Metformin Down Regulates the Oncogenic miRNA_21 and Cyclin D1 in Oral Potentially Malignant Disorders: An Emerging Role of an Old Drug in Cancer Chemoprevention

Abstract

Aim: This study aimed to compare the effect of metformin hydrochloride compared to placebo on oral potentially malignant disorders (OPMDs) regarding its efficacy in cancer chemoprevention.

Methodology:This trial was a multicenter, double-blind, placebo-controlled, randomized phase  II trial. Forty non-diabetic adult patients, clinically and histologically diagnosed with OPMDs were enrolled into the study. Eligible patients were randomly assigned (1:1) to receive oral metformin (500 mg daily) oridentical placebo tablets by a stratified computer-based randomization method for a duration of 3 months. All patients, clinicians, and outcome assessors were masked to drug allocation until the end of the trial. Recommended standard care was given to both groups. Clinical data, biopsies, immunohistochemicalstainingof cyclin D1, and RT-qPCRquantification of tissue, and salivary miRNA-21 were performed for all groups at baseline, and at three months point.

Results:The current study showed that metformin was effective as a cancer chemopreventive agent via controlling the molecular mechanisms that could lead to the malignant transformation of OPMDs. Clinical lesion size, nuclear expression of cyclin D1 and tissue, and salivary levels of cancer-associated miRNA-21 showed a statistically significant reduction in the metformin compared to the placebo group. Cyclin D1 and miRNA-21 correlated well to the degree of epithelial dysplasia. miRNA-21 demonstrated a positive correlation between tissue, and salivary levels, confirming the validity of chosenmarkers.

Conclusions:Our data emphasize the potential clinical benefits of using metformin as a cancer chemo- preventive agent in OPMDs.