Organoselenium compounds as novel adjuvants of chemotherapy drugs—a promising approach to fight cancer drug resistance
Malignant diseases present a serious public health burden and their treatment with traditional chemotherapy cannot be considered an all-round solution, due to toxic side effects. Selenium compounds (Se-compounds) have received substantial attention in medicinal chemistry, especially in experimental chemotherapy, both as cytotoxic agents and adjuvants in chemotherapy. A checkerboard microplate method was applied to study the drug interactions of Se-compounds and clinically relevant chemotherapeutic drugs against the multidrug-resistant (MDR) subtype of mouse T-lymphoma cells overexpressing the ABCB1 transporter. Se-compounds showed synergistic interactions with chemotherapeutic agents targeting the topoisomerase enzymes or the microtubule apparatus. The ketone-containing selenoesters showed synergism at lower concentrations (1.25 µM). Most of the tested compounds interacted antagonistically with alkylating agents and verapamil. A thiophene-containing Se-compound showed synergism with all tested drugs, except cisplatin. While the exact mechanism of drug interactions is yet unknown, the potency of the selenocompounds as efflux pump inhibitors or the potentiation of their efficacy as reactive oxygen species modulators may play a role in their complementary activity against the tested MDR lymphoma cell line. ; The authors would like to thank Anikó Váradi Vigyikán for the excellent laboratory assistance. This study was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 'National Excellence Program'. The study was supported by the grant 20391-3/2018/FEKUSTRAT of the Ministry of Human Capacities, Hungary. M.G. and G.S. received funding from the Márton Áron Research Programme (2017/18) financed by the Hungarian Ministry of Foreign Affairs and Trade. M.G. was supported by the UNKP-17-3 New National Excellence Program of the Ministry of Human Capacities. G.S. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Carmen Sanmartín wishes to express her gratitude to the Uned Pamplona, Fundación Bancaria "La Caixa" y Fundación Caja Navarra, for financial support for the project ; Peer Reviewed