Hypercellular proinflammatory microenvironment inhibits etoposide-induced DNA damage in acute monocytic leukemia cells

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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 single- and 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.

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Sobre autores

M. Kobyakova

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Autor responsável pela correspondência
Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

K. Krasnov

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences; Institute of Clinical and Experimental Lymphology – Branch of ICIG SB RAS

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region; 630060 Novosibirsk

O. Krestinina

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

Yu. Baburina

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

A. Senotov

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

Ya. Lomovskaya

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

E. Meshcheryakova

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences; Institute of Cell Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region; 142290 Pushchino, Moscow Region

A. Lomovsky

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

A. Zvyagina

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

K. Pyatina

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

I. Fadeeva

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

R. Fadeev

Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences

Email: kobyakovami@gmail.com
Rússia, 142290 Pushchino, Moscow Region

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2. Fig. 1. Analysis of qualitative and quantitative characteristics of induced DNA damage in THP-1 NPC and THP-1 VPC cells before and after 2, 4, and 8 h of incubation with 8 μM etoposide. Viability of THP-1 NPC and THP-1 VPC cells before and after 2, 4, and 8 h of incubation with 8 μM etoposide (a). Percentage of cells containing single-stranded (b) and double-stranded (d) DNA breaks in the THP-1 NPC and THP-1 VPC population before and after 2, 4, and 8 h of incubation with 8 μM etoposide. The degree of DNA damage (% DNA in tail) during the formation of single-stranded (r) and double-stranded (d) breaks. Data are presented as mean ± SD (n ≥ 5); *p < 0.05 – compared with THP-1 NPC cells

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3. Fig. 2. Content of pATR (Ser428), total ATR (a); pATM (Ser428), total ATM (b); pBRCA1 (Ser1524), total Brca1 (c); pChk1 (Ser139), total Chk1 (r); pChk2 (Thr68), total Chk2 (e); pH2AX (Ser139), total H2A.X (e) in THP-1 VPC and THP-1 NPC cells before and after 2, 4, and 8 h of incubation with 8 μM etoposide

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4. Fig. 3. Analysis of etoposide-induced pro-apoptotic signaling pathway activation in THP-1 NPC and THP-1 VPC cells. Mean fluorescence intensity (MFI) of AMC in THP-1 NPC and THP-1 VPC cells before and after 2, 4, and 8 h of incubation with 8 μM etoposide (a). Percentage of cells containing cleaved PARP1/2 (Asp214) (b) and aberrant nuclei (c) in the THP-1 NPC and THP-1 VPC population before and after 2, 4, and 8 h of incubation with 8 μM etoposide. Data are presented as mean ± SD (n ≥ 5); * p <0.05 – compared to THP-1 NPC cells

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5. Fig. 4. GSEA of gene sets in resistant OMol cells relative to sensitive OMol cells. GSEA results for collection H (a) for THP-1 VPC and OMol cells from treatment-resistant patients relative to THP-1 NPC and OMol cells from treatment-responsive patients, respectively. The circle size corresponds to the number of genes with variable expression relative to the total number of genes in the set. NER – normalized enrichment index; FDR ≤ 0.05. GSEA results for the KEGG, Reactome, GOBP, and WP collections (b) and the C3.TFT collection (c–g) for THP-1 VPC cells relative to THP-1 NPC cells

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6. Fig. 5. The number of THP-1 cells in the culture depending on the cultivation time. HDC – high-density cell culture; LDC – low-density cell culture. Data are presented as mean ± SD (n ≥ 5)

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7. Appendix 1
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