Hypercellular Proinflammatory Microenvironment Inhibits Etoposide-Induced Dna Damage in Acute Monocytic Leukemia Cells

The emergence of resistance in acute monocytic leukemia (AML-M5) cells to the action of antitumor agents is one of the main reasons for the extremely low survival and curability of patients with diagnosed AML-M5. It is well known that AML cells have an “inflammatory” phenotype and form a unique pro-inflammatory microenvironment. Previously, we identified an increase in the resistance of THP-1 human AML-M5 cells to the action of DNA topoisomerase I and II inhibitors (topotecan, etoposide, doxorubicin) in an in vitro model simulating the conditions of the pro-inflammatory microenvironment - a three-dimensional long-term high-density cell culture. In this research, we investigated the mechanisms of this phenomenon using fluorescence microscopy and spectrophotometry, the DNA comet method, western blot analysis, differential gene expression analysis, and flow cytometry. The results showed that an increase in resistance to the action of DNA topoisomerase inhibitors, in particular etoposide, in THP-1 AML-M5 cells in a hypercellular proinflammatory microenvironment is realized by reducing the accumulation of singleand double-stranded DNA breaks and, accordingly, the response to DNA damage. It may also be due to the pronounced activation of the signaling pathways of interferon types 1 and 2, NF-κB/STAT-dependent signaling pathways, occurring against the background of a significant suppression of the activity of transcription factors of the Myc and E2F families. The results of this work open up new ideas about the role of pro-inflammatory activation in increasing the resistance of AML cells to death induced by the action of DNA topoisomerase inhibitors.