Study on Potentiation of ATRA Activity in HL-60 Cells by Targeting Methylation Enzymes

All Trans Retinoic Acid (ATRA) is a clinically established Differentiation Inducer (DI) for Acute Promyelocytic Leukemia (APL). Its efficacy in treating other kinds of Acute Myelocytic Leukemia (AML) is limited. ATRA targets the PML-RARA (promyelocytic leukemia/retinoic acid receptor-alpha)/DNA methyltransferase (DNMT)/Histone Deacetylase (HDAC) complex in APL, causing gene silencing to be lost and Terminal Differentiation to occur (TD). ATRA targeting of WT RARA as a single drug fails to modify the epigenetic modifications that prevent differentiation in other kinds of AML. When paired with DNMT inhibitors like 5-azacytidine, however, ATRA has better in vitro and clinical effectiveness against AML. The methylation enzyme complex (MMS), which includes Methionine Adenosyltransferase (MAT), Methyltransferase (MT), and S-Adenosylhomocysteine Hydrolase (SAHH), was previously shown to trigger differentiation in the AML M2 HL-60 cell line model. Differentiation Helper Inducers are inhibitors of the ternary methylation enzyme complex (DHIs). While they can’t produce significant terminal differentiation on their own, they can help DIs work better. DHIs that destabilise SAHH enhance ATRA’s ability to induce terminal differentiation in both sensitive and resistant HL-60 cells in vitro, according to this study. We also looked at Tyrosine Kinase Inhibitors (TKIs), which block the generation of SAHH’s stabilising factor, and steroid analogues, which compete with SAHH’s endogenous steroid stabilising factor. After treatment to 1M doses of ATRA, 72 percent of early passage (sensitive) HL-60 cells displayed induction of Terminal Differentiation (TD), whereas only 43 percent of late passage (resistant) cells did. Late passage HL-60 cell TD rose dramatically when ATRA was coupled with TKI imatinib mesylate or the steroid analogues resveratrol or -sitosterol, drugs with no innate capacity to induce differentiating, reaching 98 percent, 99 percent, and 94 percent of cells, respectively. Combinations of ATRA with cytotoxic chemotherapeutic drugs resulted in very minor improvements in TD percentages: ATRA plus topotecan: 76 percent; ATRA plus oxaliplatin: 63 percent; ATRA plus paclitaxel: 59 percent. ATRA’s effects on an AML M2 cell line, and possibly other kinds of AML, were amplified when it was combined with drugs that interfere with the maintenance of the methyl group pool.

Author(S) Details

Ming C. Liau
CDA Therapeutics, CA, USA.

Jai-Hyun Kim
Chao Family Comprehensive Cancer Center, University of California, IrvineMedical Center, CA, USA.

John P. Fruehauf
Chao Family Comprehensive Cancer Center, University of California, IrvineMedical Center, CA, USA.

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