title: Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death.
abstract: Cancers illustrating resistance towards apoptosis is one of the main factors causing clinical failure of conventional chemotherapy. Innovative therapeutic methods which can overcome the non-apoptotic phenotype are needed. The AMP-activated protein kinase (AMPK) is the central regulator of cellular energy homeostasis, metabolism, and autophagy. Our previous study showed that the identified natural AMPK activator is able to overcome apoptosis-resistant cancer via autophagic cell death. Therefore, AMPK is an ideal pharmaceutical target for chemoresistant cancers. Here, we unravelled that the bisbenzylisoquinoline alkaloid thalidezine is a novel direct AMPK activator by using biolayer interferometry analysis and AMPK kinase assays. The quantification of autophagic EGFP-LC3 puncta demonstrated that thalidezine increased autophagic flux in HeLa cancer cells. In addition, metabolic stress assay confirmed that thalidezine altered the energy status of our cellular model. Remarkably, thalidezine-induced autophagic cell death in HeLa or apoptosis-resistant DLD-1 BAX-BAK DKO cancer cells was abolished by addition of autophagy inhibitor (3-MA) and AMPK inhibitor (compound C). The mechanistic role of autophagic cell death in resistant cancer cells was further supported through the genetic removal of autophagic gene7 (Atg7). Overall, thalidezine is a novel AMPK activator which has great potential to be further developed into a safe and effective intervention for apoptosis- or multidrug-resistant cancers.
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Betty Yuen Kwan
authors.initials: BYK
authors.lastname: Law
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Flora
authors.initials: F
authors.lastname: Gordillo-Martínez
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Yuan Qing
authors.initials: YQ
authors.lastname: Qu
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Su Wei
authors.initials: SW
authors.lastname: Xu
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Paolo Saul
authors.initials: PS
authors.lastname: Coghi
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Simon Wing Fai
authors.initials: SWF
authors.lastname: Mok
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Guo
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Elaine Lai Han
authors.initials: ELH
authors.lastname: Leung
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Xing Xing
authors.initials: XX
authors.lastname: Fan
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: An Guo
authors.initials: AG
authors.lastname: Wu
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Xiao Jun
authors.initials: XJ
authors.lastname: Yao
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Jing Rong
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Vincent Kam Wai
authors.initials: VKW
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D055372:AMP-Activated Protein Kinases
keywords: AMPK activator; apoptosis-resistant cancer; autophagic cell death; autophagy; thalidezine