biomolecules Review Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside? Cecilia Marini 1,2, *, Vanessa Cossu 3 , Matteo Bauckneht 2,3 , Francesco Lanfranchi 3 , Stefano Raffa 3 , Anna Maria Orengo 2 , Silvia Ravera 4 , Silvia Bruno 4 and Gianmario Sambuceti 1,2   Citation: Marini, C.; Cossu, V.; Bauckneht, M.; Lanfranchi, F.; Raffa, S.; Orengo, A.M.; Ravera, S.; Bruno, S.; Sambuceti, G. Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside? Biomolecules 2021, 11, 1231. https://doi.org/10.3390/ biom11081231 Academic Editor: Kateˇ rina Ka ˇ nková Received: 14 July 2021 Accepted: 16 August 2021 Published: 18 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 CNR Institute of Molecular Bioimaging and Physiology (IBFM), 20054 Milan, Italy; Sambuceti@unige.it 2 IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; matteo.bauckneht@hsanmartino.it (M.B.); annamaria.orengo@hsanmartino.it (A.M.O.) 3 Department of Health Sciences, University of Genoa, 16132 Genoa, Italy; vane.6291@gmail.com (V.C.); dr.francescolanfranchi@gmail.com (F.L.); stefanoraffa@live.com (S.R.) 4 Department of Experimental Medicine, Human Anatomy, University of Genoa, 16132 Genoa, Italy; silvia.ravera@unige.it (S.R.); silvia.bruno@unige.it (S.B.) * Correspondence: Cecilia.Marini@unige.it; Tel.: +39-010-555-4812 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. Keywords: metformin; glucose consumption; FDG PET/CT imaging; endoplasmic reticulum; tumor metabolism; cancer therapy 1. Introduction Since the 1950s, the biguanide metformin has been the most widely used antihy- perglycemic 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 glu- cose consumption of peripheral tissues [3]. Besides this classical indication, a wide literature proposed a potential efficacy of this biguanide in anticancer therapy, either alone or in com- bination with other approaches [4]. The mechanisms underlying this action extend beyond the antihyperglycemic action and possibly identify an anticancer potential of metformin in nondiabetic patients. As an obvious consequence, 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 (and when) the number of studies on experimental animals and containing the terms “metformin” grew simultaneously with the expansion of “non-clinical” studies containing the terms “metformin and cancer”. Biomolecules 2021, 11, 1231. https://doi.org/10.3390/biom11081231 https://www.mdpi.com/journal/biomolecules