Caffeic acid phenethyl ester as a potent adjuvant: Augmenting cisplatin’s antitumor activity while mitigating nephrotoxicity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to its aggressive nature and limited treatment options. Cisplatin is a widely used chemotherapeutic agent for TNBC, but its clinical application is hindered by dose-limiting nephrotoxicity. Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis with known antitumor and organ-protective effects, has potential as an adjuvant to chemotherapy. This study evaluates the synergistic antitumor efficacy of CAPE combined with cisplatin and its ability to mitigate nephrotoxicity. In vitro, the CAPE-cisplatin combination synergistically inhibited TNBC cell proliferation, an effect reversed by the apoptosis inhibitor Z-VAD-FMK and the ROS scavenger N-acetylcysteine. Enhanced apoptosis was confirmed by Annexin V/PI staining and elevated cleaved caspase-3 levels, while increased ROS generation was verified by DCFH-DA flow cytometry. DNA damage was further supported by comet assays, immunofluorescence, immunocytochemistry, and Western blotting. Mechanistic studies using network pharmacology, transcriptomics, and Western blotting implicated the MAPK signaling pathway in mediating the therapeutic synergy. In vivo, combination therapy significantly enhanced the antitumor efficacy of a subtherapeutic dose of cisplatin and reduced nephrotoxicity compared to monotherapies. These findings suggest that CAPE potentiates the anticancer effects of cisplatin in TNBC while providing renal protection, offering a promising strategy to improve chemotherapy outcomes with reduced toxicity.