Curcumin Synergistically Sensitizes Multidrug-Resistant Lung Cancer to Doxorubicin Through Ferroptosis-Associated Oxidative Stress

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC₅₀-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting.