Efficacious Anti-Cancer Drugs Targeting Nicotinamide N-Methyltransferase (NNMT) in Cultured Human Oral Squamous Cell Carcinoma (OSCC)

Oral squamous cell carcinoma (OSCC) is major cause of human cancer. The enzyme, nicotinamide N-methyltransferase (NNMT) is overexpressed in a variety of human cancers including OSCC. Our laboratory identified two small molecule inhibitors of NNMT (AG-670 and AO-022) based on a pharmacophore of the in silico nicotinamide binding site. These inhibitors were demonstrated to inhibit the isolated NNMT enzyme with EC50 values in the micromolar range. Using an oral squamous cancer cell line as a model, it was demonstrated that NNMT is expressed in SCC-4 cells, but not MCF 7 cells, and that the inhibitors were cytotoxic to SCC-4 cells (IC50 values in the micromolar range). In an endeavour to investigate the mechanism behind their lethality, sub-lethal doses of the inhibitors were demonstrated to inhibit in situ mitochondrial oxygen consumption in SCC-4 cells but not in MCF 7 cells. It was further demonstrated that the NNMT inhibitors did not directly inhibit mitochondrial electron transport chain activity. Thus, we can deduce that the NNMT inhibitors effect mitochondrial activity indirectly via NNMT. We conclude that NNMT is a potential drug target for oral cancer.