Abstract 378: Nicotine replacement therapy may interfere with cisplatin efficacy and promote tumor progression

Abstract Background: Smoking during cancer treatment is associated with significant risks, including treatment failure, metastasis, recurrence, and reduced quality of life. Continued smoking during therapy remains the strongest adverse predictor of survival in cancer patients. Nicotine replacement therapy (NRT) is commonly used to manage cravings in cancer patients undergoing treatment. Although nicotine has been proposed to promote cellular proliferation and tumor progression, the impact of NRT during cisplatin treatment has not been investigated. Methods: Human oral cancer cell lines (WSU-HN6 and WSU-HN30) were subjected to various treatment combinations to explore the effects of NRT on cisplatin efficacy. Cells were first exposed to nicotine (10, 20, or 40 ng/mL, consistent with plasma concentrations) for 48 hours, followed by treatment with cisplatin at its 50% inhibitory concentration (IC50) in the presence or absence of nicotine for an additional 48 hours. Then, cell viability was assessed using the MTT assay, and clonogenic survival of single cells was evaluated. Controls included exposure to nicotine only, cisplatin only, and mainstream cigarette smoke. Additionally, cells were exposed to varying concentrations of nicotine, treated with cisplatin, and then fixed with 70% ethanol, and analyzed by flow cytometry for cell cycle progression. Statistical significance between groups was determined using Student’s t-test. Results: Cisplatin treatment of cancer cells exposed to nicotine at concentrations similar to those observed in the plasma of individuals undergoing NRT, resulted in a significant decrease in cell viability but did not achieve the anticipated 50% reduction observed with cisplatin treatment alone. To explore this further, cells were exposed to nicotine for 48 hours, followed by cisplatin treatment for an additional 48 hours in the presence or absence of nicotine. The presence of nicotine during cisplatin treatment significantly impaired the efficacy of cisplatin to induce cancer cell death in a concentration-dependent manner. The nicotine presence during cisplatin treatment also altered cell cycle progression and increased clonogenic survival in both oral cancer cell lines. Conclusion: This study shows that nicotine, even at very lower concentrations, significantly impairs the efficacy of cisplatin, as evidenced by increased cell viability and altered cell cycle progression and increases clonogenic survival in both oral cancer cell lines. These findings pinpoint the potential of NRT to compromise cancer treatment outcomes by interfering with the cytotoxic effects of cisplatin and increasing the number of cancer cells able to proliferate indefinitely. Addressing nicotine exposure during cancer therapy is critical for improving treatment efficacy and patient outcomes. Grant Support: NIH/NCI (R01CA242168, Queimado); TSET HPRC (Queimado). Citation Format: Gautham Chengizkhan, Vengatesh Ganapathy, Mayilvanan Chinnaiyan, Lurdes Queimado. Nicotine replacement therapy may interfere with cisplatin efficacy and promote tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 378.