Cellular Responses to the Metal-Binding Properties of Metformin

Abstract

In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive π-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action.

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

“…These findings support the notion that since transporters involved in uptake and extrusion of metformin were designed by nature for endogenous substrates, the metabolic effects of metformin might involve substrate competition phenomena with metabolites or nutrients (Glossmann & Reider, 2013). Metformin and related biguanides are known to bind endogenous metals such as Zn 2+ , Cu 2+ , Fe 3+ that independently inhibit pro‐inflammatory proteases (Glossmann & Reider, 2013; Lockwood, 2010; Logie et al., 2012; Sweeney et al., 2003; Thorne & Lockwood, 1991). Accordingly, our systematic chemoinformatics approach confirmed that metallopeptidases and proteins with transition metal ion‐binding properties were significantly overrepresented among the predicted targets for metformin.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…Recent evidence suggests that this may involve an interaction between biguanides and copper ions critical for oxidative phosphorylation (50), and other molecular mechanisms are under study.…”

Potential applications for biguanides in oncology

“…While agents such as 2-deoxyglucose have not proven clinically useful, targeting energy metabolism remains a key research focus. There is evidence that the biguanide family of compounds induces energetic stress by inhibition of oxidative phosphorylation (2-7), but additional mechanisms have not been excluded (8,9). A long history of research supports the idea that biguanides perturb cellular and whole-organism energy metabolism; the challenge is to determine whether this can be exploited for cancer treatment or prevention (see Milestones in biguanide research related to neoplasia).…”