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

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.

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

“…A number of direct AMPK activators have been reported [17, 24]. Consistent with our previous works, we proposed a new class of compound exhibiting direct activation of AMPK, the bisbenzylisoquinoline alkaloid compounds such as liensinine, isoliensinine, dauricine, cepharanthine and hernandezine [25, 26]. Here, thalidezine (Figure 1A), a structural isomer of hernandezine C 39 H 44 N 2 O 7 (Supplementary Figure 1A), shows different structural conformation (Supplementary Figure 1B), having six different possible conformers compare with three for hernandezine [27].…”

Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells

“…Activation of AMPK can induce G0/G1 phase cell cycle arrest by downregulating cyclin D1 in CRC and myeloma cells [28,29]. Moreover, the AMPK activator hernandezine induces autophagic cell death in various human cancer cells such as HeLa, A549, MCF-7, PC3, HepG2, Hep3B, and H1299 [30]. In this study, betulin (8 µM) induced G0/G1 phase arrest and autophagy of CRC cells.…”

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

“…Phytomedicine 62 (2019) 152956 AMPK-mTOR signaling cascade and its cytotoxic action is independent of apoptosis (Law et al, 2016). Similar data were reported with CEP, and this capacity to enhance autophagy likely contributes to its anticancer activity (Law et al, 2014).…”