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

Abstract

The folate receptor (FR) type B 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-b gene transcription and FR-B 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) A, B, or ;. Chromatin immunoprecipitation assays indicate that HDAC inhibitors act on the FR-b gene by enhancing RAR-associated histone acetylation to increase the association of Sp1 with the basal FR-B 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-B 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-Btargeted therapies in AML. (Cancer Res 2006; 66(11): 5875-82)

Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?

“…[7][8][9][10] For example, HDAC inhibitors have been identified to be additive or synergistic with a number of other therapeutics including anthracyclines 11,12 tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL) 13,14 and all-transretinoic acid. 15,16 Also, HDAC inhibitors have been shown to be efficient radiation modifying agents and therefore, have been proposed as possible clinical radiation sensitizers or protectors. [17][18][19] Despite their relatively short history, HDAC inhibitors have realized both success and failure in clinical trials.…”

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

“…In this context, some recently identiWed novel antifolates structures, i.e., BGC638 [61] and BGC945 [15], with the property of not being a substrate for RFC but possessing a good binding aYnity for MFR, warrant further evaluation for selective MFR-mediated cell entry. Finally, recent observations that retinoic acid and histone deacetylase inhibitors can provoked a marked induction of MFR expression [41] may further facilitate selective targeting of MFR.…”

Enhanced Receptor-Mediated Endocytosis and Cytotoxicity of a Folic Acid-Desacetylvinblastine Monohydrazide Conjugate in a Pemetrexed-Resistant Cell Line Lacking Folate-Specific Facilitative Carriers but with Increased Folate Receptor Expression

“…The primers used were 59-CACTCTACCCAGC-CACTCTGAAC-39 and 59-GATCAGCCTTTTCCAGCATCC-39 for PCFT (Gonen and Assaraf, 2010); 59-CAAGGTCAGCAACTACAGCC-GAG-39 and 59-CATGGCTGCAGCATAGAACCTCG-39 for both FR-a and FR-b (Ashokkumar et al, 2007); 59-AGGACAGACATGGCTCAGCG-39 and 59-TGTGGTGCTTGGCGTTCATG-39 for FR-a only (Jwala et al, 2012); 59-CTGGCTCCTTGGCTGAGTTC-39 and 59-GCCCAGCCTGGT-TATCCA-39 for FR-b only (Qi and Ratnam, 2006); and 59-CGACCA-CTTTGTCAAGCTCA-39 and 59-CCCTGTTGCTGTAGCCAAAT-39 for G3PDH (Qiu et al, 2006).…”