Caffeic acid phenethyl ester promotes oxaliplatin sensitization in colon cancer by inhibiting autophagy

Abstract Colon cancer ranks as the third most prevalent form of cancer globally, with chemotherapy remaining the primary treatment modality. To mitigate drug resistance and minimize adverse effects associated with chemotherapy, selection of appropriate adjuvants assumes paramount importance. Caffeic acid phenethyl ester (CAPE), a naturally occurring compound derived from propolis, exhibits a diverse array of biological activities. We observed that the addition of CAPE significantly augmented the drug sensitivity of colon cancer cells to oxaliplatin. In SW480 and HCT116 cells, oxaliplatin combined with 10 µM CAPE reduced the IC 50 of oxaliplatin from 14.24 ± 1.03 and 84.16 ± 3.02 µM to 2.11 ± 0.15 and 3.92 ± 0.17 µM, respectively. We then used proteomics to detect differentially expressed proteins in CAPE-treated SW480 cells and found that the main proteins showing changes in expression after CAPE treatment were p62 (SQSTM1) and LC3B (MAP1LC3B). Gene ontology analysis revealed that CAPE exerted antitumor and chemotherapy-sensitization effects through the autophagy pathway. We subsequently verified the differentially expressed proteins using immunoblotting. Simultaneously, the autophagy inhibitor bafilomycin A1 and the mCherry-EGFP-LC3 reporter gene were used as controls to detect the effect of CAPE on autophagy levels. Collectively, the results indicate that CAPE may exert antitumor and chemotherapy-sensitizing effects by inhibiting autophagy, offering novel insights for the development of potential chemosensitizing agents.