A Low Dose Combination of Withaferin A and Caffeic Acid Phenethyl Ester Possesses Anti-Metastatic Potential In Vitro: Molecular Targets and Mechanisms

Withaferin A (Wi-A) and Caffeic Acid Phenethyl Ester (CAPE) are the bioactive ingredients
of Ashwagandha (Withania somnifera) and propolis, respectively. Both of these natural compounds
have been shown to possess anticancer activity. In the present study, we recruited a low dose of each
of these compounds and developed a combination that exhibited remarkably potent anti-migratory
and anti-angiogenic activities. Extensive molecular analyses including a cDNA array and expression
analyses of the specific gene targets demonstrated that such activities are mediated through their
effect on cell adhesion/tight junction proteins (Claudins, E-cadherin), inhibition of canonical Wnt/
catenin signaling pathways and the consequent downregulation of EMT-signaling proteins (Vimentin,
MMPs,VEGFandVEGFR)thatplay a critical role in cancer metastasis. The data supported that this
novel combination of Wi-A and CAPE (Wi-ACAPE, containing 0.5 M of Wi-A and 10 M of CAPE)
mayberecruited for the treatment of metastatic and aggressive cancers and, hence, warrant further
evaluation by recruiting a variety of experimental and clinical metastatic models.