Why Metformin Should Not Be Used as an Oxidative Phosphorylation Inhibitor in Cancer Patients

Abstract

Background: Preclinical studies have suggested that metformin exerts antitumor effects on various types of cancers. However, the results of human clinical trials have been inconsistent. Summary: Metformin is widely considered to be a prime example of a clinically relevant compound that inhibits oxidative phosphorylation (OXPHOS). However, the efficacy of metformin in inhibiting OXPHOS in cancer patients remains uncertain. The available evidence suggests that the plasma concentration of metformin remains within the micromolar range when administered at therapeutic doses. While millimolar concentrations are necessary to inhibit complex I activity in isolated mitochondria, there is no evidence supporting the idea that metformin accumulates within the mitochondria. Metformin exerts a modest effect on the adenosine diphosphate to adenosine triphosphate (ATP) ratio, resulting in AMP-activated protein kinase activation, which promotes ATP-generating catabolic pathways and restores cellular energy balance. Key Messages: The value of metformin as an OXPHOS inhibitor for cancer treatment is debatable, and caution should be exercised while using metformin for this purpose.

Examining the clinical relevance of metformin as an antioxidant intervention

“…Metformin exerts a subtle impact on the adenosine diphosphate to adenosine triphosphate ratio, culminating in the activation of AMP-activated protein kinase, thereby fostering the activation of ATP-generating catabolic pathways and restoration of cellular energy homeostasis. The metformin’s value as an OXPHOS inhibitor for cancer treatment remains a subject of contention, and prudence is advisable in its utilization for this purpose ( Sakellakis, 2023 ). Thus, molecular alterations under metformin intervention have not clearly demonstrated antioxidant properties.…”

Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies

“…This concentration is influenced not only by plasma level, but also by cellular uptake in cancer cells, which depends on the expression of relevant transporters including OCT1 [36]. It is worth noting that serum levels of metformin achieved in diabetic patients and in vivo models are in the micromolar range, while in vitro antitumoral activity is observed at millimolar concentrations [37]. Hence, a fundamental research inquiry is to determine the metformin concentrations achieved in tumors of patients receiving conventional antidiabetic metformin dose.…”

“…It is imperative to consider a recent review that underscores the controversy surrounding the impact of metformin treatment on tumor cells in human patients. This review posits that the concentrations of metformin required for substantial inhibition of Complex I are roughly 1000 times higher than those typically utilized for treating T2D, making its application as a neoadjuvant anticancer therapy impractical [37]. Despite the theoretical possibility of metformin accumulation in mitochondria owing to its cationic charge, there exists no definitive supportive evidence for this assertion.…”

Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies

“…This concentration is influenced not only by plasma level, but also by cellular uptake in cancer cells, which depends on the expression of relevant transporters, including OCT1 [36]. It is worth noting that serum levels of metformin achieved in diabetic patients and in vivo models are in the micromolar range, while in vitro antitumoral activity is observed at millimolar concentrations [37].…”

“…It is imperative to consider a recent review that underscores the controversy surrounding the impact of metformin treatment on tumor cells in human patients. This review posits that the concentrations of metformin required for substantial inhibition of Complex I are roughly 1000 times higher than those typically utilized for treating T2DM, making its application as a neoadjuvant anticancer therapy impractical [37]. Indeed, clinical trials involving non-diabetic individuals highlight the need to refine dosing strategies.…”