Reducing Chemotherapy-Induced DNA Damage via nAChR-Mediated Redox Reprograming—A New Mechanism for SCLC Chemoresistance Boosted by Nicotine

• Main Authors: Bian, T. (Author), Fujioka, N. (Author), Huo, Z. (Author), Jiang, Y. (Author), Jin, L. (Author), Kaye, F.J (Author), Salloum, R.G (Author), Song, L. (Author), Wang, Y. (Author), Warren, G.W (Author), Xing, C. (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: chemoresistance; cotinine; DNA damage; nicotine; platinum-based therapy; SCLC
• Online Access: View Fulltext in Publisher

 Up to 60% of patients with small cell lung cancer (SCLC) continue to smoke, which is associated with worse clinical outcomes. Platinum-based chemotherapies, in combination with topoisomerase inhibitors, are first-line therapies for SCLC, with rapid chemoresistance as a major barrier. We provided evidence in this study that nicotine and its major metabolite, cotinine, at physiologically relevant concentrations, reduced the efficacy of platinum-based chemotherapies and facilitated chemoresistance in SCLC cells. Mechanistically, nicotine or cotinine reduced chemotherapy-induced DNA damage by modulating cellular redox processes, with nAChRs as the upstream targets. Surprisingly, cisplatin treatment alone also increased the levels of nAChRs in SCLC cells, which served as a self-defense mechanism against platinum-based therapies. These discoveries were confirmed in long-term in vitro and in vivo studies. Collectively, our results depicted a novel and clinically important mechanism of chemoresistance in SCLC treatment: nicotine exposure significantly compromises the efficacy of platinum-based chemotherapies in SCLC treatment by reducing therapy-induced DNA damage and accelerating chemoresistance acquisition. The results also emphasized the urgent need for tobacco cessation and the control of NRT use for SCLC management. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.