Clinical Cancer esearch cer Therapy : Preclinical hanisms of Synergistic Antileukemic Interactions een Valproic Acid and Cytarabine in R iatric Acute Myeloid Leukemia

wnloade pose: To determine the possibility of synergistic antileukemic activity and the underlying molecular nisms associated with cytarabine combined with valproic acid (VPA; a histone deacetylase inhibitor Food and Drug Administration–licensed drug for treating both children and adults with epilepsy) iatric acute myeloid leukemia (AML). erimental Design: The type and extent of antileukemic interactions between cytarabine and VPA in lly relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined T assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting. ults: We showed synergistic antileukemic activities between cytarabine and VPA in four pediatric ell lines and nine diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensiVPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML Cytarabine and VPA cooperatively induced DNA double-strand breaks, reflected in induction of X and apoptosis, accompanied by activation of caspase-9 and caspase-3. Further, VPA induced xpression and short hairpin RNA knockdown of Bim resulted in significantly decreased apoptosis ed by cytarabine and by cytarabine plus VPA. clusions: Our results establish global synergistic antileukemic activity of combined VPA and cytarCon abine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease. Clin Cancer Res; 16(22); 5499–510. ©2010 AACR.