2,2′-Methylenebis (6-tert-butyl 4-methylphenol) enhances the antitumor efficacy of belotecan, a derivative of camptothecin, by inducing autophagy

// Minsu Jang 1 , Hyunju Kim 1 , Rackhyun Park 1 , Daum Jo 1 , Eun-Ju Lee 2 , Won Keun Oh 3 and Junsoo Park 1 1 Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea 2 Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul 06980, Republic of Korea 3 Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea Correspondence to: Junsoo Park, email: junsoo@yonsei.ac.kr Keywords: autophagy; cancer; methylenebis; belotecan; camptothecin Received: August 24, 2017     Accepted: November 13, 2017     Published: December 01, 2017 ABSTRACT Autophagy regulation is important for tumor cell survival. Activation and inhibition of autophagy can sensitize tumor cells to anticancer drugs. However, few autophagy-regulating small molecules are available to increase the efficacy of anticancer drugs. Here, we report that 2,2’-methylenebis (6-tert-butyl 4-methylphenol), hereafter referred to as methylenebis, is a novel autophagy-regulating small molecule that sensitizes tumor cells to belotecan, which is a derivative of camptothecin, a topoisomerase I inhibitor. Methylenebis activates autophagic flux by increasing the level of LC3-II and forming autolysosome puncta. Moreover, methylenebis enhances the antitumor efficacy of belotecan by activating both autophagy and apoptosis. Interestingly, methylenebis increased the level of LC3-II and belotecan independently decreased the level of p62, suggesting that methylenebis and belotecan target different steps of autophagy. Finally, we searched for compounds that are structurally similar to methylenebis. Our results imply that the specific structure of methylenebis contributes to its ability to activate autophagy.