Efficacy of MK-0457 and in combination with vorinostat against Philadelphia chromosome positive acute lymphoblastic leukemia cells.

Abstract

Aurora kinases play a pivotal role in the regulator of mitotic processes during cell division and Aurora kinases are overexpressed in a number of human cancers. In this study, we examined the intracellular signaling of Aurora kinases inhibitor, MK-0457 (VX-680), in BCR-ABL positive cell lines and in primary samples. MK-0457 induced apoptosis. Caspase 3 and poly (ADP-ribose) polymerase (PARP) were activated and heat shock proteins were reduced. A combination of MK-0457 and histone deacetylase inhibitor, vorinostat, increased apoptosis. Caspase 3 and PARP were activated and phosphorylation of BCR-ABL, Lyn, and Crk-L were reduced. BCR-ABL and Aurora A and B were reduced after vorinostat treatment. Moreover, combination of vorinostat and MK-0457 synergistically increased the extent of apoptosis in primary acute lymphoblastic leukemia cells with T315I mutation. Our study increases insight into how MK-0457 may mediate its effects on BCR-ABL positive leukemia cells with T315I mutation, and information of potential therapeutic relevance.

• Authors: Seiichi Okabe, Tetsuzo Tauchi, Kazuma Ohyashiki
• Journal: Annals of hematology (Ann Hematol) Vol. 89 Issue 11 Pg. 1081-7 (Nov 2010) ISSN: 1432-0584 [Electronic] Germany
• PMID: 20563869 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Piperazines
• tozasertib
• Vorinostat
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Adult
• Antineoplastic Agents (pharmacology, therapeutic use)
• Aurora Kinases
• Cell Line, Tumor
• Cell Proliferation
• Drug Therapy, Combination
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• Hydroxamic Acids (pharmacology, therapeutic use)
• Piperazines (pharmacology, therapeutic use)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Vorinostat