Molecular and Functional Interactions Between Cisplatin and Nicotinamide: A Combined Computational, Spectroscopic,...

Cisplatin remains a widely used anticancer agent; however, its effectiveness can be influenced by systemic toxicity, resistance mechanisms, and interactions with exogenous compounds. Nicotinamide (vitamin B3), an NAD⁺ precursor and a commonly used dietary supplement, is involved in cellular metabolism, redox homeostasis, and DNA repair pathways, which may potentially modulate the cellular responses to Platinum-based agents. Here, we combine chemical synthesis, computational studies, spectroscopic analysis, and biological assays to investigate the molecular and biological aspects of Cisplatin-Nicotinamide interactions. A novel cis-[Pt(NH₃)₂NicotinamideCl]NO₃ complex was obtained and its structure analyzed. Density functional theory (DFT) calculations indicate a thermodynamically favorable coordination of Nicotinamide to the first hydrolysis product of Cisplatin (CisPt1) with binding energies comparable to those calculated for nucleobase coordination under the same theoretical conditions. In non-small cell lung cancer cell lines (A549 and PC-9), in vitro results suggest that Nicotinamide pre-treatment reduces Cisplatin cytotoxicity under specific experimental conditions, but the pre-formed complex does not exert anticancer effects. These data are consistent with a model in which Nicotinamide may interact with reactive Cisplatin species, potentially contributing to the reduced availability of reactive Platinum(II) species. This work provides mechanistic insight into potential drug-nutrient interactions involving Platinum-based chemotherapy and highlights the need for further investigation under clinically relevant conditions in the near future.