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

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.

AMPK activator; apoptosis-resistant cancer; autophagic cell death; autophagy; thalidezine.