Abstract 3574: Nicotine prevents chemotherapy-induced peripheral neuropathy in vivo, and fails to stimulate the growth of lung cancer cells or interfere with the effectiveness of chemotherapy in vitro

Abstract

Abstract Chemotherapy has played a significant and unparalleled role in the treatment and survival of cancer patients. However, this pharmacological approach can lead to long-term symptoms of drug toxicity, including chemotherapy-induced peripheral neuropathy (CIPN), a result of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, tingling, cold sensitivity, or allodynia, and 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 to 78% of patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can present either during or after chemotherapy administration. Without the development of an efficacious treatment, CIPN can be a dose-limiting factor for chemotherapy or delay treatment, thereby influencing survival and quality of life. Our studies have revealed that the prototypical nicotinic acetylcholine receptor agonist, nicotine, is capable of reversing and preventing the development of paclitaxel-induced CIPN in vivo, and does not interfere with the cytotoxic properties of paclitaxel in vitro. Male C57BL/6J mice were infused with 24 mg/kg of nicotine via subcutaneous 7-day osmotic minipumps starting 48 hours prior to paclitaxel treatment, which consisted of 8 mg/kg intraperitoneal injections every other day for a total of four injections. The use of von Frey filament testing revealed that nicotine dose-dependently reverses and prevents paclitaxel-induced mechanical allodynia. In regards to the in vitro studies, MTT and MTS colorimetric assays showed that concentrations of nicotine ranging from 0.1 to 10 μM fail to significantly increase or decrease the viability of A549, H460, Lewis lung carcinoma, or human explant lung cancer cells. Similar results were obtained in ovarian cancer cell lines, where no significant difference in cell growth was observed following nicotine treatment of SKOV-3/DDP and OVCAR-3 cells. Most importantly, the paclitaxel-induced decreases in both H460 cell viability and growth were not significantly attenuated by nicotine. Moreover, 1 μM nicotine did not interfere with paclitaxel-induced sub-G1 DNA content or apoptosis of A549 cells. These findings suggest that nicotinic acetylcholine receptors may be promising drug targets for the prevention and treatment of CIPN. Citation Format: Sarah L. Kyte, Wisam Toma, M I. Damaj, Xianjun Fang, David A. Gewirtz. Nicotine prevents chemotherapy-induced peripheral neuropathy in vivo, and fails to stimulate the growth of lung cancer cells or interfere with the effectiveness of chemotherapy in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3574.