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Blood, 15 July 2006, Vol. 108, No. 2, pp. 645-652.
Prepublished online as a Blood First Edition Paper on March 14, 2006; DOI 10.1182/blood-2005-11-4639.
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NEOPLASIA
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl–expressing human leukemia cells
Warren Fiskus,
Michael Pranpat,
Purva Bali,
Maria Balasis,
Sandhya Kumaraswamy,
Sandhya Boyapalle,
Kathy Rocha,
Jie Wu,
Francis Giles,
Paul W. Manley,
Peter Atadja, and
Kapil Bhalla
From the Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; the MD Anderson Cancer Center, Houston, TX; and Novartis Pharmaceutical Inc, Cambridge, MA
AMN107 (Novartis Pharmaceuticals, Basel, Switzerland) has potent in vitro and in vivo activity against the unmutated and most common mutant forms of Bcr-Abl. Treatment with the histone deacetylase inhibitor LBH589 (Novartis) depletes Bcr-Abl levels. We determined the effects of AMN107 and/or LBH589 in Bcr-Abl–expressing human K562 and LAMA-84 cells, as well as in primary chronic myelogenous leukemia (CML) cells. AMN107 was more potent than imatinib mesylate (IM) in inhibiting Bcr-Abl tyrosine kinase (TK) activity and attenuating p-STAT5, p-AKT, Bcl-xL, and c-Myc levels in K562 and LAMA-84 cells. Cotreatment with LBH589 and AMN107 exerted synergistic apoptotic effects with more attenuation of p-STAT5, p-ERK1/2, c-Myc, and Bcl-xL and increases in p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of Bcr-Abl or the IM-resistant, point-mutant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis of IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared with either agent alone, cotreatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Thus, cotreatment with LBH589 and AMN107 is active against cultured or primary IM-resistant CML cells, including those with expression of Bcr-AblT315I.
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