Abstract 3895: Verrucarin J targets both cancer cells and cancer stem cells

Abstract Ovarian cancer is the fifth leading cause of death among women in the United States. The American Cancer Society estimates that approximately 22,280 women in the United States will be diagnosed with ovarian cancer and approximately 14,240 women will die as a result of ovarian cancer in 2016. The most common treatment for ovarian cancer is cytoreductive surgery, followed by chemotherapy (combination of carboplatin and paclitaxel). Although this regimen is initially effective in a high percentage of cases, unfortunately, within few months of initial treatment, tumor relapse occurs because of platinum-resistance. The presence of cancer stem cells (CSCs) are the main cause of this phenomenon. CSCs are a small population (2-5%) of cells in solid cancer which are chemo-resistant, highly tumorigenic, possess a self-renewal capacity, and the capability to differentiate into multiple lineage. Therefore, there is an urgent, unmet need for a more effective therapy that targets cancer cells as well as cancer stem cells. We screened for a novel drug that can target both cancer cells as well cancer stem cells and came cross Verrucarin J, a metabolite of the Myrothecium fungus family, which has not been tested for its antitumor activity. In our experiments, we treated two cisplatin-sensitive ovarian cancer cell lines (A2780 and OVCAR5) and one cisplatin-resistant cell line (A2780/CP70) with various concentrations of Verrucarin J. After treatment of cells, Verrucarin J showed: i) a highly significant inhibition of ovarian cancer cell proliferation in a dose- and time-dependent manner, with an IC50 value of approximately 10 nM after 48 h of treatment for all the three cell lines, ii) a significant increase in cell apoptosis, iii) a significant increase in DNA damage and generation of reactive oxygen species (ROS) compared to vehicle treated cells, iv) a significant down regulation of expression of cancer stem cells markers, and v) a significant inhibition of Notch1, Wnt1 and Shh signaling genes in a dose-dependent manner. Notch1, Wnt1 and Shh are major regulatory pathways for self-renewal and maintenance of cancer stem cells. Additionally, our experiments revealed that Verrucarin J inhibited the tumorigenic function (spheroid formation on ultra-low attachment plates) of isolated ALDH1 positive CSCs from ovarian cancer cell line A2780. Based on our results, we conclude that Verrucarin J is a highly potent anti-tumor drug and targets both cancer cells and cancer stem cells. Therefore, it may serve as a potential candidate for ovarian cancer treatment and replace currently used chemo-therapy. Note: This abstract was not presented at the meeting. Citation Format: Kelsey Carter, Seema Parte, Surinder K. Batra, Mariusz Z. Ratajczak, Sham S. Kakar. Verrucarin J targets both cancer cells and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3895. doi:10.1158/1538-7445.AM2017-3895