Molecular Characterization and Enhancement of Anticancer Activity of Caffeic Acid Phenethyl Ester by γ Cyclodextrin

Caffeic Acid Phenethyl Ester (CAPE) is a key component in New Zealand propolis, known for a variety of health promoting and therapeutic potentials. We investigated the molecular mechanism of anticancer and anti-metastasis activities of CAPE. cDNA array performed on the control and CAPE-treated breast cancer cells revealed activation of DNA damage signaling involving upregulation of GADD45 alpha and p53 tumor suppressor proteins. Molecular docking analysis revealed that CAPE is capable of disrupting mortalin-p53 complexes. We provide experimental evidence and demonstrate that CAPE induced disruption of mortalin-p53 complexes led to nuclear translocation and activation of p53 resulting in growth arrest in cancer cells. Furthermore, CAPE-treated cells exhibited downregulation of mortalin and several other key regulators of cell migration accountable for its anti-metastasis activity. Of note, we found that whereas CAPE was unstable in the culture medium (as it gets degraded into caffeic acid by secreted esterases), its complex with gamma cyclodextrin (gamma CD) showed high efficacy in anti-tumor and anti-metastasis assays in vitro and in vivo (when administered through either intraperitoneal or oral route). The data proposes that CAPE-gamma CD complex is a potent anti-cancer and anti-metastasis reagent.