Abstract 602: The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity
Authors: Kyte S Lauren , Toma Wisam , Thakur Ganeshsingh , Damaj M Imad , Gewirtz David A. 
Published: August 2018

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result 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, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison 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 for chemotherapy or delay treatment. Our laboratories have previously shown that nicotine, the prototypical nicotinic acetylcholine receptor (nAChR) agonist, can prevent and reverse paclitaxel-induced peripheral neuropathy without increasing lung tumor growth in mice. Our current studies have demonstrated that the α7 nAChR silent agonist R-47 may be a promising preventative and therapeutic treatment for CIPN as well. R-47 (10 mg/kg, p.o.) was administered to male C57BL/6J mice treated with paclitaxel (8 mg/kg, i.p., every other day for a total of four injections). Von Frey filament testing revealed that R-47 can both prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect can be inhibited by the α7 nAChR antagonist methyllycaconitine. In support of these findings, R-47 also prevents the reduction of intra-epidermal nerve fibers in the hind paws of paclitaxel-treated mice. In addition, α7 nAChR knockout mice exhibit a greater and sustained increase in mechanical allodynia after paclitaxel administration when compared to wild-type mice, suggesting the involvement of this receptor subtype in hindering CIPN development and/or maintenance. With regard to cancer, R-47 fails to increase A549 and H460 non-small cell lung cancer cell viability, colony formation, or proliferation alone, and does not interfere with paclitaxel-induced growth arrest, apoptosis, or DNA fragmentation. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These data suggest that the use of an α7 nAChR silent agonist may be a safe and efficacious approach for the prevention and treatment of CIPN.

Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 602.