Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells

Rosato, Roberto R.; Almenara, Jorge A.; Maggio, Sonia C.; Atadja, Peter; Craig, Ruth W.; Vrana, Julie A.; Dent, Paul; Grant, Steven

doi:10.1158/1535-7163.mct-05-0157

Cited by 25 publications

(16 citation statements)

References 53 publications

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“…S1). Earlier investigations have suggested links between cdc2, survivin, and TRAIL sensitivity (39,(42)(43)(44)(45), and we found that these were clearly operational in colon carcinoma in which the CDK inhibitor flavopiridol provokes reductions in survivin expression and enhances lexatumumabinduced apoptosis independent of p21. Investigation of the efficacy of lexatumumab in combination with SAHA or flavopiridol in colon cancer xenograft models in vivo are planned as a follow-up to the current study.…”

Section: Discussionsupporting

confidence: 60%

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Nawrocki¹,

Carew

Leslie³

et al. 2007

Cancer Research

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumabinduced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21 +/+ cells but not in the HCT116 p21 À/À cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab. [Cancer Res 2007;67(14):6987-94]

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Section: Discussionsupporting

confidence: 60%

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Nawrocki¹,

Carew

Leslie³

et al. 2007

Cancer Research

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“…In addition, when administered alone, roscovitine failed to exert an inhibitory effect on XIAP or Mcl-1 mRNA levels, whereas flavopiridol was very effective in this regard. Moreover, coexposure to roscovitine and NVP-LAQ-824 had no inhibitory effect on Mcl-1 transcription; instead, downregulation of this protein was principally caspase dependent (13). In contrast, in flavopiridol/vorinostat -treated cells, Mcl-1 down-regulation chiefly occurred at the transcriptional level but was enhanced by caspase-mediated degradation.…”

Section: Discussionmentioning

confidence: 90%

“…U937 cells stably expressing XIAP or Mcl-1 and their empty vector counterparts were obtained as reported previously (7,13). All experiments used cells in logarithmic phase at 2.5 Â 10 5 /mL.…”

Section: Methodsmentioning

confidence: 99%

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Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions

Rosato

Almenara

Kolla

et al. 2007

Molecular Cancer Therapeutics

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The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclindependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-KB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from flavopiridol/vorinostat -mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/vorinostat -mediated transcriptional repression of XIAP, Mcl-1 -enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials. [Mol Cancer Ther 2007;6(2):692 -702]

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“…In addition, given data from several groups indicating that MS-275 as a single agent or combined with other anti-tumor agents generates reactive oxygen species (ROS) in certain tumor cell lines (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), the potentiation of ROS with the combined exposure was studied. Our findings show that the production of ROS in AML and ALL cells is an indicator for the synergistic, cytotoxic effects of MS-275 and 5-azacytidine.…”

Section: Introductionmentioning

confidence: 99%

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Gao¹,

Mobley²,

Miller³

et al. 2008

Leukemia Research

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Epigenetic modifiers are currently in clinical use for various tumor types. Recently, numerous studies supporting the combination of histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors have emerged, encouraging early clinical trials of these agents together. Here we show that MS-275, an HDACi, and 5-azacytidine, a methyltransferase inhibitor, display synergistic cytotoxicity and apoptosis in AML and ALL cells. Intracellular production of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, is a novel marker for this synergism in ALL cells. These data suggest that assessment of oxidative stress can serve as a marker of the concerted action of MS-275 and 5-azacytidine.

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Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells

Cited by 25 publications

References 53 publications

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

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