Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog

  • Cell Death Dis. 2019 Mar 8;10(3):232. doi: 10.1038/s41419-019-1470-z.
Nan Yao  1  2 ,  Chenran Wang  1  2 ,  Nan Hu  1  2 ,  Yingjie Li  1  2 ,  Mingqun Liu  1  2 ,  Yuhe Lei  1  2 ,  Minfeng Chen  1  2 ,  Liping Chen  1  2 ,  Chen Chen  1 ,  Ping Lan  1 ,  Weimin Chen  1 ,  Zhesheng Chen  1  3 ,  Dengrui Fu  4 ,  Wencai Ye  1  2 ,  Dongmei Zhang  5  6
Affiliations
  • 1. College of Pharmacy, Jinan University, 510632, Guangzhou, China.
  • 2. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, 510632, Guangzhou, China.
  • 3. College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY, 11439, USA.
  • 4. Guangzhou Yucai Middle School, 510080, Guangzhou, China.
  • 5. College of Pharmacy, Jinan University, 510632, Guangzhou, China. [email protected].
  • 6. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, 510632, Guangzhou, China. [email protected].
PMID: 30850585 DOI: 10.1038/s41419-019-1470-z
Abstract

Betulinic acid (BA) and its derivatives are a class of high-profile drug candidates, but their Anticancer effects on resistant Cancer have rarely been reported. Although a few studies indicated Mitophagy is related with drug resistance, its role in different Cancer types and Anticancer agents treatment remains largely unclear. Here, we find that B5G1, a new derivative of BA, induces cell death in multidrug resistant Cancer cells HepG2/ADM and MCF-7/ADR through mitochondrial-apoptosis pathway. B5G1 also triggers Mitophagy independent on Atg5/Beclin 1. Further mechanistic study indicates that B5G1 upregulates PTEN-induced putative kinase 1 (PINK1) to recruit Parkin to mitochondria followed by ubiquitination of Mfn2 to initiate Mitophagy. Inhibition of Mitophagy by PINK1 siRNA, mdivi-1, or bafilomycin A1 (Baf A1) promotes B5G1-induced cell death. In addition, ROS production and mitochondrial damage in B5G1-treated HepG2/ADM cells cause mitochondrial Apoptosis and Mitophagy. In vivo study shown that B5G1 dramatically inhibits HepG2/ADM xenograft growth accompanied by Apoptosis and Mitophagy induction. Together, our results provide the first demonstration that B5G1, as a novel Mitophagy inducer, has the potential to be developed into a drug candidate for treating multidrug resistant Cancer.

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