Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the in vitro effect of trichostatin (histone deacetylase inhibitor) on cell proliferation, cell cycle regulation and apoptosis in renal cell carcinoma cell lines. Trichostatin significantly inhibited the proliferation of all six cell lines examined in dose-dependent manner with IC50 of about 125-250 nM. Trichostatin (72-h incubation) induced a G1 phase arrest in ACHN, Caki-1, Caki-2 and Renca cell lines and a G2-M phase arrest in A498 cells. When we examined the effects of this drug on ACHN cells, trichostatin decreased the levels of CDK4, CDK6, cyclin D1 and cyclin A proteins. p27 protein was increased by trichostatin. In addition, trichostatin markedly enhanced the binding of p27 with CDK2 and CDK4. Furthermore, the activities of CDK2, CDK4- and CDK6-associated kinase were reduced and the lack of the CDK activity was paralleled by increased hypophosphorylation of Rb protein. Trichostatin also induced apoptosis in all the renal cell carcinoma cell lines. Apoptotic process of ACHN cells was associated with the changes of Bcl-2, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (deltapsim) loss. Taken together, these results demonstrate that trichostatin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
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PMID:Trichostatin inhibits the growth of ACHN renal cell carcinoma cells via cell cycle arrest in association with p27, or apoptosis. 1268 81

Pentagalloylglucose (5GG) is a potent and specific inhibitor of NADPH dehydrogenase or xanthine oxidase. In our previous study, we showed that 5GG was able to induce apoptosis in HL-60 cells in a time- and concentration-dependent manner via the activation of caspase-3. Recently, we found that 5GG was capable of perturbing the cell cycle of the human breast cancer cell line MCF-7. DNA flow cytometric analysis showed that 5GG exhibited the ability of blocking MCF-7 cell cycle progression at the G1 phase. The level of several G1 phase-related cyclins and cyclin-dependent kinases did not change in these cells during a 24-hr exposure to 5GG. However, the activity of cyclin E/CDK2 was decreased in a concentration- and time-dependent manner and the activity of cyclin D/CDK4 was inhibited when serum-starved synchronized cells were released from synchronization. p27(Kip) and p21(Cip), inhibitors of cyclin/CDK complexes in G1-phase, were gradually increased after 5GG treatment in a time-dependent manner and the induction of p21(Cip) was correlated with an increase in p53 levels. These results suggest that the suppression of cell-cycle progression in the G1 phase by 5GG was mediated in MCF-7 cells, at least in part, by either the inhibition of cyclin D/CDK4 and cyclin E/CDK2 activity or the induction of the CDK inhibitors p27(Kip) and p21(Cip).
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PMID:Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). 1278 29

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

Flavopiridol was developed as a drug for cancer therapy due to its ability to inhibit cell cycle progression by targeting cyclin-dependent kinases (CDKs). In this study, we show that flavopiridol may also have a neuroprotective action. We show that at therapeutic dosage (or at micromolar range), flavopiridol almost completely prevents colchicine-induced apoptosis in cerebellar granule neurones. In agreement with this, flavopiridol inhibits both the release of cyt c and the activation of caspase-3 induced in response to colchicine treatment. We demonstrate that in this cellular model for neurotoxicity, neither re-entry in the cell cycle nor activation of stress-activated protein kinases, such as c-Jun N-terminal kinase (JNK) or p38 MAP kinase, is involved. In contrast, we show that colchicine-induced apoptosis correlates with a substantial increase in the expression of cdk5 and Par-4, which is efficiently prevented by flavopiridol. Accordingly, a cdk5 inhibitor such as roscovitine, but not a cdk4 inhibitor such as 3-ATA, was also able to protect neurons from apoptosis as well as prevent accumulation of cdk5 and Par-4 in response to colchicine. Our data suggest a potential therapeutic use of flavopiridol in disorders of the central nervous system in which cytoskeleton alteration mediated by cdk5 activation and Par-4 expression has been demonstrated, such as Alzheimer's disease.
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PMID:Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. 1294 80

beta-Phenylethyl isothiocyanate (PEITC) is a promising chemoprotective compound that is routinely consumed in the diet as its glucosinolate precursor. Previous studies have shown that PEITC can inhibit phase I enzymes and induce phase II detoxification enzymes along with apoptosis in vitro. The detailed mechanisms involved in the apoptotic cascade, however, have not been elucidated. In the present study, we demonstrate that PEITC can induce apoptosis in hepatoma HepG2 cells in a concentration- and time-dependant manner as determined by TUNEL positive and SubG1 population analysis. Caspase-3-like activity and poly(ADP-ribosyl)polymerase cleavage increased during treatment with 20 microM PEITC; high concentrations, however, induced necrosis. Pre-treatment with Z-VAD-FMK and the caspase-3-specific inhibitor Ac-DEVD-CHO prevented PEITC-induced apoptosis, as determined by caspase-3-like activity and DNA fragmentation. Additional investigations also showed that at concentrations of 5-10 microM PEITC, DNA synthesis was inhibited and G2/M phase cell cycle arrest occurred, correlating with an alteration in cyclin B1 and p34(cdc2) protein levels. Furthermore, we also demonstrate a concentration- and time-dependant burst of superoxide (O2*-) in PEITC-treated cells. However, pre- and co-treatment with the free radical scavengers Trolox, ascorbate, mannitol, uric acid and the superoxide mimetic manganese (III) tetrakis (N-methyl-2-pyridyl) porphyrin failed to prevent PEITC-mediated apoptosis. Taken together, these results suggest that PEITC potently induces apoptosis and cell cycle arrest in HepG2 cells and that the generation of reactive oxygen species appears to be a secondary effect.
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PMID:beta-Phenylethyl isothiocyanate-mediated apoptosis in hepatoma HepG2 cells. 1294 35

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-PGJ2) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR-gamma-dependent manner. PPAR-gamma was expressed in these cells, and 15-deoxy-PGJ2 increased expression, DNA binding activity, and transcriptional activity of PPAR-gamma. 15-Deoxy-PGJ2 also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G2/M phase after 15-deoxy-PGJ2 treatment with concomitant increase in the expression of G2/M phase regulatory protein cyclin B1 but decrease in the expression of cdk2, cdk4, cyclin A, cyclin D1, cyclin E, and cdc25C. Conversely, related to the growth inhibitory effect, 15-deoxy-PGJ2 increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ2 increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ2 also activated extracellular signal-regulated kinase (ERK) 2. In addition, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (2'-amino-3'-methoxyflavone) decreased 15-deoxy-PGJ2-induced ERK2 activation, and expression of PPAR-gamma, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ2-induced cell growth inhibition. We also found that PPAR-gamma antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ2-induced cell growth inhibition, PPAR-gamma expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ2 inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR-gamma-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ2 may have promising application as a therapeutic agent for neuroblastoma.
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PMID:Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway. 1296 53

We first report the mechanism for the inhibitory effect of the lysine analog, thialysine on human acute leukemia Jurkat T cells. When Jurkat T cells were treated with thialysine (0.32-2.5 mM), apoptotic cell death along with several biochemical events such as mitochondrial cytochrome c release, caspase-9 activation, caspase-3 activation, degradation of poly (ADP-ribose) polymerase, and DNA fragmentation was induced in a dose- and time-dependent manner. However, these thialysine-induced apoptotic events were significantly abrogated by an ectopic expression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also suppressed thialysine-induced apoptotic events. Comparison of the thialysine-induced alterations in the cell cycle distribution between Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat T cells transfected with vector (J/Neo) revealed that the apoptotic cells were mainly derived from the cells accumulated in S and G2/M phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A, cyclin B1, and cyclin E. These results demonstrate that the cytotoxic activity of thialysine toward Jurkat T cells is attributable to not only apoptotic cell death mediated by a mitochondria-dependent death signaling pathway, but also interruption of cell cycle progression by a massive down-regulation in the level of cdks and cyclins.
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PMID:Mechanism underlying cytotoxicity of thialysine, lysine analog, toward human acute leukemia Jurkat T cells. 1463 87

Interactions between the histone deacetylase inhibitors (HDACIs) suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino-17-demethoxygeldanamycin (17-AAG) have been examined in human leukemia cells (U937). Coadministration of marginally toxic concentrations of 17-AAG with sublethal concentrations of SB or SAHA resulted in highly synergistic induction of mitochondrial damage (i.e., cytochrome c release), caspase-3 and -8 activation, and apoptosis. Similar interactions were noted in human promyelocytic (HL-60) and lymphoblastic (Jurkat) leukemia cells. These events were accompanied by multiple perturbations in signal transduction, cell cycle, and survival-related pathways, including early down-regulation of Raf-1, inactivation of extracellular signal-regulated kinase (ERK) 1/2 and mitogen-activated protein/ERK kinase (MEK) 1/2, diminished expression of phospho-Akt, and late activation of c-Jun-NH(2)-terminal kinase, but no changes in expression of phospho-p38 mitogen-activated protein kinase. Coadministration of 17-AAG blocked SAHA-mediated induction of the cyclin-dependent kinase inhibitor p21(CIP1) and resulted in reduced expression of p27(KIP1) and p34(cdc2). 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic protein Mcl-1 and evidence of Bcl-2 cleavage. Enforced expression of doxycycline-inducible p21(CIP1) or constitutively active MEK1 significantly diminished 17-AAG/SAHA-mediated lethality, indicating that interference with ERK activation and p21(CIP1) induction play important functional roles in the lethal effects of this regimen. In contrast, enforced expression of constitutively active Akt failed to exert cytoprotective actions. Together, these findings indicate that coadministration of SAHA or SB with the Hsp90 antagonist 17-AAG in human leukemia cells leads to multiple perturbations in signaling, cell cycle, and survival pathways that culminate in mitochondrial injury and apoptosis. They also raise the possibility that combining such agents with Hsp90 antagonists may represent a novel antileukemic strategy.
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PMID:Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. 1467 5

Human cytomegalovirus (HCMV) has many strategies to survive the attack of the host. HCMV infection of host cells induces cellular activation and disturbance of the cell cycle. It is possible that HCMV modulates the behavior of certain cancer cells that are susceptible to HCMV infection. This study was performed to identify the possible mechanism of resistance to apoptotic stimuli in some cancer cell lines by HCMV infection. HCMV-infected cancer cells showed resistance to apoptosis induced by the topoisomerase II inhibitor etoposide. UMG1-2, which constitutively expresses HCMV immediate-early protein-1 (IE1), had resistance to apoptosis induced by etoposide as compared with the parental cell line U373MG. Measurement of caspases activity with fluorogenic substrates in etoposide-treated U373MG and UMG1-2 cells and the direct activation of caspase-3 with peptides containing arginine-glycine-aspartate in U373MG and UMG1-2 cells revealed that the inhibition level of apoptosis by HCMV IE1 would be upstream of caspase-3 in the caspase cascade pathway. Cellular expression of Cdk2 was increased in UMG1- 2 after etoposide treatment while the expression of E2F-1 in UMG1-2 was decreased as compared with that in U373MG. The Cdk2 inhibitor, roscovitine, decreased the resistance to apoptosis on etoposide-treated UMG1-2. These results suggest that aberrant HCMV infection confers resistance to anticancer drugs on some cancer cells and protects cells from apoptosis, possibly due to the deregulation of cyclin-dependent kinase by HCMV immediate-early protein.
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PMID:Human cytomegalovirus (HCMV) IE1 plays role in resistance to apoptosis with etoposide in cancer cell line by Cdk2 accumulation. 1469 46

A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells. At 20 microM, Roscovitine induced apoptosis in 21 of 28 B-CLL samples and was equally effective in zap-70-positive or -negative samples. Caspase-3 was cleaved in B-CLL cells exposed to Roscovitine and the pancaspase inhibitor z.VAD.fmk-blocked Roscovitine-induced apoptosis. Expression of the proapoptotic protein Bak was increased and Bax cleavage and conformational change was observed in Roscovitine-treated B-CLL cells. Antiapoptotic proteins Mcl-1 and XIAP were downregulated, but the expression of Bcl-2 remained unchanged. In contrast to previous reports in cancer cell lines, Roscovitine treatment was not accompanied by nuclear accumulation of p53. Cyc202 (R-Roscovitine) is in early clinical trials in cancer patients. Given its powerful effects on zap-70-positive and -negative B-CLL cells, but not on normal lymphocytes, Roscovitine might be an attractive drug to be tested in this incurable disease.
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PMID:Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. 1497 97


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