2-Amino-Pyrrole-Carboxylate Attenuates Homology-Mediated DNA Repair and Sensitizes Cancer Cells to Doxorubicin

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Sergei Boichuk^1,2,a*, Firuza Bikinieva¹, Ilshat Mustafin¹, Svetlana Zykova³, Sergei Ryzkin², and Aigul Galembikova¹

¹Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia

²Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia

³Perm State Academy of Pharmacy, 614990 Perm, Russia

^* To whom correspondence should be addressed.

Received March 22, 2022; Revised March 25, 2022; Accepted March 25, 2022

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Despite a high efficacy of chemotherapy in cancer treatment, acquired resistance of tumors to certain chemotherapeutic agents and frequent side effects remain the major factors of unfavorable prognosis in most cancer patients with unresectable, metastatic and recurrent forms of the disease. The discovery of novel molecular targets in tumors and development of new therapeutic approaches to enhance the efficiency of chemotherapeutic agents remain the biggest challenges in current oncology. Here we examined the ability of pyrrole-based heterocyclic compound 2-APC to sensitize tumor cells to the topoisomerase II inhibitor doxorubicin. The study was performed on human cancer cell lines treated with 2-APC, paclitaxel, and doxorubicin. Expression of DNA repair was investigated by Western blotting, whereas protein–protein interactions were examined by co-immunoprecipitation. The synergism between the chemotherapeutic agents was assessed with the Synergy Finder program. Doxorubicin exhibited moderate cytotoxic effect against cancer cell lines (in particular, osteosarcoma cell lines). 2-APC in non-toxic concentrations substantially potentiated the cytotoxic effect of doxorubicin and induced apoptosis of cancer cells. This activity of 2-APC was due to its ability to impair DNA damage repair by decreasing the content of Rad51 recombinase via promoting its proteasomal degradation. Similar effects were observed for paclitaxel, which affects tubulin polymerization. Therefore, chemotherapeutic agents and chemical compounds interfering with the microtubule dynamics can potentiate the cytotoxic effects of DNA-damaging chemotherapeutic agents via impairment of DNA damage repair mechanisms in cancer cells.

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KEY WORDS: pyrrole-based heterocyclic compounds, cancer, tubulin polymerization, paclitaxel, doxorubicin, sensitization, apoptosis

DOI: 10.1134/S0006297922050017

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