Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients

Abstract

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the “drug plus diet” approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

“…The capacity of metformin to affect the availability of substrates/cofactors required for specific chromatin modifications could alter the height of phenotypic barriers, thereby facilitating (or impeding) the transition from one cell type to another (e.g., differentiation). Indeed, several examples illustrate the ability of metformin to alter the levels of metabolites related to chromatin remodeling, namely: NAD + (by acting as an inhibitor of mitochondrial NADH (nicotinademide adenine dinucleotide reduced) dehydrogenase and preventing NAD + regeneration [34][35][36][37]), acetyl-CoA (by impeding the acetyl-CoA carboxylase-catalyzed conversion of acetyl-CoA to malonyl-CoA [38]), α-ketoglutarate (by decreasing mitochondrial respiration and TCA cycle activity [39][40][41]), the SAM:SAH ratio (by targeting the coupling between serine mitochondrial one-carbon flux and AMPK-sensed complex I activity) [22,23], or β-hydroxybutyrate (by promoting mitochondrial fatty acid β-oxidation [42][43][44][45]). Since glucose induces histone O-GlcNAcylation (O-N-acetyl glucosaminylation) via the hexosamine biosynthesis pathway [46,47], the ability of metformin to impair glucose consumption by acting as an inhibitor of hexokinase-II [48,49] may globally link the cellular energy status with the regulation of the epigenome [50,51].…”

The mystery of the ketogenic diet: benevolent pseudo-diabetes

“…Ketogenesis is suppressed in aged mice and rapamycin increases ketone production [101]. Also, metformin increases blood levels of beta-hydroxybutyrate and alpha-ketoglutarate in cancer patients [102]. Remarkably, alpha-ketoglutarate inhibits MTOR and extends lifespan in Drosophila [103].…”

Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

“…Metformin might alter the general performance of immune system via modification of the microbiome 26 (4), specifically by changing microbial folate and serine/methionine metabolism. [27][28][29] Metformin might reverse an inhibitory tumor metabolism by remodeling the hypoxic TME via reduction of intratumoral hypoxia (5), a key driver of poor outcomes upon ICIs. Metformin might sustain or restore the infiltration of tumor-reactive T-cells into the tumor (6) by preventing the occurrence of dysfunctional states characterized by impaired activity and proliferative activity, increase apoptotic rate, and reduced production of effector cytokines (i.e., T-cell exhaustion).…”