Abstract 3229: Drug repurposing of topiramate in obesity-driven endometrial cancer

Abstract

Abstract Introduction: Topiramate (TPM) is a B-D-fructopyranose sulfamate that acts by inhibiting carbonic anhydrases (CAs) and has been implicated as a novel inhibitor of angiogenesis. TPM is commonly used for the treatment of epilepsy and migraine headaches; however, when combined with phentermine, TPM can induce weight loss. Due to its weight loss and anti-angiogenic properties, we assessed TPM’s potential as an anti-tumorigenic agent in endometrial cancer (EC), a highly obesity-driven disease. Methods: Cell proliferation was assessed by MTT assay after exposure to TPM for 72 hours in the HEC-1A, KLE, Ishikawa and ECC-1 EC cell lines. Two representative cell lines, ECC-1 and Ishikawa, were used to analyze apoptosis, cell cycle progression, cell adhesion and invasion. Apoptosis was analyzed by Annexin V-FITC assay. Inhibition of adhesion and invasion by TPM were assessed by ELISA and transwell assay, respectively. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to assess downstream targets of the MAPK and mTOR pathways. The LKB1fl/flp53fl/fl EC mouse model was utilized to assess the in vivo effects of TPM. AdCre was injected at six weeks of age to induce invasive EC. Eight wks following AdCre injection, mice (N=10 per group) were treated with placebo or TPM (200 mg/kg/day, oral) for four weeks. The expression of phosphorylated-S6 and Ki-67 was assessed by IHC. Results: TPM inhibited cell proliferation in a dose dependent manner in all four EC cell lines (IC50 range=1500-3000 mM). Treatment with TPM resulted in G1 arrest and induction of apoptosis (p<0.05). TPM also reduced adhesion and invasion in the EC cell lines (p=0.05), with a corresponding decrease in VEGF expression. In addition, TPM significantly inhibited phosphorylation of p42/44 and S6 in the EC cell lines. Lastly, TPM decreased tumor weight in the LKB1fl/flp53fl/fl mice by 68% compared to those treated with placebo (p<0.05), accompanied by a reduction in Ki-67 and phosphorylated-S6 expression (p<0.05). Conclusion: TPM inhibited cell proliferation and tumor growth in EC cell lines and an EC mouse model. Therefore, TPM may be worthy of drug repurposing as an anti-tumorigenic agent in EC, with the potential added benefit of weight loss in this obesity-linked disease. Citation Format: Arthur-Quan Tran, Stephanie A. Sullivan, Chunxiao Zhou, David Kaufman, Victoria Bae-Jump. Drug repurposing of topiramate in obesity-driven endometrial cancer [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 3229. doi:10.1158/1538-7445.AM2017-3229