Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma.

Selena Z Kuo,Elizabeth Kim,Jessica Wang-Rodriguez,Christine O Honda,Thomas K Honda,Eric Abhold,Weg M Ongkeko,Xabier Altuna,Wei Tse Li

doi:10.3390/ijms20010193

Abstract

Cancer stem cells (CSCs) have been shown as a distinct population of cancer cells strongly implicated with resistance to conventional chemotherapy. Metformin, the most widely prescribed drug for diabetes, was reported to target cancer stem cells in various cancers. In this study, we sought to determine the effects of metformin on head and neck squamous cell carcinoma (HNSCC). CSCs and non-stem HNSCC cells were treated with metformin and cisplatin alone, and in combination, and cell proliferation levels were measured through MTS assays. Next, potential targets of metformin were explored through computational small molecule binding analysis. In contrast to the reported effects of metformin on CSCs in other cancers, our data suggests that metformin protects HNSCC CSCs against cisplatin in vitro. Treatment with metformin resulted in a dose-dependent induction of the stem cell genes CD44, BMI-1, OCT-4, and NANOG. On the other hand, we observed that metformin successfully decreased the proliferation of non-stem HNSCC cells. Computational drug–protein interaction analysis revealed mitochondrial complex III to be a likely target of metformin. Based on our results, we present the novel hypothesis that metformin targets complex III to reduce reactive oxygen species (ROS) levels, leading to the differential effects observed on non-stem cancer cells and CSCs.

Highlights

Metformin is a biguande class compound that is the most widely prescribed and well-tolerated drug for type II diabetes
We have previously verified the stemness of JLO-1 by demonstrating significantly higher levels of aldehyde dehydrogenase (ALDH1), Oct-4, and Nanog compared to established head and neck squamous cell carcinoma (HNSCC) cell lines [17], and by demonstrating self-renewal
Several studies have indicated that metformin treatment alone can decrease cancer proliferation using HNSCC cell lines, each study describes a different mechanism of action, including AMPK-independent downregulation of the mammalian target of rapamycin (mTOR) pathway or global inhibition of protein translation [27,28]

Summary

Introduction

Metformin is a biguande class compound that is the most widely prescribed and well-tolerated drug for type II diabetes. In recent years, it has received attention as a potential anticancer agent. A retrospective study done by Evan et al was the first to show a correlation between metformin treatment for diabetes and a decreased risk of various cancer types [1]. A more recent clinical study reported that metformin improves response to chemotherapy in breast cancer patients with diabetes [2]. The ability of metformin to act as an anticancer drug has been attributed to both the indirect effects of lowered insulin levels and the direct targeting of tumor cells.

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Results

Conclusion