Research Papers:

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

Minsu Jang, Hyunju Kim, Rackhyun Park, Daum Jo, Eun-Ju Lee, Won Keun Oh and Junsoo Park _

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Oncotarget. 2017; 8:115068-115078. https://doi.org/10.18632/oncotarget.22858

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Minsu Jang1, Hyunju Kim1, Rackhyun Park1, Daum Jo1, Eun-Ju Lee2, Won Keun Oh3 and Junsoo Park1

1Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea

2Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul 06980, Republic of Korea

3Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

Correspondence to:

Junsoo Park, email: [email protected]

Keywords: autophagy; cancer; methylenebis; belotecan; camptothecin

Received: August 24, 2017    Accepted: November 13, 2017    Published: December 01, 2017


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.

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