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

Abstract

Salicylates are among the oldest and most widely used medications, 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. Due to its acetyl group, aspirin irreversibly inhibits cyclooxygenases and thus blocks platelet aggregation, while 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. KeywordsAMPK; aspirin; salicylate; inflammation; diabetes; cancer Salicylates -origin and discovery of medicinal propertiesSalicylates are hormones produced by plants in response to infection, which are critical in their defence against attack by pathogens [1]. Salicylate and derivatives such as salicin (a β-glucosyl ester, Fig. 1) are transported to neighbouring tissues, triggering defensive responses; volatile derivatives such as methyl salicylate can even spread to neighbouring plants. Salicylates can therefore be regarded as the equivalent of cytokines operating in the plant version of the innate immune system. They are produced by essentially all plants, but are named after the willow Salix alba due to the high levels of salicin found in its bark. The medicinal effects of willow were known to ancient humans, making natural salicylates almost certainly the oldest drugs known to mankind (Box 1). A synthetic derivative, acetyl salicylic acid (Fig. 1) Recently, evidence has accumulated that salicylates are effective not only in their original roles of reducing pain, fever, inflammation and blood clotting, but also for treating insulin resistance and protecting against cancer. It seems unlikely that all of these beneficial effects can be explained by a single molecular target, and we discuss below the idea that some of these effects might be mediated by AMP-activated protein kinase (AMPK), a recently discovered new target [3,4]. Mechanism of action of salicylates: inhibition of cyclo-oxygenases?In 1971, Vane showed that aspirin inhibited prostaglandin synthesis [5]. The first two steps in this pathway are catalysed by cyclo-oxygenases that occur as two major isoforms, the ubiquitous COX1 form and COX2, whose expression is induced at sites of inflammation. Interestingly, the acetyl group of aspirin is transferred to a serine residue in the active site of both isoforms, causing irreversible inhibition [6]. Inhibition of synthesis of the prothrombotic prostanoid, thromboxane, elegantly explains the ability of aspirin to inhibit blood clotting triggered by platelets; because acetylation is irreversible and platelets cannot resynthesize COX1, the inhibition lasts for the full lifetime of the platelet [6]. ...

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

“…Interestingly, salicylates and other nonsteroidal anti‐inflammatory drugs were also shown to extend lifespan of yeast and fly through inhibition of tryptophan uptake (Danilov et al, 2015; He et al, 2014). Salicylates have also been shown to activate the adenosine monophosphate‐activated protein kinase (AMPK) (Hawley et al, 2012; Steinberg, Dandapani, & Hardie, 2013). This may in part explain why they held promise as treatments to improve insulin resistance and type 2 diabetes.…”

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

“…It has been suggested that aspirin may significantly impact cellular metabolism (Steinberg et al, 2013;Kamble et al, 2015). Furthermore, studies have suggested that SIRT1 or AMPK may contribute to the anticancer activity of aspirin mediating its ability to inhibit cell growth (Motoshima et al, 2006;Liu et al, 2009;Kumazaki et al, 2013).…”

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…The mechanism of action most commonly associated with salsalate is the direct repressing effect of salicylate on inhibitor of nuclear factor κ-B kinase subunit β (IKK-β) to reduce inflammation (11-13). However, the concentration of salicylate used in these studies nonspecifically inhibits many protein kinases through direct competition with their ATP binding sites (16)(17)(18). In contrast to kinase inhibition, salicylate has also been shown to directly activate AMPK, a metabolicsensing enzyme important for regulating inflammation (19), liver lipid metabolism (20), and brown fat thermogenesis (21,22).…”

“…Because the dose of salicylate used in this study results in serum concentrations of salicylate more than double the clinical levels after the oral intake of salsalate (~2.4 mmol/L compared with ~1.0 mmol/L, respectively) we hypothesized that the AMPK-β1-independent effects may have been a result of off-target kinase inhibition (16)(17)(18).…”