This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, C. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Yu, C. Articles by Grant, S.

Histone Deacetylase Inhibitors Promote STI571-mediated Apoptosis in STI571-sensitive and -resistant Bcr/Abl⁺ Human Myeloid Leukemia Cells¹

Departments of Medicine [C. Y., M. R., J. A., G. K., S. G.], Microbiology [G. K., D. C., S. G.], Human Genetics [M. S.], Pharmacology [S. G.], and Radiation Oncology [P. D.], Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts [L. V.]

Interactions between the Bcr/Abl kinase inhibitor STI571 (Gleevec, imatinib mesylate) and histone deacetylase inhibitors (HDIs) have been examined in STI571-sensitive and -resistant Bcr/Abl⁺ human leukemia cells (K562 and LAMA 84). Cotreatment of K562 cells with 250 nM imatinib mesylate and 2.0 µM suberoylanilide hydroxamic acid (SAHA) for 24 h, exposures that were minimally toxic alone, resulted in a marked increase in mitochondrial damage (e.g., cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), caspase activation, and apoptosis. Similar events were observed in other Bcr/Abl⁺ cells (i.e., LAMA 84), and in cells exposed to STI571 in combination with the HDI sodium butyrate. Coexposure of cells to HDIs in conjunction with STI571 resulted in multiple perturbations in signaling and cell cycle-regulatory proteins, including down-regulation of Raf, phospho-mitogen-activated protein kinase kinase (MEK), phospho-extracellular signal-regulated kinase (ERK), phospho-Akt, phospho-signal transducers and activators of transcription 5, cyclin D1, and Mcl-1, accompanied by dephosphorylation and cleavage of retinoblastoma protein and a striking increase in phosphorylation of c-Jun NH₂-terminal kinase. Coexposure of Bcr/Abl⁺ cells to STI571 also blocked SAHA-mediated induction of p21^CIP1 and resulted in down-regulation of Bcr/Abl protein expression. STI571 and SAHA also interacted synergistically to induce apoptosis in STI571-resistant K562 and LAMA 84 cells that display increased Bcr/Abl protein expression. Lastly, inducible expression of a constitutively active MEK1/2 construct significantly attenuated SAHA/STI571-mediated apoptosis in K562 cells, implicating disruption of the Raf/MEK/ERK axis in synergistic antileukemic effects of this drug combination. Together, these findings indicate that combined exposure of Bcr/Abl⁺ cells to the kinase inhibitor STI571 and HDIs leads to diverse perturbations in signaling and cell cycle-regulatory proteins, associated with a marked increase in mitochondrial damage and cell death. They also raise the possibility that this strategy may be effective in some Bcr/Abl⁺ cells that are resistant to STI571 through increased Bcr/Abl expression.

This article has been cited by other articles:

				E. P. Jane, D. R. Premkumar, S. O. Addo-Yobo, and I. F. Pollack Abrogation of Mitogen-Activated Protein Kinase and Akt Signaling by Vandetanib Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis in Human Glioma Cells J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 327 - 337. [Abstract] [Full Text] [PDF]

				E. W. Schaefer, A. Loaiza-Bonilla, M. Juckett, J. F. DiPersio, V. Roy, J. Slack, W. Wu, K. Laumann, I. Espinoza-Delgado, S. D. Gore, et al. A phase 2 study of vorinostat in acute myeloid leukemia Haematologica, October 1, 2009; 94(10): 1375 - 1382. [Abstract] [Full Text] [PDF]

				T. Muhlenberg, Y. Zhang, A. J. Wagner, F. Grabellus, J. Bradner, G. Taeger, H. Lang, T. Taguchi, M. Schuler, J. A. Fletcher, et al. Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors Cancer Res., September 1, 2009; 69(17): 6941 - 6950. [Abstract] [Full Text] [PDF]

				M. Bots and R. W. Johnstone Rational Combinations Using HDAC Inhibitors Clin. Cancer Res., June 15, 2009; 15(12): 3970 - 3977. [Abstract] [Full Text] [PDF]

				K. Schmidt, K. Seeger, C. Scheibenbogen, R. Bender, M. Abdulla, S. Sussmilch, A. Salama, and A. Moldenhauer Histone deacetylase inhibition improves differentiation of dendritic cells from leukemic blasts of patients with TEL/AML1-positive acute lymphoblastic leukemia J. Leukoc. Biol., March 1, 2009; 85(3): 563 - 573. [Abstract] [Full Text] [PDF]

				K. Shiozawa, T. Nakanishi, M. Tan, H.-B. Fang, W.-c. Wang, M. J. Edelman, D. Carlton, I. Gojo, E. A. Sausville, and D. D. Ross Preclinical Studies of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytosine Arabinoside and Etoposide for Treatment of Acute Leukemias Clin. Cancer Res., March 1, 2009; 15(5): 1698 - 1707. [Abstract] [Full Text] [PDF]

				J. A. Woyach, R. T. Kloos, M. D. Ringel, D. Arbogast, M. Collamore, J. A. Zwiebel, M. Grever, M. Villalona-Calero, and M. H. Shah Lack of Therapeutic Effect of the Histone Deacetylase Inhibitor Vorinostat in Patients with Metastatic Radioiodine-Refractory Thyroid Carcinoma J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 164 - 170. [Abstract] [Full Text] [PDF]

				Y. Dai, S. Chen, C. A. Venditti, X.-Y. Pei, T. K. Nguyen, P. Dent, and S. Grant Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate Blood, August 1, 2008; 112(3): 793 - 804. [Abstract] [Full Text] [PDF]

				G. Garcia-Manero, H. Yang, C. Bueso-Ramos, A. Ferrajoli, J. Cortes, W. G. Wierda, S. Faderl, C. Koller, G. Morris, G. Rosner, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes Blood, February 1, 2008; 111(3): 1060 - 1066. [Abstract] [Full Text] [PDF]

				J. V. Melo and C. Chuah Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond Hematology, January 1, 2008; 2008(1): 427 - 435. [Abstract] [Full Text] [PDF]

				S. M. Lee, J. H. Bae, M. J. Kim, H. S. Lee, M. K. Lee, B. S. Chung, D. W. Kim, C. D. Kang, and S. H. Kim Bcr-Abl-Independent Imatinib-Resistant K562 Cells Show Aberrant Protein Acetylation and Increased Sensitivity to Histone Deacetylase Inhibitors J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1084 - 1092. [Abstract] [Full Text] [PDF]

				G. Dasmahapatra, N. Yerram, Y. Dai, P. Dent, and S. Grant Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation Clin. Cancer Res., July 15, 2007; 13(14): 4280 - 4290. [Abstract] [Full Text] [PDF]

				T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Blood, May 1, 2007; 109(9): 4006 - 4015. [Abstract] [Full Text] [PDF]

				C. Yu, B. B. Friday, J.-P. Lai, A. McCollum, P. Atadja, L. R. Roberts, and A. A. Adjei Abrogation of MAPK and Akt Signaling by AEE788 Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis through Reactive Oxygen Species Generation Clin. Cancer Res., February 15, 2007; 13(4): 1140 - 1148. [Abstract] [Full Text] [PDF]

				A. Quintas-Cardama and J. E. Cortes Chronic Myeloid Leukemia: Diagnosis and Treatment Mayo Clin. Proc., July 1, 2006; 81(7): 973 - 988. [Abstract] [Full Text] [PDF]

				Y. Takada, A. Gillenwater, H. Ichikawa, and B. B. Aggarwal Suberoylanilide Hydroxamic Acid Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis by Suppressing Nuclear Factor-{kappa}B Activation J. Biol. Chem., March 3, 2006; 281(9): 5612 - 5622. [Abstract] [Full Text] [PDF]

				N. Gao, M. Rahmani, X. Shi, P. Dent, and S. Grant Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress Blood, January 1, 2006; 107(1): 241 - 249. [Abstract] [Full Text] [PDF]

				E. J. Chung, S. Lee, E. A. Sausville, Q. Ryan, J. E. Karp, I. Gojo, W. G. Telford, M.-J. Lee, H. S. Kong, and J. B. Trepel Histone Deacetylase Inhibitor Pharmacodynamic Analysis by Multiparameter Flow Cytometry Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 397 - 406. [Abstract] [Full Text] [PDF]

				M. R. Acharya, A. Sparreboom, J. Venitz, and W. D. Figg Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review Mol. Pharmacol., October 1, 2005; 68(4): 917 - 932. [Abstract] [Full Text] [PDF]

				J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF]

				P.-H. Tseng, H.-P. Lin, J. Zhu, K.-F. Chen, E. M. Hade, D. C. Young, J. C. Byrd, M. Grever, K. Johnson, B. J. Druker, et al. Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance Blood, May 15, 2005; 105(10): 4021 - 4027. [Abstract] [Full Text] [PDF]

				K. J. Aichberger, M. Mayerhofer, M.-T. Krauth, H. Skvara, S. Florian, K. Sonneck, C. Akgul, S. Derdak, W. F. Pickl, V. Wacheck, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides Blood, April 15, 2005; 105(8): 3303 - 3311. [Abstract] [Full Text] [PDF]

				M. Rahmani, E. Reese, Y. Dai, C. Bauer, L. B. Kramer, M. Huang, R. Jove, P. Dent, and S. Grant Cotreatment with Suberanoylanilide Hydroxamic Acid and 17-Allylamino 17-demethoxygeldanamycin Synergistically Induces Apoptosis in Bcr-Abl+ Cells Sensitive and Resistant to STI571 (Imatinib Mesylate) in Association with Down-Regulation of Bcr-Abl, Abrogation of Signal Transducer and Activator of Transcription 5 Activity, and Bax Conformational Change Mol. Pharmacol., April 1, 2005; 67(4): 1166 - 1176. [Abstract] [Full Text] [PDF]

				A. Moldenhauer, R. C. Frank, J. Pinilla-Ibarz, G. Holland, P. Boccuni, D. A. Scheinberg, A. Salama, K. Seeger, M. A. S. Moore, and S. D. Nimer Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins J. Leukoc. Biol., September 1, 2004; 76(3): 623 - 633. [Abstract] [Full Text] [PDF]

				Y. Dai, M. Rahmani, X.-Y. Pei, P. Dent, and S. Grant Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Blood, July 15, 2004; 104(2): 509 - 518. [Abstract] [Full Text] [PDF]

				S. C. Maggio, R. R. Rosato, L. B. Kramer, Y. Dai, M. Rahmani, D. S. Paik, A. C. Czarnik, S. G. Payne, S. Spiegel, and S. Grant The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells Cancer Res., April 1, 2004; 64(7): 2590 - 2600. [Abstract] [Full Text] [PDF]

				C. Yu, M. Rahmani, D. Conrad, M. Subler, P. Dent, and S. Grant The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571 Blood, November 15, 2003; 102(10): 3765 - 3774. [Abstract] [Full Text] [PDF]