Abstract 2993: Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines

Abstract

Abstract Objective: Dichloroacetate (DCA) is a well-tolerated, oral drug used in the treatment of hereditary lactic acidosis. DCA has been found to have anti-tumorigenic activity in various non-gynecologic cancers through its inhibition of pyruvate dehydrogenase, leading to profound mitochondrial defects in cancer cells. Thus, we sought to assess the effects of DCA on human endometrial cancer cell lines. Methods: Three endometrial cancer cell lines (KLE, Ishikawa, and ECC-1) were treated with varying concentrations of DCA from 0.1uM to 100 uM. Cell proliferation was measured using the MTT assay. Cell cycle progression was assessed by Cellometer. Apoptosis was evaluated by the Annexin V-FITC assay using Cellometer. Western immunoblotting was performed to assess effects of DCA on cell cycle and cellular stress proteins. In addition, cellular stress was measured using a reactive oxygen species assay. All experiments were performed in triplicate. Results: DCA inhibited cell proliferation in a dose-dependent manner in all three endometrial cancer cell lines following 72 hours of exposure. The IC50 was 30 uM for KLE, 78 uM for Ishikawa, and 72 uM for ECC-1. Treatment with DCA resulted in G1 phase cell cycle arrest in all three cell lines. DCA induced apoptosis in all three cell lines. Western blotting analysis demonstrated that DCA increased cyclin D1 expression, decreased CDK4 expression, and increased PERK expression after 24 hours of DCA exposure. A dose dependent increase in reactive oxygen species was seen in all three cell lines. At a maximum dose of 100 uM DCA, ROS production compared to controls for KLE increased 3.2-fold (p = 0.002), Ishikawa increased 1.8-fold (p = 0.003), and ECC-1 increased 2.1-fold (p = 0.002). Conclusions: DCA effectively inhibited cell proliferation via G1 cell cycle arrest and induced apoptosis in human endometrial cancer cell lines. DCA induced significant cellular stress as evidenced by a dose dependent increase in reactive oxygen species. Further evaluation of DCA as a targeted metabolic therapy in endometrial cancer is warranted. Citation Format: Leslie H. Clark, Chunxiao Zhou, Victoria Bae-Jump. Dichloroacetate inhibits cell proliferation and induces apoptosis in human endometrial cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2993.