Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 3 166 28 Prague 6 Czechia

Department of Medical Microbiology Albert Szent Györgyi Medical School University of Szeged Semmelweis utca 6 Szeged 6725 Hungary

Institute of Medical Biology Genetics and Clinical Genetics Faculty of Medicine Comenius University in Bratislava Sasinkova 4 811 08 Bratislava Slovakia

Instituto de Química Orgánica General Consejo Superior de Investigaciones Científicas Juan de la Cierva 3 28006 Madrid Spain

Laboratory of Pharmacogenomics Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 323 00 Pilsen Czechia

Toxicogenomics Unit National Institute of Public Health Šrobárova 49 100 00 Prague Czechia

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