Abstract 5379: Ciclopirox induces autophagy through reactive oxygen species-mediated inhibition of mTOR signaling pathway

Abstract

Abstract Ciclopirox olamine (CPX), a synthetic antifungal agent clinically used to treat mycoses of the skin and nails, has been recently found to inhibit tumor growth in mouse model of leukemia and breast cancer MDA-MB231. The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine kinase, is known as a negative regulator of autophagy. Herein, we found that CPX substantially increased GFP-LC3 dots and expression of LC3-II, a hallmark of autophagy, suggesting that CPX induced autophagy. Meanwhile, we discovered that CPX inhibited mTOR signaling in different cancer cell lines, as evidenced by reduced phosphorylation of the downstream targets of mTOR, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). Recently, it has been demonstrated that autophagy can be induced by reactive oxygen species (ROS). Interestingly, we further found that CPX treatment dose-dependently induced ROS generation. Pretreatment with N-acetyl-L-cysteine (NAC) suppressed CPX-induced ROS and the conversion of LC3I to LC3II, suggesting that CPX-induced autophagy is mediated by ROS generation. Moreover, the inhibition of phosphorylation of S6K1 and 4E-BP1 by CPX were partially rescued by NAC pretreatment as well. These data suggest that CPX-induced autophagy may be attributed to induction of ROS and subsequent inhibition of mTOR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5379. doi:10.1158/1538-7445.AM2011-5379