AMPK: mediating the metabolic effects of salicylate-based drugs?

• Salicylates, which include aspirin, are among the oldest drugs known to man.
• Their known targets, COX1/2, cannot explain all anti-inflammatory actions.
• Salicylate also activates AMPK by direct binding involving the β1 subunit.
• By modulating metabolism, this may account for some anti-inflammatory effects.
• It might also explain beneficial effects of salicylates in diabetes and cancer.

Salicylates are among the oldest medicinal compounds known to humans, and have been used to reduce fever, pain, and inflammation. The major oral salicylates are aspirin and salsalate, both of which are rapidly metabolized to salicylate in vivo. Owing to its acetyl group, aspirin irreversibly inhibits cyclo-oxygenases and thus blocks platelet aggregation, whereas salsalate has been used for treatment of inflammatory diseases such as rheumatoid arthritis. Recently, beneficial effects of salicylates in type 2 diabetes and cancer have been proposed. This has led to renewed interest in understanding how these simple molecules have such diverse and multifaceted effects. Here we discuss the idea that AMP-activated protein kinase (AMPK) might mediate some effects of salicylate-based drugs, particularly by modulating cellular metabolism.