Epigenetic Reversal And Cytotoxicity Of Phytochemicals In Chemoresistant HL-60 Cells

Abstract

Acute myeloid leukemia (AML) represents one of the most aggressive forms of haematological malignancy, marked by the clonal expansion of undifferentiated myeloid progenitors that disrupt normal hematopoiesis. Despite decades of progress in diagnostic stratification and chemotherapy, relapse due to chemoresistance continues to be the principal cause of treatment failure and mortality. Increasing evidence suggests that beyond genetic lesions, epigenetic alterations—particularly aberrant DNA methylation—play a decisive role in leukemogenesis, disease progression, and therapeutic resistance. DNA methylation is regulated by a balance between DNA methyltransferases (DNMTs) and the ten-eleven translocation (TET) family of demethylases, both of which are tightly linked to the cell's metabolic state. Mutations in isocitrate dehydrogenase (IDH1 and IDH2) genes generate the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate–dependent enzymes, including TET2, leading to promoter hypermethylation and gene silencing. Reversal of these aberrant methylation patterns is therefore a promising therapeutic strategy for overcoming chemoresistance in AML.