Abstract
Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function.
Highlights
Introduction with regard to jurisdictional claims inSince the 1950s, the biguanide metformin has been the most widely used antihyperglycemic drug to treat patients with type 2 diabetes
Since the 1950s, the biguanide metformin has been the most widely used antihyperglycemic drug to treat patients with type 2 diabetes. This drug exerts its effects by reducing hepatic gluconeogenesis [1,2] and by increasing insulin sensitivity as well as glucose consumption of peripheral tissues [3]
The mechanisms underlying this action extend beyond the antihyperglycemic action and possibly identify an anticancer potential of metformin in nondiabetic patients. These expectations increased the interest in metformin up to contaminate the field of basic research activity, as documented by the PubMed database reported in Figure 1 that shows how the number of studies on experimental animals and containing the terms “metformin” grew simultaneously with the expansion of
Summary
Since the 1950s, the biguanide metformin has been the most widely used antihyperglycemic drug to treat patients with type 2 diabetes. Biomolecules 2021, 11, 1231 tabase reported in Figure 1 that shows how (and when) the number of studies on experimental animals and containing the terms “metformin” grew simultaneously with the ex of 10 pansion of “non-clinical” studies containing the terms “metformin and cancer”. Metformin in several experimental of solid tumors thatthe the evident approach to energy effect metabolism might represent a models new, ofpotentially solid tumors indicates that to theneoplastic approachpatients to energy represent a new, effective approach [8,9].metabolism This reviewmight aims to provide a detailed and, underapproach some aspects, challenging description the review mechanism potentially effective to neoplastic patients [8,9]. Derlying metformin interference on energy metabolism and glucose consumption as possible clues to develop innovative approaches for metabolic targeting in cancer
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