Small Molecule Inhibitors of Nicotinamide N-Methyltransferase Enzyme for the Treatment of Osteosarcoma and Merkel Cell Carcinoma: Potential for the Development of a Targeted Therapeutic Strategy

TL;DR

This study explores small molecule inhibitors of the NNMT enzyme to treat osteosarcoma and Merkel cell carcinoma by reducing cancer cell growth and chemoresistance.

Contribution

The study introduces NNMT inhibition as a novel therapeutic strategy for osteosarcoma and Merkel cell carcinoma.

Findings

NNMT inhibitors significantly reduced cell viability in osteosarcoma and Merkel cell carcinoma cell lines.

Inhibitors increased reactive oxygen species production and activated apoptotic pathways in cancer cells.

Combined treatment with NNMT inhibitors and cisplatin enhanced the anti-cancer effects observed.

Abstract

Nicotinamide N-methyltransferase (NNMT) enzyme catalyzes the N-methylation of nicotinamide and its overexpression has been reported in many neoplasms, favoring traits featuring an aggressive tumor cell phenotype. Our recent data demonstrated that NNMT upregulation in osteosarcoma (OS) and Merkel cell carcinoma (MCC) led to a significant increase in cell proliferation and migration ability, together with a reduction in sensitivity to chemotherapeutic treatment. Based on these findings, we investigated the impact of small molecule NNMT inhibitors 5-amino-1-methyl quinolinium (5-AMQ), 6-methoxynicotinamide (6MeONa) and Eli Lilly’s pyrimidine 5-carboxamide (EL-1) on U-2 OS and Saos-2 OS cell lines and MCC13 and MCC26 MCC cell lines. Following incubation of the cells with these compounds, cell viability, reactive oxygen species (ROS) production and apoptosis induction were evaluated. Cells were then subjected to combined treatment with inhibitors and cisplatin (CDDP), and viability and ROS levels were further analyzed. Our results clearly illustrate that cells treated with NNMT inhibitors underwent significant reductions in viability, increased ROS production and activation of apoptotic pathways. Given the association of NNMT with cancer aggressiveness, inhibiting its catalytic activity might present a novel strategy for counteracting cancer growth and chemoresistance, providing the rationale for an effective anti-cancer therapy based on the use of specific NNMT inhibitors.

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