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

Author:

Amengual-Cladera Emilia12,Morla-Barcelo Pere Miquel23ORCID,Morán-Costoya Andrea12,Sastre-Serra Jorge234ORCID,Pons Daniel Gabriel23ORCID,Valle Adamo124ORCID,Roca Pilar234ORCID,Nadal-Serrano Mercedes23ORCID

Affiliation:

1. Grupo Metabolismo Energético y Nutrición, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain

2. Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain

3. Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain

4. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, 28029 Madrid, Spain

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 in 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.

Funder

Balearic Islands Government

European Social Fund

Publisher

MDPI AG

Reference207 articles.

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