Abstract 45: Preventing and treating hepatic metastatic colon and pancreatic cancers by targeting cell metabolism

Abstract One fundamental change in cancer cells in oncogenesis is the alteration of glucose metabolism. With few exceptions, cancer cells exhibit aerobic glycolysis. A majority of pyruvate derived from glycolysis is converted to lactate instead of entering mitochondria for oxidative phosphorylation. This feature of cancer cells is also referred as “the Warburg effect”. The functional significance of the inefficient metabolic mode to cancer cells is becoming clear. In essence, reduction in the flux of pyruvate into mitochondria prevents complete oxidation of glucose. This increases production of NADPH and metabolic intermediates required for biosynthesis of macromolecules essential for cell proliferation. Pyruvate flux into mitochondria can be dramatically enhanced through mitochondrial uncoupling, a process that allows protons cross the mitochondrial inner membrane without producing ATP. As a result, mitochondrial uncoupler promotes “futile” oxidation of acetyl-CoA, leading to complete glucose oxidation. Therefore, safe mitochondrial uncouplers could be potent anti-cancer agents by antagonizing the function of the Warburg effect. Here we tested this novel cancer chemotherapeutic strategy with niclosamide ethanolamine (NEN), a well-characterized mitochondrial uncoupler with an excellent safety profile, and one of its derivative (OXY-1) in culture cell models and a mouse model. Mouse colon cancer cells (MC38) and mouse pancreatic cells (Panc02) were treated with NEN and OXY-1. At effective mitochondrial uncoupling concentrations, NEN and OXY-1 reduced cells viability, induced cell cycle arrest, and reduced clonegenicity. Moreover, NEN and OXY-1 also inhibited cell migration. These effects were associated with the activation of AMPK and reduction of NADPH/NADP ratio. We further examined the anti- cancer effect of NEN and OXY-1 on a metastatic cancer mouse model. First, we tested if the uncouplers are effective in inhibiting cancer growth. The MC38 or Panc02 cells were injected into the liver of NOD mice. Oral treatment of OXY-1 (800 ppm in food) significantly reduced tumor size and tumor incidence in mouse liver. We then tested if these drugs could inhibit tumor metastasis. MC38 or Panc02 cells were intrasplenically injected into the mice and the tumor metastasis to liver was analyzed. Oral NEN (2000 ppm in food) or OXY-1 (800 ppm in food) either totally prevented tumor metastasis to liver or drastically reduced metastatic tumor numbers and tumor volume. Taken together, our results strongly suggest that the safe and mild mitochondrial uncouplers NEN and OXY-1 could be effective in preventing and treating hepatic metastasis of colon and pancreatic cancers. Our results may provide a new and attractive way for preventing and treating these incurable tumors. Citation Format: AMER H. ALASADI, Jingjing Guo, Hanlin Tao, Shengkan Jin. Preventing and treating hepatic metastatic colon and pancreatic cancers by targeting cell metabolism. [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 45.