Jang Minsu, Kim Hyunju, Park Rackhyun, Jo Daum, Lee Eun-Ju, Oh Won Keun, Park Junsoo
Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea.
Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul 06980, Republic of Korea.
Oncotarget. 2017 Dec 1;8(70):115068-115078. doi: 10.18632/oncotarget.22858. eCollection 2017 Dec 29.
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.
自噬调节对肿瘤细胞存活至关重要。自噬的激活和抑制可使肿瘤细胞对抗癌药物敏感。然而，可用于提高抗癌药物疗效的自噬调节小分子却很少。在此，我们报告2,2'-亚甲基双（6-叔丁基-4-甲基苯酚），以下简称亚甲基双，是一种新型的自噬调节小分子，它能使肿瘤细胞对喜树碱衍生物贝洛替康敏感，喜树碱是一种拓扑异构酶I抑制剂。亚甲基双通过提高LC3-II水平和形成自噬溶酶体斑点来激活自噬流。此外，亚甲基双通过激活自噬和凋亡来增强贝洛替康的抗肿瘤疗效。有趣的是，亚甲基双提高了LC3-II水平，而贝洛替康独立降低了p62水平，这表明亚甲基双和贝洛替康靶向自噬的不同步骤。最后，我们寻找与亚甲基双结构相似的化合物。我们的结果表明，亚甲基双的特定结构有助于其激活自噬的能力。
