Redox-related Molecular Mechanism of Sensitizing Colon Cancer Cells to Camptothecin Analog SN38

BILIANA NIKOLOVA; SEVERINA SEMKOVA; IANA TSONEVA; ELENA STOYANOVA; PAVEL LEFTEROV; DESSISLAVA LAZAROVA; ZHIVKO ZHELEV; ICHIO AOKI; TATSUYA HIGASHI; RUMIANA BAKALOVA

doi:10.21873/anticanres.14519

Abstract

Background/Aim: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP). Materials and Methods: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests. Results: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters – up-regulation of SLCO1B1 and retention of SN38 in the cells. Conclusion: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.

Footnotes

Authors' Contributions
SS, BN, ZZ and RB conceived the idea for the study. SS and BN produced the first draft. SS, BN, ES, DL and IT were involved in the experiments, PL was involved in image preparation and improvements. RB, ZZ, IA and TH were involved in critical review of subsequent drafts. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
The study was partially supported by the Japanese Society for the Promotion of Science (JSPS; Grant-in-aid “Kakenhi-C” granted to RB) and COST Action COMULIS CA171121 (granted to BN, SS and IT).