Wang Yuzhi, Bian Tengfei, Song Lina, Jiang Yunhan, Huo Zhiguang, Salloum Ramzi G, Warren Graham W, Kaye Frederic J, Fujioka Naomi, Jin Lingtao, Xing Chengguo
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX 78229, USA.
Cancers (Basel). 2022 May 2;14(9):2272. doi: 10.3390/cancers14092272.
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.
高达60%的小细胞肺癌（SCLC）患者持续吸烟，这与更差的临床结果相关。以铂类为基础的化疗联合拓扑异构酶抑制剂是SCLC的一线治疗方法，快速产生化疗耐药性是主要障碍。我们在本研究中提供了证据，表明在生理相关浓度下，尼古丁及其主要代谢物可替宁降低了以铂类为基础的化疗疗效，并促进了SCLC细胞的化疗耐药性。从机制上讲，尼古丁或可替宁可通过调节细胞氧化还原过程来减少化疗诱导的DNA损伤，以烟碱型乙酰胆碱受体（nAChRs）作为上游靶点。令人惊讶的是，单独使用顺铂治疗也会增加SCLC细胞中nAChRs的水平，这是一种针对以铂类为基础的治疗的自我防御机制。这些发现在长期的体外和体内研究中得到了证实。总体而言，我们的结果描绘了SCLC治疗中一种新的且具有临床重要性的化疗耐药机制：尼古丁暴露通过减少治疗诱导的DNA损伤和加速化疗耐药性的获得，显著损害了以铂类为基础的化疗在SCLC治疗中的疗效。结果还强调了迫切需要戒烟以及控制用于SCLC管理的尼古丁替代疗法（NRT）的使用。
