AMPK: a target for drugs and natural products with effects on both diabetes and cancer

Abstract

The AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy that appears to have arisen at an early stage during eukaryotic evolution. In 2001 it was shown to be activated by metformin, currently the major drug for treatment for type 2 diabetes. Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, as discussed below it now appears unlikely that AMPK is the sole target of the drug. AMPK is also activated by several natural plant products derived from traditional medicines, and the mechanisms by which they activate AMPK are discussed. One of these is salicylate, probably the oldest medicinal agent known to humankind. The salicylate prodrug salsalate has been shown to improve metabolic parameters in subjects with insulin resistance and prediabetes, and whether this might be mediated in part by AMPK is discussed. Interestingly, there is evidence that both metformin and aspirin provide some protection against development of cancer in humans, and whether AMPK might be involved in these effects is also discussed.

FIG. 1.

Tripartite mechanism by which AMPK is activated by changes in cellular energy status. Displacement of ATP by ADP and/or AMP at one or more of the sites on the AMPK-γ subunit causes a conformational change in the heterotrimeric complex that 1) promotes phosphorylation, and 2) inhibits dephosphorylation of Thr-172, causing a large (up to 100-fold) increase in kinase activity. Binding of AMP, but not ADP, causes 3) further activation of the phosphorylated kinase of up to 10-fold. The upstream kinase LKB1 appears to be constitutively active, and increased Thr-172 phosphorylation in response to energy stress does not normally occur in tumor cells lacking LKB1. However, AMPK can also be activated by Thr-172 phosphorylation catalyzed by CaMKKβ via a mechanism that requires an increase in intracellular Ca²⁺ but can be independent of changes in AMP and/or ADP.

FIG. 2.

Structures of AMPK activators based on guanidine, including the biguanides metformin and phenformin.

FIG. 3.

Schematic diagram of the proposed new mechanism by which metformin inhibits hepatic gluconeogenesis (42). Up or down arrows next to a metabolite or enzyme show the direction the concentration or activity changes in response to metformin. Metformin (whose uptake into hepatocytes is promoted by the organic cation transporter [OCT1]) accumulates in mitochondria where it inhibits Complex 1 of the respiratory chain, lowering cytoplasmic ATP and increasing ADP and AMP. AMP activates AMPK but also inhibits adenylate cyclase, reducing effects of glucagon on cAMP and PKA and thus reducing the ability of PKA to promote gluconeogenesis by phosphorylation of PFK2 and other targets regulating transcription of gluconeogenic genes. F16BP, fructose-1,6-bisphosphate; F16BPase, fructose-1,6-bisphosphatase; F26BP, fructose-2,6-bisphosphate; G6Pase, glucose-6-phosphatase; PFK1, 6-phosphofructo-1-kinase; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

FIG. 4.

Structures of plant polyphenols that have been reported to be AMPK activators.

FIG. 5.

Structures of medicinal salicylates and the AMPK activator A-769662.