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Synergistic Induction of Folate Receptor ß by All-Trans Retinoic Acid and Histone Deacetylase Inhibitors in Acute Myelogenous Leukemia Cells: Mechanism and Utility in Enhancing Selective Growth Inhibition by Antifolates

Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio

Requests for reprints: Manohar Ratnam, Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614. Phone: 419-383-3862; E-mail: mratnam{at}meduohio.edu.

The folate receptor (FR) type ß is a promising target for therapeutic intervention in acute myelogenous leukemia (AML), owing particularly to its selective up-regulation in the leukemic cells by all-trans retinoic acid (ATRA). Here we show, using KG-1 and MV4-11 AML cells and recombinant 293 cells, that the histone deacetylase (HDAC) inhibitors trichostatin A (TSA), valproic acid (VPA), and FK228 potentiated ATRA induction of FR-ß gene transcription and FR-ß mRNA/protein expression. ATRA and/or TSA did not induce de novo FR synthesis in any of a variety of FR-negative cell lines tested. TSA did not alter the effect of ATRA on the expression of retinoic acid receptor (RAR) , ß, or . Chromatin immunoprecipitation assays indicate that HDAC inhibitors act on the FR-ß gene by enhancing RAR-associated histone acetylation to increase the association of Sp1 with the basal FR-ß promoter. Under these conditions, the expression level of Sp1 is unaltered. A decreased availability of putative repressor AP-1 proteins may also indirectly contribute to the effect of HDAC inhibitors. Finally, FR-ß selectively mediated growth inhibition by (6S) dideazatetrahydrofolate in a manner that was greatly potentiated in AML cells by ATRA and HDAC inhibition. Therefore, the combination of ATRA and innocuous HDAC inhibitors may be expected to facilitate selective FR-ß–targeted therapies in AML. (Cancer Res 2006; 66(11): 5875-82)