Erastin Enhances Bortezomib Efficacy Through ROS-Mediated DNA Damage Repair and Ferroptosis in Multiple Myeloma

Abstract

Background: Multiple myeloma (MM) is characterized by destructive osteolytic lesions, hypercalcemia, renal insufficiency, and anemia. However, bortezomib (Btz) has been recognized as a cornerstone treatment for various types of MM. Therefore, this study explored the effect of erastin on the efficacy of Btz and evaluated the synergistic effects of erastin in combination with Btz on MM cells. Methods: Glutathione (GSH) level was evaluated in MM cell lines to determine its effects on redox balance and cell growth. Furthermore, Solute Carrier Family 7 Member 11 (SLC7A11) was inhibited in MM cells using small-interfering RNA (siRNA) and erastin to determine its effect of redox balance on cell proliferation. Moreover, western blot analysis, flow cytometry, and ferroptosis-related verification experiments were employed to assess the changes that occur after treatment in the cell cycle, the expression of DNA damage repair marker protein, and ferroptosis. Additionally, the synergistic zero interaction potency (ZIP) scores and combination indexes (CIs) of these two drugs were calculated using different concentrations of Btz and erastin, and MM cell proliferation was compared when treated with single and combined drugs. Results: It was observed that increased GSH levels (p < 0.05) disrupted the redox equilibrium and promoted MM cell proliferation. Moreover, activation of siSLC7A11 induced the Ataxia Telangiectasia and Rad3-related Checkpoint Kinase 1 (ATR-CHK1) DNA repair pathway, resulting in a decrease in GSH levels (p < 0.05), a rise in intracellular reactive oxygen species (ROS) levels, alterations in intracellular redox equilibrium, and the induction of ferroptosis. Additionally, the ATR-CHK1 DNA repair pathway resulted in cell cycle S-phase arrest and effectively reduced MM cell growth. However, inhibiting SLC7A11 (p < 0.05) led to higher MM cell response to Btz. Moreover, the combination of erastin and Btz significantly increased cytotoxicity in MM cells (p < 0.05). Conclusion: Erastin increases the level of reactive oxygen species (ROS) in MM cells by inhibiting SLC7A11, which activates the ATR-CHK1 DNA damage repair pathway and causes MM cells to ferroptosis. Furthermore, erastin synergistically increases the cytotoxicity of Btz in multiple myeloma.