Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells.

Abstract

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-x(L), 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-x(L) 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.

• Authors: Warren Fiskus, Michael Pranpat, Purva Bali, Maria Balasis, Sandhya Kumaraswamy, Sandhya Boyapalle, Kathy Rocha, Jie Wu, Francis Giles, Paul W Manley, Peter Atadja, Kapil Bhalla
• Journal: Blood (Blood) Vol. 108 Issue 2 Pg. 645-52 (Jul 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16537804 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Panobinostat
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• nilotinib

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drug Synergism
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Imatinib Mesylate
• Indoles
• Leukemia (drug therapy, pathology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Mice
• Panobinostat
• Piperazines (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology)
• Tumor Cells, Cultured