Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

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

Emilia Amengual-Cladera
,
Pere Miquel Morla-Barcelo
ORCID logo ,
Andrea Morán-Costoya
,
Adamo Valle
ORCID logo ,
Daniel Gabriel Pons
ORCID logo ,
Jorge Sastre-Serra
ORCID logo ,
Pilar Roca
* ORCID logo ,
Mercedes Nadal-Serrano
Version 1 : Received: 21 March 2024 / Approved: 21 March 2024 / Online: 22 March 2024 (07:28:16 CET)

A peer-reviewed article of this Preprint also exists.

Amengual-Cladera, E.; Morla-Barcelo, P.M.; Morán-Costoya, A.; Sastre-Serra, J.; Pons, D.G.; Valle, A.; Roca, P.; Nadal-Serrano, M. Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies. Biology 2024, 13, 302. Amengual-Cladera, E.; Morla-Barcelo, P.M.; Morán-Costoya, A.; Sastre-Serra, J.; Pons, D.G.; Valle, A.; Roca, P.; Nadal-Serrano, M. Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies. Biology 2024, 13, 302.

Abstract

Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin’s role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement of survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.

Keywords

Metformin, Diabetes; Mitochondria; Breast Cancer; Colorectal Cancer

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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