# Biological Anti-Tumoral Mechanisms of Metformin in Head and Neck Squamous Cell Carcinomas: A Systematic Review

## TL;DR

This paper reviews how Metformin, a diabetes drug, may help fight head and neck cancer by slowing tumor growth and boosting other treatments.

## Contribution

The paper systematically reviews Metformin's biological anti-tumoral mechanisms in head and neck squamous cell carcinomas.

## Key findings

- Metformin reduces HNSCC proliferation by inducing G0/G1 cell cycle arrest and apoptosis.
- Metformin modulates tumor microenvironment and activates immune cells.
- Metformin enhances the effectiveness of other anti-tumoral therapies when used in combination.

## Abstract

Background/Objectives: Recent studies suggest Metformin could be a potential anti-tumoral agent. This review aims to understand the biological anti-tumoral mechanisms of Metformin in head and neck cancer squamous cell carcinomas (HNSCC) both in vitro and in vivo. Methods: Two investigators screened publications on the biological anti-tumoral effects of Metformin in HNSCC. The literature search was conducted on PubMed, Cochrane Library, and Scopus using PICOTS and PRISMA statements. Results: A total of 30 papers were identified, including 18 studies exploring the effect of Metformin alone and 12 studies exploring its effect in association with another drug or therapy for HNSCC lines. The results suggest that Metformin decreases the proliferation rate of HNSCC through inhibition of cell proliferation by the induction of G0/G1 cell cycle arrest and activation of apoptosis, by regulating proteins involved in carcinogenesis pathways, and also affects the tumor microenvironment by switching the metabolism and activating immune cells. In addition, Metformin can potentiate the efficiency and/or sensibility of other anti-tumoral treatments. The present systematic review highlights the biological anti-tumoral effects of Metformin used alone or in combination with traditional therapies for HNSCC. Conclusions: This review of the literature summarizes the biological anti-tumoral effects associated with Metformin alone or in combination with other therapies. While the molecular effects of Metformin on signaling pathways are different when used alone than in combination, they converge in a decreased proliferation of tumor cells and/or a sensitization of HNSCC to other anti-cancer therapies.