title: 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.affiliation: First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan. okabe@tokyo-med.ac.jp
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okabe
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tauchi
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D000077337:Vorinostat; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines