Hernandezine, a novel AMPK activator induces autophagic cell death in drug-resistant cancers

// Betty Yuen Kwan Law 1 , Simon Wing Fai Mok 1 , Wai Kit Chan 1 , Su Wei Xu 1 , An Guo Wu 1 , Xiao Jun Yao 1 , Jing Rong Wang 1 , Liang Liu 1 , Vincent Kam Wai Wong 1 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China Correspondence to: Vincent Kam Wai Wong, e-mail: bowaiwong@gmail.com Liang Liu, e-mail: lliu@must.edu.mo Keywords: hernandezine, AMPK activator, autophagy, autophagic cell death, drug-resistant cancer Received: September 13, 2015 Accepted: January 01, 2016 Published: January 22, 2016 ABSTRACT Drug resistance hinder most cancer chemotherapies and leads to disease recurrence and poor survival of patients. Resistance of cancer cells towards apoptosis is the major cause of these symptomatic behaviours. Here, we showed that isoquinoline alkaloids, including liensinine, isoliensinine, dauricine, cepharanthine and hernandezine, putatively induce cytotoxicity against a repertoire of cancer cell lines (HeLa, A549, MCF-7, PC3, HepG2, Hep3B and H1299). Proven by the use of apoptosis-resistant cellular models and autophagic assays, such isoquinoline alkaloid-induced cytotoxic effect involves energy- and autophagy-related gene 7 (Atg7)-dependent autophagy that resulted from direct activation of AMP activated protein kinase (AMPK). Hernandezine possess the highest efficacy in provoking such cell death when compared with other examined compounds. We confirmed that isoquinoline alkaloid is structurally varied from the existing direct AMPK activators. In conclusion, isoquinoline alkaloid is a new class of compound that induce autophagic cell death in drug-resistant fibroblasts or cancers by exhibiting its direct activation on AMPK.