Abstract 986: Targeting nicotinic acetylcholine receptors for the prevention and reversal of chemotherapy-induced peripheral neuropathy

Abstract

Abstract While chemotherapy has played a significant role in the survival of cancer patients, exposure to drugs such as the taxanes, platinum-based compounds, and bortezomib often results in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, burning pain, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a taxane that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor or delay treatment. Our studies have established that the prototypical nicotinic acetylcholine receptor (nAChR) agonist, nicotine, is capable of preventing and reversing the development of paclitaxel-induced CIPN, and does not stimulate tumor growth or interfere with the cytotoxic properties of paclitaxel. Male C57BL/6J mice were treated with paclitaxel (8 mg/kg, i.p.) every other day for a total of four injections. Nicotine was either infused via a subcutaneous 7-day osmotic minipump (24 mg/kg/day) starting 48 hours prior to paclitaxel treatment, or acutely injected (0.9 mg/kg, i.p.) following paclitaxel treatment. Von Frey filament testing revealed that nicotine can prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect of nicotine can be inhibited by the α7 nAChR antagonist methyllycaconitine (10 mg/kg, s.c.). Also, α7 nAChR knockout mice exhibit a greater sustained decrease in mechanical threshold after paclitaxel administration than wild-type mice, suggesting the involvement of this receptor in CIPN development and maintenance. This hypothesis was supported by the reversal of paclitaxel-induced mechanical allodynia by the α7 nAChR silent agonist R-47. While nicotine activates its receptors in the tumors cells, based on stimulation of the PI3K/Akt pathway, MTT/MTS colorimetric assays showed that concentrations of nicotine ranging from 0.1 to 10 µM fail to significantly increase the viability of A549 or H460 non-small cell lung cancer cells, murine Lewis lung carcinoma cells, or primary human lung cancer cells. Most importantly, the paclitaxel-induced decreases in H460 proliferation and LLC viability are not significantly attenuated by 1 µM nicotine. Moreover, 1 µM nicotine does not interfere with paclitaxel-induced apoptosis of A549 cells. Finally, R-47 also suppresses CIPN without increasing lung tumor cell viability and colony formation, or interfering with the cytotoxicity of paclitaxel. Our in vitro findings are supported by studies demonstrating that nicotine does not enhance tumor volume or cause premature death in tumor-bearing mice. These data suggest that nAChRs may be promising drug targets for the prevention and treatment of CIPN. Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. Targeting nicotinic acetylcholine receptors for the prevention and reversal of chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 986. doi:10.1158/1538-7445.AM2017-986