Fig. 3

Anti-cancer mechanisms of doxorubicin (DOX): DOX primarily exerts its cytotoxic effects by intercalating into DNA and inhibiting the activity of topoisomerase IIα (TOP2A), resulting in DNA double-strand (dsDNA) breaks and activation of apoptotic signaling pathways (e.g., TP53, ERK1/2, and MSK2). Additionally, DOX generates reactive oxygen species (ROS) through redox cycling, mediated by NAD(P)H: quinone oxidoreductases (NQO1 and NQO2), and through interactions with mitochondrial complexes. Excessive ROS production leads to oxidative stress, membrane damage, and mitochondrial dysfunction, culminating in cell death. Protective mechanisms within the cell, such as the activity of glutathione peroxidase 1 (GPX1) and catalase (CAT), counteract oxidative damage caused by ROS in the heart. However, the overwhelming ROS generation by DOX often surpasses these antioxidant defenses, leading to apoptosis. DOX also engages the protein kinase (PK) pathway and proteasomal degradation to further disrupt cellular homeostasis Efflux of DOX from the cell is regulated by ATP-binding cassette (ABC) transporters such as ABCG1, ABCG2, ABCC1, and ABCC2, as well as the multidrug resistance-associated protein RALBP1. These transporters contribute to chemoresistance by reducing intracellular DOX accumulation. Conversely, the solute carrier SLC22A16 facilitates DOX uptake, enhancing its intracellular effects