Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traits via targeting the Wnt/β-catenin signaling pathway and inducing G1 cell cycle arrest

Cancer stem cells (CSCs) represent a small population of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. Ovarian cancer is one of the leading causes of death related to the female reproductive system in Western countries and has been evaluated as a type of CSC-related cancer in recent years. Natural products have attracted great attention in cancer treatment in recent years due to drug resistance and a high relapse rate of ovarian cancer. Chinese bayberry leaf proanthocyanidins (BLPs) contain epigallocatechin-3-O-gallate as their terminal and major extension units, which is quite unusual in the plant kingdom. BLPs showed strong antioxidant and antiproliferative abilities in previous studies. In the present study, chemotherapy-resistant OVCAR-3 spheroid (SP) cells were obtained by sphere culturing and exhibited CSC-like properties by showing a higher ALDH(+) population and higher expression of stemness-related proteins. BLPs exhibited inhibitory effects on the growth and CSC characteristics of OVCAR-3 SP cells by showing decreased cell viability, sphere and colony formation ability, ALDH+ population and expression of stemness-related proteins. BLPs also targeted the Wnt/beta-catenin pathway by reducing the expression of beta-catenin, cyclin D1 and c-Myc and thus inhibited the self-renewal ability of OVCAR-3 SP cells. Furthermore, BLPs also induced G1 cell cycle arrest in OVCAR-3 SP cells. Taken together, these findings suggested that BLPs may be an important agent in the development of therapeutics for ovarian cancer patients.