Solasodine Downregulates ABCB1 Overexpression in Multidrug Resistant Cancer Cells Via Inhibiting Nrf2/Keap1 Signaling Pathway

ABSTRACT Multidrug‐resistant (MDR) cancer cells maintain redox homeostasis to eliminate oxidative stress‐mediated cell death. This study explores the effects of solasodine on regulating P‐glycoprotein (P‐gp) expression through the Nrf2/Keap1 signaling pathway and oxidative stress‐induced sensitization of drug‐resistant cancer cells to chemotherapeutics. Initially, the oxidative stress indicators such as intracellular ROS generation, the levels of 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and gamma‐H2AX (γ‐H2AX) in the KBChR‐8‐5 drug‐resistant cells were measured. Additionally, the protein expression levels of Nuclear factor erythroid 2‐related factor 2 (Nrf‐2), Kelch‐like ECH‐associated protein 1 (Keap1), and ATP Binding Cassette Subfamily B Member 1 (ABCB1)/P‐gp were measured at various concentrations of solasodine (1, 5, & 10 µM) through immunofluorescence and western blot analysis. The antioxidant activities in the KBChR‐8‐5 cells were assessed using established protocols. In this investigation, the treatment with solasodine and doxorubicin combination showed a notable increase in intracellular ROS generation in KBChR‐8‐5 cells. Furthermore, this combination treatment led to enhanced nuclear condensation, elevated levels of 8‐OHdG, and increased γ‐H2AX foci formation in the KBChR‐8‐5 cells. Solasodine treatment effectively inhibited the nuclear translocation of Nrf2 and activation of the ABCB1 gene, consequently preventing overexpression of P‐gp in KBChR‐8‐5 cells. Additionally, the combination therapy increased the lipid peroxidation levels while simultaneously reducing the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and the levels of glutathione (GSH). These results demonstrated that solasodine disrupts redox balance, and overcomes drug resistance by downregulating P‐gp via regulating Nrf2/Keap1 signaling pathway in MDR cancer cells.