Mechanisms of nicotine-induced resistance to treatment with chemotherapy and radiotherapy

Abstract

e22008 Background: Nicotine (NIC), used for smoking cessation in cancer patients, is associated with increased tumor growth, angiogenesis, migration, invasion, growth factor production, and inhibition of apoptosis. The effects of NIC on the efficacy of radiotherapy (XRT) and/or chemotherapy (CT) have not been well characterized. Methods: A review of the literature produced a construct demonstrating that NIC generates more than 100 interactions with 40 proteins involved in tumor promotion and progression. From this construct, nicotinic acetylcholine receptors (nAChR), PI3K/Akt, and MAPK were identified as potential critical upstream targets modulating the effects of NIC. The effect of NIC on cell proliferation, cell survival, and protein activation was analyzed following CT, XRT, or chemoradiotherapy (CRT) in FaDu, A549, and H460 human cancer cell lines. Results: Proliferation measured with the WST-1 (tetrazolium) assay demonstrated that NIC increased proliferation following cisplatin, XRT, and cisplatin with XRT. NIC administration increased cell survival (colony survival) following XRT and following CT (cisplatin, doxorubicin, or etoposide) regimens in all cell lines. nAChR expression was verified in each cell line using Western blot. Non-specific inhibition of nAChR demonstrated no consistent effect on preventing NIC induced resistance to CT, XRT, or CRT; however, specific inhibition of the alpha-3- or alpha-7-nAChR had variable cell specific ability to prevent NIC induced resistance. Inhibition of MAPK activity (using PD98059) produced marked reduction in proliferation of all cell lines, but generally had no effect on NIC induced resistance. PI3K inhibition (using LY294002) generally increased sensitivity to cisplatin and XRT; however, some PI3K activity was required to achieve the full effect of cisplatin. NIC prevented LY294002 induced sensitization to chemotherapy with no effect on sensitization to XRT. Conclusions: Nicotine induces a broad spectrum of resistance to CT, XRT, and CRT and serves as an excellent model of treatment resistance. Mechanisms of NIC induced resistance to CT and XRT appear to diverge. These findings have significant clinical implications including smoking cessation, treatment efficacy, and outcomes research in cancer patients. No significant financial relationships to disclose.