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 T315I 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, T315I, E255K, and M351T), as well as IM-resistant K562 cells exhibiting Bcr/Abl-independent, Lyn-dependent resistance. These events were associated with inactivation and down-regulation of wild-type (wt) and mutated Bcr/Abl (particularly T315I). 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 CML cells through inactivation of Bcr/Abl and aurora kinases, as well as by induction of Bim.
Dai
Yun
Y
Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA 23298, USA.
Chen
Shuang
S
Venditti
Charis A
CA
Pei
Xin-Yan
XY
Nguyen
Tri K
TK
Dent
Paul
P
Grant
Steven
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D064096:Aurora Kinase A; D064127:Aurora Kinases; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011743:Pyrimidines; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles
D051017:Apoptosis Regulatory Proteins; D064096:Aurora Kinase A; D064127:Aurora Kinases; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D006877:Hydroxamic Acids; D000068877:Imatinib Mesylate; D008565:Membrane Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000077337:Vorinostat; C000606775:BCL2L11 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C576917:AURKA protein, human