Abstract P70: Reverse Transcriptase Inhibitors Decrease Adverse DNA Damage Caused By Anticancer Demethylating Drugs

Decitabine and 5-azacytidine were approved for the treatment of patients with acute myeloid leukemia. Their main mechanism of action is considered to inhibit DNA methyltransferase, restoring expression of tumor suppressor genes. However, demethylating agents activate undesirable transcription from genome non-coding regions, including LINEs retrotransposons. Active LINE1retrotransposition is accompanied by DNA damage, genomic rearrangements and, as a result, rapid relapse of the disease. To minimize undesirable consequences, we proposed to use demethylating agents in combination with nucleoside inhibitors of viral reverse transcriptase (RTIs) actively applied in antiretroviral therapy. We studied effects of reverse transcriptase inhibitors on the level of DNA damage caused by active retrotransposition of LINE1 under the influence of hypomethylating agents decitabine and 5-azacytidine using THP-1 cells. DNA damage levels were assessed by DNA comet assay in accordance with OECD recommendations and by counting the number of γ-H2AX-foci using fluorescent microscopy. We demonstrated that in THP1 cells treated with 5-azacytidine and decitabine at IC20 concentrations statistically significant increase in the value of the “comet tail moment” relatively to untreated cells. In particular, decitabine caused 2-fold increase and 5-azacytidine - 1.7-fold increase. In THP-1 cells treated with demethylating agents we also observed statistically significant increases of the number of γ-H2AX foci. RTIs do not change significantly the level of DNA damage. RTIs decreased undesirable DNA damage caused by demethylating agents when the drugs were used in combinations. According to comet assay results and γ-H2AX-foci numbers statistically significant decrease up to the control level was observed for the combination of decitabine (IC20) + RTIs (lamivudine 20 μM/zidovudine 20 μM/efavirenz 20 μM) and for the combination of 5-azacytidine (IC20) + RTIs. Thus, we demonstrate that application of RTIs in demethylating agent therapy is promising. This work was supported by the grant of the Russian Science Foundation 23-25-00276. Citation Format: Strelkov M.S., Vlasova O.A., Antonova I. A., Magomedova Kh.M., Kirsanov K.I., Yakubovskaya M.G.. Reverse Transcriptase Inhibitors Decrease Adverse DNA Damage Caused By Anticancer Demethylating Drugs [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P70.