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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.
 Previous Article | Next Article 
Submitted November 23, 2005
Accepted February 28, 2006
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*
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
MD Anderson Cancer Center, Houston, Texas, USA
Novartis Pharmaceutical Inc., Cambridge, Massachusetts, USA
* Corresponding author; email: bhallakn{at}moffitt.usf.edu.
AMN107 (Novartis Pharmaceuticals, Basel, Switzerland) has potent in vitro and in vivo activity against the un-mutated 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 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. Co-treatment with LBH589 and AMN107 exerted synergistic apoptotic effects with more attenuation of p-STAT5, p-ERK1/2, c-Myc and Bcl-xL and increase 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 to either agent alone, co-treatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Thus, co-treatment 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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