Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate

Interactions between the dual Bcr/Abl and aurora kinase inhibitor MK-0457 and the histone deacetylase inhibitor vorinostat were examined in Bcr/Abl+ leukemia cells, including those resistant to imatinib mesylate (IM), particularly those with the T3151 mutation. Coadministration of vorinostat dramatically increased MK-0457 lethality in K562 and LAMA84 cells. Notably, the MK-0457/vorinostat regimen was highly active against primary CD34+ chronic myelogenous leukemia (CML) cells and Ba/F3 cells bearing various Bcr/ Abl mutations (ie, T3151, E255K, and M351T), as well as IM-resistant K562 cells exhibiting Bcr/Abl-independent, Lyndependent resistance. These events were associated with inactivation and downregulation of wild-type (wt) and mutated Bcr/Abl (particularly T3151). Moreover, treatment with MK-0457 resulted in accumulation of cells with 4N or more DNA content, whereas coadministration of vorinostat markedly enhanced aurora kinase inhibition by MK-0457, and preferentially killed polyploid cells. Furthermore, vorinostat also interacted with a selective inhibitor of aurora kinase A and B to potentiate apoptosis without modifying Bcr/Abl activity. Finally, vorinostat markedly induced Bim expression, while blockade of Bim induction by siRNA dramatically diminished the capacity of this agent to potentiate MK-0457 lethality. Together, these findings indicate that vorinostat strikingly increases MK-0457 activity against IM-sensitive and -resistant CIVIL cells through inactivation of Bcr/Abl and aurora kinases, as well as by induction of Bim.