|
|
Blood, 1 October 2008, Vol. 112, No. 7, pp. 2896-2905.
Prepublished online as a Blood First Edition Paper on July 25, 2008; DOI 10.1182/blood-2007-10-116319.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor–resistant acute myeloid leukemia cells
Warren Fiskus1,
Rekha Rao1,
Pravina Fernandez1,
Bryan Herger1,
Yonghua Yang1,
Jianguang Chen1,
Ravindra Kolhe1,
Aditya Mandawat1,
Yongchao Wang1,
Rajeshree Joshi1,
Kelly Eaton1,
Pearl Lee1,
Peter Atadja2,
Stephen Peiper1, and
Kapil Bhalla1
1 MCG Cancer Center, Medical College of Georgia, Augusta; and
2 Novartis Institute for Biomedical Research, Cambridge, MA
Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI–resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. A. Lane and B. A. Chabner
Histone Deacetylase Inhibitors in Cancer Therapy
J. Clin. Oncol.,
November 10, 2009;
27(32):
5459 - 5468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. W. Schaefer, A. Loaiza-Bonilla, M. Juckett, J. F. DiPersio, V. Roy, J. Slack, W. Wu, K. Laumann, I. Espinoza-Delgado, S. D. Gore, et al.
A phase 2 study of vorinostat in acute myeloid leukemia
Haematologica,
October 1, 2009;
94(10):
1375 - 1382.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Fiskus, Y. Wang, A. Sreekumar, K. M. Buckley, H. Shi, A. Jillella, C. Ustun, R. Rao, P. Fernandez, J. Chen, et al.
Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells
Blood,
September 24, 2009;
114(13):
2733 - 2743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Schrump
Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications
Clin. Cancer Res.,
June 15, 2009;
15(12):
3947 - 3957.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. N. Bhalla
Combined Therapy with Agents Targeted against Deregulated Epigenetic Mechanisms in Cancer
Am. Assoc. Cancer Res. Educ. Book,
April 18, 2009;
2009(1):
233 - 236.
[Full Text]
[PDF]
|
|
|
|
|
