Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS)

Abstract

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or –KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions

“…In bladder cancer cell lines, Cur induced tumor suppressor miRNA, miR-203, DNA hypermethylation of the miR-203 promoter, hypomethylation of the miR-203 promoter, upregulation of the miR-203 expression, and downregulation of miR-203 target genes Akt2 and Src [326]. In MCF-7 cells, Cur downregulated mRNA and DNMT1 protein levels and decreased the DNA methylation activity of nuclear extract [327] which was predicted for leukemia cell line in a molecular docking investigation [328,329], while the docking-based on virtual screening reported by Medina-Franco et al [155] did not show DNA demethylation in three human cancer cell lines, which was confirmed in vitro in the study conducted by Link et al [330] where Cur did not affect the global DNA methylation changes. Similar to RSV, the decrease in the transcript levels of several DNMTs and their regulation have been widely described in vitro and in vivo by targeting the expression of numerous enzymes and proteins [290,318,319,[331][332][333][334][335][336][337].…”