Original articles
Yancheng Tang, Liming Wang, Tao Yi, Jun Xu, Jigang Wang, Jiang-Jiang Qin, Qilei Chen, Ka-Man Yip, Yihang Pan, Peng Hong, Yingying Lu, Han-Ming Shen, Hu-Biao Chen. Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3966-3982

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy
Yancheng Tanga, Liming Wangb,c, Tao Yia, Jun Xua, Jigang Wangd,e, Jiang-Jiang Qinf, Qilei Chena, Ka-Man Yipa, Yihang Pang, Peng Hongg, Yingying Lug,h, Han-Ming Shenc,i, Hu-Biao Chena
a. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China;
b. School of Biomedical Sciences, Hunan University, Changsha 410082, China;
c. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
d. Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China;
e. The First Affiliated Hospital of Southern University of Science and Technology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China;
f. The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China;
g. Department of Medical Research, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China;
h. Department of Biomedical Science, City University of Hong Kong, Hong Kong SAR 999077, China;
i. Faculty of Health Sciences, University of Macau, Macau SAR 999078, China
Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.
Key words:    PINK1-Parkin-mediated mitophagy    Magnolol    Combination therapy    Apoptosis    Tumor suppression   
Received: 2021-02-01     Revised: 2021-04-20
DOI: 10.1016/j.apsb.2021.06.007
Funds: This work was supported by research grants from Innovation and Technology Fund (PRP/036/20FX, China) and Health and Medical Research Fund (MHRF-16170251, China) of Hong Kong to Hu-Biao Chen, Singapore Ministry of Education (MOE) Tier 2 (MOE2018-T2-1-060, Singapore) to Han-Ming Shen, National Natural Science Foundation of China (82074123 to Hu-Biao Chen; 31501116 to Yingying Lu; 82071441 to Liming Wang). We thank members of Chen's laboratory and Shen's laboratory for valuable discussion. We gratefully thank the support from Dr. Richard Youle for providing the YFP-Parkin-HeLa cells; Dr. Noboru Mizushima for providing the GFP-LC3B-HeLa cells. We thank Dr. Martha Dahlen for polishing this manuscript.
Corresponding author: Yingying Lu,E-mail:Luyy39@sysu.edu.cn;Han-Ming Shen,E-mail:phsshm@nus.edu.sg;Hu-Biao Chen,E-mail:hbchen@hkbu.edu.hk     Email:Luyy39@sysu.edu.cn;phsshm@nus.edu.sg;hbchen@hkbu.edu.hk
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Yancheng Tang
Liming Wang
Tao Yi
Jun Xu
Jigang Wang
Jiang-Jiang Qin
Qilei Chen
Ka-Man Yip
Yihang Pan
Peng Hong
Yingying Lu
Han-Ming Shen
Hu-Biao Chen

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