Verrucarin J inhibits ovarian cancer and targets cancer stem cells

// Kelsey Carter 1 , Pranela Rameshwar 2 , Mariusz Z. Ratajczak 2, 3, 4 and Sham S. Kakar 1, 3 1 Department of Physiology, University of Louisville, Louisville, KY, USA 2 Department of Medicine, Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ, USA 3 James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA 4 Department of Medicine, University of Louisville, Louisville, KY, USA Correspondence to: Sham S. Kakar, email: sskaka01@louisville.edu Keywords: Verrucarin J, ovarian cancer, cancer stem cells, securin, tumor recurrence Received: June 14, 2017      Accepted: September 08, 2017      Published: October 06, 2017 ABSTRACT Ovarian Cancer is the fifth leading cause of death among women from cancer. Cancer stem cells are a small population of cells present in cancer and the cause of chemoresistance and recurrence of cancer. We tested a new compound “Verrucarin J (VJ)”, a metabolite of the Myrothecium fungus family, and showed that VJ significantly inhibits cell proliferation of both cisplatin-sensitive (A2780 and OVCAR5) and cisplatin-resistant (A2780/CP70) cell lines in a dose- and time-dependent manner with IC 50 value of approximately 10 nM after 48 h of treatment. VJ was found to induce apoptosis, DNA damage, and generation of reactive oxygen species (ROS). Treatment of A2780 cells with VJ resulted in a significant suppression of expression of CSCs markers including ALDH1, LGR5, NANOG and OCT4 in a dose-dependent manner, elimination of ALDH1 + CSC population and inhibition of expression of Notch1 and Wnt1 signaling pathways. Our study also showed that VJ inhibited the tumorigenic potential (spheroid formation on ultralow attachment plates) of isolated ALDH1 + CSCs in vitro and tumor growth and metastasis in vivo . VJ resulted downregulation of expression of securin an “oncogene” involved in tumor growth and progression, indicating that securin may serve as a downstream signaling gene to mediate antitumor effects of VJ.