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

Cancers

Zhiguang Huo¹  Ramzi G. Salloum²  Chengguo Xing³  Tengfei Bian³  Yuzhi Wang³  Frederic J. Kaye⁴  Naomi Fujioka⁵  Lingtao Jin⁶  Lina Song⁶  Yunhan Jiang⁶  Graham W. Warren⁷ 

[1] Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL 32610, USA;Department of Health Outcomes & Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL 32610, USA;Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA;Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA;Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN 55455, USA;Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX 78229, USA;Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA;

关键词: SCLC;    nicotine;    cotinine;    platinum-based therapy;    DNA damage;    chemoresistance;   

DOI  :  10.3390/cancers14092272

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown