Phenformin and Oral Cancer: The Role of Organic Cation Transporters

Abstract

Abstract: Background: Compelling preclinical evidence indicates that the biguanide metformin, the most widely prescribed oral antidiabetic drug in the United States, prevents the progression of oral premalignant lesions into oral squamous cell carcinoma (OSCC). Metformin triggers antitumoral responses in part by inhibiting the oncogenic mammalian target of rapamycin (mTOR) pathway through activation of one of its key negative regulators and critical sensor of cellular bioenergetics, the AMP-activated protein kinase (AMPK). As a small hydrophilic cationic compound, metformin enters cells through cell membrane organic cation transporters (OCTs) belonging to the SLC22A gene family. Emerging evidence also shows that OCT expression is significantly reduced or absent as OSCC tumors become more aggressive and less differentiated. Therefore, we hypothesized that phenformin, another biguanide compound with a more hydrophobic structure and possibly more potent antineoplastic activity, might exert its antitumoral effects through an OCT-independent manner. This hypothesis was tested through the following specific aims: (1) To determine whether phenformin induces OSCC growth inhibitory actions; (2) To determine whether OCT function is necessary for phenformin-induced activation of the AMPK signaling pathway. Methods and Materials: Cell viability assays and immunoblotting techniques were conducted by using human-derived OSCC cell lines HN6 and HN13. Results: Our results demonstrated that: (1) phenformin significantly reduced OSCC cell viability, and (2) phenformin appeared to activate AMPK signaling through an OCT-independent manner. Conclusion: This in vitro study shows that phenformin, in contrast to metformin, may exert a more potent antineoplastic effect since it decreased OSCC cell viability with much lower doses. In addition, phenformin appears not to be dependent on OCT expression and activity to activate AMPK signaling. Collectively, these studies suggest that phenformin might become an alternative biguanide, alone or in combination with conventional chemotherapy agents, when treating OCT-deficient OSCC tumors.