Abstract 5409: MEI-344, a novel isoflavone with activity as a mitochondrial oxygenase inhibitor

Abstract

Abstract ME-344, a second-generation derivative of a natural product isoflavone is being developed as a clinical candidate in small cell lung and ovarian cancer by MEI Pharma (San Diego, CA). Treatment of tumor cells in culture with low micromolar ME-344 decreased mitochondrial ATP production and increased ROS, with subsequent disruption of mitochondrial integrity. To gain further insight into this unusual mechanism of action, we compared ME-344 activity in sensitive and naturally resistant lung cancer cell lines, together with primary human lung embryonic fibroblasts (HLEF). Using SeaHorse technology we measured the impact of ME-344 on oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in these cells under conditions of mitochondrial and glycolytic stress. In a dose dependent manner, the drug caused instantaneous and pronounced inhibition of OCR in drug-sensitive lung cancer cells; significantly less in drug-resistant cells. These results are consistent with targeting of mitochondria by ME-344 with specific effects to the respiratory chain (drug resistance correlated with higher glycolytic indexes in these cells.) Inhibition of OCR did not occur in primary HLEF. ME-344 increased ECAR in drug-resistant lung cancer cells, where this effect was significantly diminished in drug-sensitive cells. Such data suggest that ME-344 specifically targets mitochondrial proton channels (pumps). Only in drug sensitive cells, ME-344 dose-dependently increased the intracellular generation of ROS (detected by H2DCF-DA or Deep Red fluorescent dye staining assays) and caused oxidation of intracellular low molecular weight (mainly GSH) and protein thiols and of NAD(P)H. In vivo studies used the PyMT mouse model, which gives rise to spontaneous breast tumors that are highly glycolytic, useful in assessing the comparative roles of aerobic and glycolytic metabolism. In this model, chronic treatments with the small molecule anti-angiogenic agent BIBF1120 (nintedanib) significantly diminished glycolysis, with the consequence that the growing tumor shifted to reliance on mitochondrial metabolism as the primary energy source. As monotherapy, ME-344 caused minimal inhibition of primary tumors. However, tumors primed by treatment with BIBF1120 showed significantly enhanced sensitivity to ME344, with synergistic antitumor activity. These data indicate complex, but mitochondria-specific effects of ME-344 in cancer cells, differing in extent from normal and linked with drug sensitivity profile with clinical potential through its specific targeting of bioenergetics pathways in cancer cells with the potential for beneficial therapeutic index. Citation Format: Yefim Manevich, Miguel Quintela-Fandino, Paloma Navarro, Carolyn Britten, Kenneth D. Tew, Danyelle M. Townsend. MEI-344, a novel isoflavone with activity as a mitochondrial oxygenase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2015-5409