The radiosensitizing effect of Caffeic Acid Phenethyl Ester in breast cancer is dependent on p53 status

Background and purpose: Radiotherapy is one of the standard treatments for breast cancer, but causes adverse effects in normal tissues, narrowing the therapeutic window. Caffeic Acid Phenethyl Ester (CAPE) has been proposed to have cytotoxic and radiosensitizing effects in cancer cells, whilst protective properties in normal tissues. We have investigated the anti-tumour effects of CAPE in breast cancer in vitro and in vivo and provided evidence regarding its radioprotective effect. Materials and methods: Cytotoxic and radiosensitizing effects were determined in vitro in luminal A, HER2+ and triple negative breast cancer and in normal breast cell lines by cell viability and clonogenic survival assays, respectively. Effects on cell metabolism, mitochondrial function and inflammation were investigated. CAPE anti-tumour effects were also investigated in vivo in a MDA-MB-231 tumour-bearing mouse model. Results: Cell viability decreased upon CAPE treatment in a dose dependent manner (IC ₅₀ 53.5 ± 33.7 µM). CAPE shifted cellular metabolism towards glycolysis (p < 0.05) and induced mitochondrial membrane depolarization (p < 0.01). CAPE sensitized only p53 mutated or deficient cell lines to radiotherapy (p < 0.05), but not p53 proficient lines. In normal breast cells, CAPE increased the surviving fraction upon radiation (p = 0.03). NF-κB activity was decreased in p53 mutant cancer cells (p < 0.01), but increased in p53 proficient lines (p < 0.01) upon CAPE treatment. Combination of radiotherapy and CAPE resulted in increased survival (22 days) compared to control (p < 0.05). Conclusion: Our findings highlight that CAPE could widen the therapeutic window in breast cancer with non-functional p53, by radiosensitizing the tumour cells while protecting the normal tissue.