses such as dengue virus (DEN) and Japanese encephalitis virus (JEV) are medically important in humans. The lipid kinase, phosphatidylinositol 3-kinase (PI3K) and its downstream target Akt have been implicated in the regulation of diverse cellular functions such as proliferation, and apoptosis. Since JEV and DEN appear to trigger apoptosis in cultured cells at a rather late stage of infection, we evaluated the possible roles of the PI3K/Akt signaling pathway in flavivirus-infected cells. We found that Akt phosphorylation was noticeable in the JEV- and DEN serotype 2 (DEN-2)-infected neuronal N18 cells in an early, transient, PI3K- and lipid raft-dependent manner. Blocking of PI3K activation by its specific inhibitor LY294002 or wortmannin greatly enhanced virus-induced cytopathic effects (CPEs), even at an early stage of infection, but had no effect on virus production. This severe CPE was characterized as apoptotic cell death as evidenced by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining and cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Mechanically, the initiator and effector caspases involved are mainly caspase-9 and caspase-6, since only a pan-caspase inhibitor and the inhibitors preferentially target caspase-9 and -6, but not the ones antagonizing caspase-8, -3, or -7 alleviated the levels of PARP cleavage after virus infection and PI3K blockage. Furthermore, Bcl-2 appears to be a crucial mediator downstream of PI3K/Akt signaling, since overexpression of Bcl-2 reduced virus-induced apoptosis even when PI3K activation was repressed. Collectively, our results suggest an anti-apoptotic role for the PI3K/Akt pathway triggered by JEV and DEN-2 to protect infected cells from early apoptotic cell death.
 ...
PMID:Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection. 1595 83

DNA damaging chemotherapeutic agents like carboplatin (Carb) and 5-fluorouracil (5-FU), whose effects are mediated through diverse intracellular targets, induce apoptosis in various cancer cells including human papillomavirus (HPV) positive HEp-2 and KB cells. The present work reports the involvement of Bcl-2 in response to the exposure of HEp-2 and KB cells to Carb or 5-FU. We demonstrate that both these drugs are potent inducers of apoptosis. Apoptosis was preceded by decrease in Bcl-2 protein level accompanied by caspase-9 activation and poly(ADP-ribose) polymerase (PARP) cleavage without altering Bax expression. Further analysis revealed down-regulation of Bcl-2 mRNA as well as protein in drugs treated cells. Ectopic expression of Bcl-2 protected cells against drugs mediated DNA damage-induced apoptosis. Overall, data indicates that genotoxic stress leads to down-regulation of Bcl-2 in HEp-2 and KB cells, which plays a decisive role in the outcome of stress in these cells.
 ...
PMID:DNA damaging drugs-induced down-regulation of Bcl-2 is essential for induction of apoptosis in high-risk HPV-positive HEp-2 and KB cells. 1599 12

The present in vitro study demonstrates the effect of androgen on thymocyte apoptosis leading to thymic atrophy in the wall lizard, Hemidactylus flaviviridis. Thymocytes collected from castrated lizards were incubated with varying concentrations of dihydrotestosterone (DHT) to observe its effect on proliferation and apoptosis. DHT treatment reduced the tritiated thymidine incorporation in thymocytes, suggesting that androgen directly inhibits thymocyte proliferation. It also caused apoptosis of thymocytes effectively at 10(-7)M. However, the increased apoptotic action of DHT was indirectly mediated through thymic epithelial cell-rich stromal cell components (TEC). This observation was reaffirmed by in vitro incubation of thymocytes with DHT-pretreated TEC-conditioned medium. However, the DHT-induced TEC-secreted apoptotic factors could induce thymocyte DNA fragmentation only when DHT was added to the conditioned medium. It implies that DHT priming of thymocytes is required for the apoptotic effect of DHT-induced TEC-secreted factor. DHT-induced thymocyte apoptosis was found to be caspase-dependent since it activated the initiator (caspase-9) and effector caspases (caspases-3 and -7) as well as cleaved the enzyme substrate poly(ADP-ribose) polymerase (PARP). Further, the apoptotic effect of DHT was routed through its classical receptors, as non-steroidal antiandrogen flutamide blocked the DHT-induced thymocyte apoptosis. The inhibition of apoptosis by transcription/translation inhibitors further substantiates the genomic pathway of DHT action. It can be concluded that DHT, in addition to inhibiting thymocyte proliferation directly, accelerates caspase-dependent apoptotic process in thymocytes indirectly through TEC via a genomic pathway. Nevertheless, the priming of thymocytes with DHT is required for the apoptotic effect of TEC-secreted factor.
 ...
PMID:Mechanism of androgen-induced thymic atrophy in the wall lizard, Hemidactylus flaviviridis: an in vitro study. 1600 99

Adenosine triphosphate (ATP) has been shown to induce programmed cell death in various systems. However, little is known about the effect of ATP on human granulosa-luteal cells (hGLCs). The present study was designed to examine the effect of ATP on the activation of the caspase signaling pathway and its role in inducing programmed cell death. Human GLCs were collected from patients undergoing in vitro fertilization programs, and then were cultured in FBS-supplemented DMEM for 3 days prior to our studies. To examine the dose-response relationship, hGLCs were treated with increasing concentrations of ATP (10 microM, 100 microM, 1 mM or 10 mM) for 24 hours. For time-course experiments, hGLCs were treated with 10 mM ATP for 6, 12, or 24 hours. Western blot analysis was performed using antibodies against the pro- and active forms of caspase-3, -9, or PARP. To quantify the induction of apoptosis, DNA fragmentation was measured using the cell death detection enzyme-linked immunosorbent assay. To examine the effect of human chorionic gonadotropin (hCG) in protecting cells from apoptosis, hGLCs were treated with 10 IU hCG in the presence of 10 mM ATP for 12 hours. It was demonstrated that ATP was capable of inducing DNA fragmentation in a dose- and time-dependent manner. Furthermore, Western blot analysis, which detected the pro- and active forms of caspase-3, or PARP, demonstrated that ATP activated the caspase-signaling pathway, leading to the proteolytic conversion of pro-caspase-3 to active caspase-3, and the subsequent cleavage of the caspase substrate PARP. Based on our observation, caspase-9 was not triggered by ATP. Interestingly, hCG attenuated the effect of ATP in activating the caspase signaling pathway. To our knowledge, this is the first demonstration of the ATP-induced activation of the caspase signaling pathway in the human ovary. These results support the notion that the caspase-signaling pathway is involved in mediating ATP actions in the human ovary.
 ...
PMID:Adenosine triphosphate induces activation of caspase-3 in apoptosis of human granulosa-luteal cells. 1600 27

Flavopiridol and UCN-01 are two novel protein kinase inhibitors with diverse cellular effects that may complement each other with regards to induction of apoptosis. HeLa cells engineered to overexpress human survivin (HeLa-S) were at least approximately 4.8-fold resistant to UCN-01 relative to proliferation observed in control HeLa cells (HeLa-V). Flavopiridol cytotoxicity as measured using the MTT assay was unaffected in HeLa-S cells when compared with HeLa-V cells. Similarly, simultaneous treatment of HeLa-V cells with flavopiridol and UCN-01 for 72 hours did not result in synergistic inhibition of proliferation; however, in HeLa-S cells, this combination resulted in synergistic inhibition of cell proliferation. Flavopiridol and UCN-01 augmented apoptosis in HeLa-S cells (as compared with HeLa-V cells) as measured by caspase-3 cellular activity assay, DNA fragmentation and PARP cleavage by western blot. In HeLa-V and -S cells, combination treatment resulted in caspase-8 cleavage. Caspase-9 was expressed in HeLa-V cells; however, there was a marked reduction of caspase-9 content in HeLa-S cells only. Combination treatment resulted in a significant reduction in survivin abundance in HeLa-S and SKBR3-UR cells, but not in their respective parental lines. The synergy of Flavopiridol and UCN-01 are selectively toxic to survivin-overexpressing cell lines and the mechanism of toxicity involves caspase-dependent cell death.
 ...
PMID:A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines. 1601 89


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