Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between proteasome and cyclin-dependent kinase inhibitors have been examined in human leukemia cells in relation to induction of apoptosis. Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 nM flavopiridol and 300 nM MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c, Smac/DIABLO release, loss of deltaPsi(m)), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential. Similar effects were observed with other proteasome inhibitors (e.g., Bortezomib (VELCADE trade mark bortezomib or injection), lactacystin, LLnL) and cyclin-dependent kinase inhibitors (e.g., roscovitine), as well as other leukemia cell types (e.g., HL-60, Jurkat, Raji). In U937 cells, synergistic interactions between MG-132 and flavopiridol were associated with multiple perturbations in expression/activation of signaling- and survival-related proteins, including downregulation of XIAP and Mcl-1, activation of JNK and p34(cdc2), and diminished expression of p21(CIP1). The lethal effects of MG-132/flavopiridol were not reduced in leukemic cells ectopically expressing Bcl-2, but were partially attenuated in cells ectopically expressing dominant-negative caspase-8 or CrmA. Flavopiridol/proteasome inhibitor-mediated lethality was also significantly diminished by agents and siRNA blocking JNK activation. Lastly, coadministration of MG-132 with flavopiridol resulted in diminished DNA binding of NF-kappaB. Notably, pharmacologic interruption of the NF-kappaB pathway (e.g., by BAY 11-7082, PDTC, or SN-50) or molecular dysregulation of NF-kappaB (i.e., in cells ectopically expressing an IkappaBalpha super-repressor) mimicked the actions of proteasome inhibitors in promoting flavopiridol-induced mitochondrial injury, JNK activation, and apoptosis. Together, these findings indicate that proteasome inhibitors strikingly lower the apoptotic threshold of leukemic cells exposed to pharmacologic CDK inhibitors, and suggest that interruption of the NF-kappaB cytoprotective pathway and JNK activation both play key roles in this phenomenon. They also raise the possibility that combining proteasome and CDK inhibitors could represent a novel antileukemic strategy.
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PMID:Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. 1456 39

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

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.
Leukemia 2004 Apr
PMID:Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. 1497 97

Previous studies demonstrated that hydroxyl groups play important roles in the antioxidative activities of flavonoids; however, the importance of structurally related hydroxylation in their apoptosis-inducing activities is still undefined. In the present study, flavanone with hydroxylation at C4' and C6 had a significant cytotoxic effect in human leukemia HL-60 cells accompanied by the occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells, characteristics of apoptosis. The replacement of a hydroxyl group (OH) by a methoxyl (OCH3) group at C4' or C6 attenuated the apoptotic effect in cells, and there was no significant cytotocity of flavanone or flavanone with OH or OCH3 in C7-treated HL-60 cells. Induction of enzyme activity of caspase-3 and -9, but not caspase-1 and -8, accompanied by release of cytocrome C from mitochondria to cytosol and the appearance of cleaved of PARP (85 kDa), D4-GDI (23 kDa), and caspase-3 (p17/p15) fragments, was identified in 4'-OH- or 6-OH- flavanone-treated HL-60 cells. Caspase-3 and -9 inhibitors Ac-DEVD-FMK and Ac-LEHD-FMK, but not caspase-1 and -8 inhibitors Ac-YVAD-FMK and Ac-LETD-FMK, attenuated 4'-OH- or 6-OH-flavanone-induced cell death. And, inhibition of capsase-9 activity by Ac-LEHD-FMK suppresses caspase-3 protein procession induced by 4'-OH- and 6-OH-flavanone, indicative of caspase-9 activation locating upstream of caspase-3. A decrease in the antiapoptotic protein Mcl-1 and increases in the pro-apoptotic proteins Bax and Bad were found in 4'-OH- or 6-OH-flavanone-treated HL-60 cells. Induction of endogenous ROS production was detected in 4'-OH- or 6-OH-flavanone-treated HL-60 cells by the DCHF-DA assay. Antioxidants such as N-acetylcysteine (NAC), catalase (CAT), superoxide dismutase (SOD), and allopurinol (ALL), but not pyrrolidine dithiocarbamate (PDTC) or diphenylene iodonium (DPI), significantly inhibited 4'-OH- or 6-OH-flavanone-induced ROS production, with blocking of the apoptosis induced by 4'-OH- or 6-OH-flavanone. The apoptosis-inducing activity of 4'-OH- or 6-OH-flavanone was also observed in another leukemia cell line (Jurkat), but was not found in mature monocytic cells (THP-1) and normal human polymorphonuclear neutrophils (PMNs). This suggests that hydroxylation at C4' or C6 is important to the apoptosis-inducing activities of flavanone through ROS production, and that activation of the caspase-3 cascade, downstream of caspase-9 activation, is involved.
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PMID:Hydroxylation at C4' or C6 is essential for apoptosis-inducing activity of flavanone through activation of the caspase-3 cascade and production of reactive oxygen species. 1501 74

Interactions between the novel benzamide histone deacetylase (HDAC) inhibitor MS-275 and fludarabine were examined in lymphoid and myeloid human leukemia cells in relation to mitochondrial injury, signal transduction events, and apoptosis. Prior exposure of Jurkat lymphoblastic leukemia cells to a marginally toxic concentration of MS-275 (e.g., 500 nM) for 24 h sharply increased mitochondrial injury, caspase activation, and apoptosis in response to a minimally toxic concentration of fludarabine (500 nM), resulting in highly synergistic antileukemic interactions and loss of clonogenic survival. Simultaneous exposure to MS-275 and fludarabine also led to synergistic effects, but these were not as pronounced as observed with sequential treatment. Similar interactions were noted in the case of (a) other human leukemia cell lines (e.g., U937, CCRF-CEM); (b) other HDAC inhibitors (e.g., sodium butyrate); and (c) other nucleoside analogues (e.g., 1-beta-D-arabinofuranosylcytosine, gemcitabine). Potentiation of fludarabine lethality by MS-275 was associated with acetylation of histones H3 and H4, down-regulation of the antiapoptotic proteins XIAP and Mcl-1, enhanced cytosolic release of proapoptotic mitochondrial proteins (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor), and caspase activation. It was also accompanied by the caspase-dependent down-regulation of p27(KIP1), cyclins A, E, and D(1), and cleavage and diminished phosphorylation of retinoblastoma protein. However, increased lethality of the combination was not associated with enhanced fludarabine triphosphate formation or DNA incorporation and occurred despite a slight reduction in the S-phase fraction. Prior exposure to MS-275 attenuated fludarabine-mediated activation of MEK1/2, extracellular signal-regulated kinase, and Akt, and enhanced c-Jun NH(2)-terminal kinase phosphorylation; furthermore, inducible expression of constitutively active MEK1/2 or Akt significantly diminished MS-275/fludarabine-induced lethality. Combined exposure of cells to MS-275 and fludarabine was associated with a significant increase in generation of reactive oxygen species; moreover, both the increase in reactive oxygen species and apoptosis were largely attenuated by coadministration of the free radical scavenger L-N-acetylcysteine. Finally, prior administration of MS-275 markedly potentiated fludarabine-mediated generation of the proapoptotic lipid second messenger ceramide. Taken together, these findings indicate that the HDAC inhibitor MS-275 induces multiple perturbations in signal transduction, survival, and cell cycle regulatory pathways that lower the threshold for fludarabine-mediated mitochondrial injury and apoptosis in human leukemia cells. They also provide insights into possible mechanisms by which novel, clinically relevant HDAC inhibitors might be used to enhance the antileukemic activity of established nucleoside analogues such as fludarabine.
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PMID:The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. 1505 16

Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitors (HDACIs) sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) have been examined in human leukemia cells in relation to effects on nuclear factor kappaB (NF-kappaB) activation. Exposure (24 h) of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 microM) resulted in a marked increase in NF-kappaB DNA binding, effects that were essentially abrogated by coadministration of flavopiridol (100 nM). These events were accompanied by a marked increase in mitochondrial injury, caspase activation, and apoptosis. Mutant cells expressing an IkappaBalpha super-repressor exhibited impairment of NF-kappaB DNA binding in response to HDACIs and a significant although modest increase in apoptosis. However, disruption of the NF-kappaB pathway also increased mitochondrial injury and caspase activation in response to flavopiridol and to an even greater extent to the combination of flavopiridol and HDACIs. Coadministration of flavopiridol with HDACIs down-regulated the X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p21CIP1/WAF1 and activated c-Jun NH2-terminal kinase; moreover, these effects were considerably more pronounced in IkappaBalpha mutants. Similar responses were observed in U937 mutant cells stably expressing RelA/p65 small interfering RNA. In all cases, flavopiridol was significantly more potent than genetic interruption of the NF-kappaB cascade in promoting HDACI-mediated lethality. Together, these findings are consistent with the notion that although inhibition of NF-kappaB activation by flavopiridol contributes to antileukemic interactions with HDACIs, other NF-kappaB-independent flavopiridol actions (e.g., down-regulation of Mcl-1, XIAP, and p21CIP1/WAF1) play particularly critical roles in this phenomenon.
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PMID:Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol. 1523 3

The canine Mcl-1 gene was cloned and sequenced. Canine Mcl-1 clone was 2694 base pairs in length and encoded 350 amino acids. The predicted amino acid sequence was 87.7%, 77.1% and 75.7% homologous to predicted human, mouse and rat Mcl-1, respectively. RT-PCR analysis revealed that canine Mcl-1 mRNA was expressed in PBMCs (peripheral blood mononuclear cells), bone marrow cells, MDCK (Madin-Darby canine kidney) and GL-1 (canine B cell leukemia) whereas undetectable in CL-1 (canine T cell lymphoma) cell line.
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PMID:Molecular cloning of canine Mcl-1 gene and its expression in tumor cell lines. 1524 Sep 48

Bryostatin, a macrocyclic lactone and protein kinase C (PKC) modulator, has been shown to have differentiation and anti-tumor activity against several leukemia cell lines in vitro. In this study, we demonstrated Bryostatin-induced differentiation in B-cell chronic lymphocytic leukemia (B-CLL) cells, characterized by an increase in cell size and a marked up-regulation of CD11c expression. The specific inhibitors of the extracellular signal-regulated kinase (ERK) and protein kinase C pathways, PD98059 and GF 109203X respectively, each completely blocked Bryostatin-induced differentiation of B-CLL cells, suggesting that activation of the ERK pathway plays a direct role in this process in a PKC-dependent manner. Furthermore, Bryostatin reduced both spontaneous and drug-induced apoptosis with chlorambucil, fludarabine and 2-chloro-2'-deoxyadenosine (2-Cda) in B-CLL cells. This resistance was associated with an early up-regulation of the anti-apoptotic protein Mcl-1 and post-translational phosphorylation of Bcl-2 at serine 70. The anti-apoptotic effects of Bryostatin were abrogated by GF 109203X, and to a lesser extent by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002. Interestingly, the ERK inhibitor, PD98059 inhibited Mcl-1 expression but had little effect on Bryostatin-induced survival suggesting that the ERK pathway predominantly affects differentiation. Taken together these results present an explanation for Bryostatin-induced B-CLL cell survival in which modulation of the PKC pathway couples differentiation with an increase in antiapoptotic protein expression and calls into question the rationale for its use in the treatment of B-CLL.
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PMID:Bryostatin induces protein kinase C modulation, Mcl-1 up-regulation and phosphorylation of Bcl-2 resulting in cellular differentiation and resistance to drug-induced apoptosis in B-cell chronic lymphocytic leukemia cells. 1529 60

B-cell chronic lymphocytic leukemia (B-CLL) cells develop resistance to nucleoside analogs over time. This chemoresistance may be caused by selection for B-CLL cells with defects in the particular apoptosis pathway triggered by these drugs. Therefore, anticancer agents that induce apoptosis through alternative pathways might be useful in treating chemoresistant B-CLL. Farnesyltransferase inhibitors (FTIs) are a class of synthetic drugs with definite molecular targets, which have demonstrated cytotoxicity against leukemic cell lines. We have studied the ex vivo effect of the FTI BMS-214662 on cells from 18 patients with B-CLL. Low concentrations (<1 microM) of BMS-214662 prevented farnesylation of the chaperone marker HDJ-2 and had no effect on Akt activation. BMS-214662 induced apoptosis in B-CLL cells from all patients studied, including those showing resistance to cladribine and fludarabine ex vivo and in vivo. Treatment with BMS-214662 induced loss of mitochondrial membrane potential (DeltaPsi(m)), phosphatidylserine exposure, proapoptotic conformational changes of Bax and Bak, reduction in Mcl-1 levels and activation of caspases 9 and 3. The general caspase inhibitor Z-VAD-fmk did not prevent BMS-214662-induced cell death. These results indicate that BMS-214662 may be a useful drug for treating B-CLL and, in particular, an alternative for the therapy of purine analog-resistant or relapsed B-CLL.
Leukemia 2004 Oct
PMID:Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells. 1535 56

Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x(L), or a phosphorylation loop-deleted form of Bcl-2 (DeltaBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FP-mediated XIAP downregulation.
Leukemia 2004 Nov
PMID:Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. 1538 34


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