Hypercellular Proinflammatory Microenvironment Inhibits the Etoposide-Induced DNA Damage in Acute Monocytic Leukemia...

Emergence of resistance in acute monocytic leukemia cells (AMoL, AML-M5) to the action of antitumor agents is one of the main reasons for the extremely low survival and curability of the patients diagnosed with AMoL. It is well known that the AML cells have an "inflammatory" phenotype and form a unique pro-inflammatory microenvironment. Previously, we identified increase in the resistance of the THP-1 human AML-M5 cells to the action of DNA topoisomerase I and II inhibitors (topotecan, etoposide, doxorubicin) in the in vitro model simulating conditions of 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, DNA comet assay, Western blot analysis, differential gene expression analysis, and flow cytometry. The results showed that the increase in resistance to the action of DNA topoisomerase inhibitors, in particular etoposide, in the THP-1 AML-M5 cells in a hypercellular proinflammatory microenvironment is realized through reduced accumulation of the single- and double-strand DNA breaks and, accordingly, reduced 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 provide new ideas about the role of pro-inflammatory activation in the increased resistance of AML cells to the death induced by the action of DNA topoisomerase inhibitors.