Title: Elimination of quiescent slow-cycling cells via reducing quiescence depth by natural compounds purified from <i>Ganoderma lucidum</i>
Abstract: // Jian Dai 1, 4 , Matthew A. Miller 1 , Nicholas J. Everetts 1 , Xia Wang 1 , Peng Li 2 , Ye Li 3 , Jian-Hua Xu 2 , Guang Yao 1, 5 1 Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA 2 School of Pharmacy and Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, Fujian, China 3 Fujian Xianzhilou Biological Science and Technology Co, Ltd, Fuzhou, Fujian, China 4 Jiangsu Academy of Agricultural sciences, Nanjing, Jiangsu, China 5 Arizona Cancer Center, University of Arizona, Tucson, AZ, USA Correspondence to: Guang Yao, email: [email protected] Jian-Hua Xu, email: [email protected] Ye Li, email: [email protected] Keywords: quiescence, natural compounds, ganoderma lucidum, slow-cycling cells, cancer stem cells Received: May 01, 2016 Accepted: January 03, 2017 Published: January 13, 2017 ABSTRACT The medical mushroom Ganoderma lucidum has long been used in traditional Chinese medicine and shown effective in the treatment of many diseases including cancer. Here we studied the cytotoxic effects of two natural compounds purified from Ganoderma lucidum , ergosterol peroxide and ganodermanondiol. We found that these two compounds exhibited cytotoxicity not only against fast proliferating cells, but on quiescent, slow-cycling cells. Using a fibroblast cell-quiescence model, we found that the cytotoxicity on quiescent cells was due to induced apoptosis, and was associated with a shallower quiescent state in compound-treated cells, resultant from the increased basal activity of an Rb-E2F bistable switch that controls quiescence exit. Accordingly, we showed that quiescent breast cancer cells (MCF7), compared to its non-transformed counterpart (MCF10A), were preferentially killed by ergosterol peroxide and ganodermanondiol treatment presumably due to their already less stable quiescent state. The cytotoxic effect of natural Ganoderma lucidum compounds against quiescent cells, preferentially on quiescent cancer cells vs. non-cancer cells, may help future antitumor development against the slow-cycling cancer cell subpopulations including cancer stem and progenitor cells.