2025/02/27 by Sahib Zada, Md Entaz Bahar, Wanil Kim +1
paper · doi:10.1002/cbin.70006
ABSTRACT Resistance to apoptosis‐inducing drugs frequently occurs in cancer cells, limiting their usefulness in ongoing cancer treatment. Despite ongoing efforts to overcome drug resistance, a definitive solution remains elusive. However, autophagy inhibition has been shown to enhance the effectiveness of some anticancer drugs and is a possible strategy for overcoming drug resistance. In this study, we demonstrate that chlorogenic acid (CGA), a natural antioxidant, significantly enhances beta‐lapachone (β‐Lap)‐induced cell death in cancer cells. The augmented apoptosis induced by CGA is associated with activation of protein kinase A (PKA) in β‐Lap–treated cells, independent of the antioxidant properties of CGA. As a result, PKA activation in cancer cells co‐treated with β‐Lap and CGA effectively inhibits autophagy. Notably, PKA activation leads to phosphorylation of microtubule‐associated protein 1 A/1B‐light chain 3 (LC3) at the serine 12 residue, causing autophagy suppression irrespective of mTORC activity. Importantly, the cell death induced by β‐Lap and CGA in NQO1‐overexpressing breast or lung cancers is closely linked to autophagy inhibition. These findings suggest that combining β‐Lap and CGA might be a novel strategy for cancer therapy, particularly for overcoming drug resistance caused by autophagy induction in cancer cells.