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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1174-1182.
Prepublished online as a Blood First Edition Paper on May 4, 2006; DOI 10.1182/blood-2005-09-008086.
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Submitted September 8, 2005
Accepted March 28, 2006
Antileukemia activity of the combination of an
anthracycline with a histone deacetylase inhibitor
Blanca Sanchez-Gonzalez, Hui Yang, Carlos Bueso-Ramos, Koyu Hoshino, Alfonso Quintas-Cardama, Victoria M. Richon, and Guillermo Garcia-Manero*
Department of Leukemia, University of Texas MD Anderson Cancer CenterHouston, TX, USA
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Merck & Co, Boston, MA, USA
* Corresponding author; email: ggarciam{at}mdanderson.org.
We studied the cellular and molecular effects of the
combination of an anthracycline with two different
histone deacetylase inhibitors (HDACI): vorinostat
(suberoylanilide hydroxamic acid) and valproic acid
(VPA). The IC10 of idarubicin was 0.5 nM in MOLT4, and
1.5 nM HL-60 cells. Concentrations above 0.675 uM of
vorinostat resulted in ? 80% loss of cell viability in
both cell lines. Concentrations of 1.5-3 mM of VPA
induced 50 to 60% loss in viability in HL-60 and 80% in
MOLT4. The combination of idarubicin with vorinostat at
0.075 uM or VPA at 0.25 mM resulted in at least an
additive loss of cell viability in both lines.
Vorinostat (0.35 uM) and VPA (0.25 mM) in combination
with idarubicin (0.5 nM) resulted in a significant
increase in apoptotic cells in MOLT4. The combination
resulted in an increase in histone H3 and H4 acetylation
at 24 hours, phosphorylated H2AX, as well as in the
induction of p21CIP1 mRNA. No effect on cell cycle
transition was observed. Of importance, the cellular and
molecular effects observed were independent of the
sequence used. In summary, the combination of an
anthracycline with a HDACI should have significant
clinical activity in patients with leukemia.
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