Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells

Warren Fiskus, Yongchao Wang, Rajeshree Joshi, Rekha Rao, Yonghua Yang, Jianguang Chen, Ravindra Kolhe, Ramesh Balusu, Kelly Eaton, Pearl Lee, Celalettin Ustun, Anand Jillella, Carolyn A. Buser, Stephen Peiper, Kapil Bhalla

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Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)6106-6115
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number19
DOIs
StatePublished - Oct 1 2008

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Acute Myeloid Leukemia
Aurora Kinases
Apoptosis
K562 Cells
Leukemia
Endoreduplication
Hydroxamic Acids
B-Lymphoid Precursor Cells
VX680
vorinostat
HL-60 Cells
Mitosis
Histones
Serine
Research Design
Phosphotransferases
Stem Cells
Phosphorylation
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. / Fiskus, Warren; Wang, Yongchao; Joshi, Rajeshree; Rao, Rekha; Yang, Yonghua; Chen, Jianguang; Kolhe, Ravindra; Balusu, Ramesh; Eaton, Kelly; Lee, Pearl; Ustun, Celalettin; Jillella, Anand; Buser, Carolyn A.; Peiper, Stephen; Bhalla, Kapil.

In: Clinical Cancer Research, Vol. 14, No. 19, 01.10.2008, p. 6106-6115.

Research output: Contribution to journalArticle

Fiskus, W, Wang, Y, Joshi, R, Rao, R, Yang, Y, Chen, J, Kolhe, R, Balusu, R, Eaton, K, Lee, P, Ustun, C, Jillella, A, Buser, CA, Peiper, S & Bhalla, K 2008, 'Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells', Clinical Cancer Research, vol. 14, no. 19, pp. 6106-6115. https://doi.org/10.1158/1078-0432.CCR-08-0721
Fiskus, Warren ; Wang, Yongchao ; Joshi, Rajeshree ; Rao, Rekha ; Yang, Yonghua ; Chen, Jianguang ; Kolhe, Ravindra ; Balusu, Ramesh ; Eaton, Kelly ; Lee, Pearl ; Ustun, Celalettin ; Jillella, Anand ; Buser, Carolyn A. ; Peiper, Stephen ; Bhalla, Kapil. / Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 19. pp. 6106-6115.
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T1 - Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells

AU - Fiskus, Warren

AU - Wang, Yongchao

AU - Joshi, Rajeshree

AU - Rao, Rekha

AU - Yang, Yonghua

AU - Chen, Jianguang

AU - Kolhe, Ravindra

AU - Balusu, Ramesh

AU - Eaton, Kelly

AU - Lee, Pearl

AU - Ustun, Celalettin

AU - Jillella, Anand

AU - Buser, Carolyn A.

AU - Peiper, Stephen

AU - Bhalla, Kapil

PY - 2008/10/1

Y1 - 2008/10/1

N2 - Purpose: 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. Experimental Design: 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.

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