Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells.
OBJECTIVE
We determined the effects of vorinostat (suberoylanalide hydroxamic acid) and/or MK-0457 (VX-680), an Aurora kinase inhibitor on the cultured human (HL-60, OCI-AML3, and K562) and primary acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and mutant forms of Bcr-Abl.


METHODS
Following exposure to MK-0457 and/or vorinostat, apoptosis, loss of viability, as well as activity and levels of Aurora kinase and Bcr-Abl proteins were determined.


RESULTS
Treatment with MK-0457 decreased the phosphorylation of Aurora kinase substrates including serine (S)10 on histone H3 and survivin, and led to aberrant mitosis, DNA endoreduplication as well as apoptosis of the cultured human acute leukemia HL-60, OCI-AML3, and K562 cells. Combined treatment with vorinostat and MK-0457 resulted in greater attenuation of Aurora and Bcr-Abl (in K562) kinase activity and levels as well as synergistically induced apoptosis of OCI-AML3, HL-60, and K562 cells. MK-0457 plus vorinostat also induced synergistic apoptosis of BaF3 cells with ectopic overexpression of wild-type or mutant Bcr-Abl. Finally, cotreatment with MK-0457 and vorinostat induced more loss of viability of primary AML and imatinib-refractory CML than treatment with either agent alone, but exhibited minimal toxicity to normal CD34+ progenitor cells.


CONCLUSIONS
Combined in vitro treatment with MK-0457 and vorinostat is highly active against cultured and primary leukemia cells. These findings merit in vivo testing of the combination against human AML and CML cells, especially against imatinib mesylate-resistant Bcr-AblT315I-expressing CML Cells.
Fiskus
Warren
W
MCG Cancer Center, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA.
Wang
Yongchao
Y
Joshi
Rajeshree
R
Rao
Rekha
R
Yang
Yonghua
Y
Chen
Jianguang
J
Kolhe
Ravindra
R
Balusu
Ramesh
R
Eaton
Kelly
K
Lee
Pearl
P
Ustun
Celalettin
C
Jillella
Anand
A
Buser
Carolyn A
CA
Peiper
Stephen
S
Bhalla
Kapil
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051034:Inhibitor of Apoptosis Proteins; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D000077022:Survivin; D000077337:Vorinostat; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D016044:Fusion Proteins, bcr-abl; D006657:Histones; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D000077022:Survivin; D000077337:Vorinostat; C107489:BIRC5 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines