Abstract
Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59–78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3–0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non–small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor–mediated pathways may be promising drug targets for the prevention and treatment of CIPN.
Footnotes
- Received July 14, 2017.
- Accepted October 16, 2017.
↵1 S.L.K. and W.T. contributed equally to this work.
The research was supported by the National Institutes of Health (NIH) [Grant 1R01-CA-206028-01] (to M.I.D. and D.A.G.), [Grant T32-DA-007027-41] (to S.L.K.), [Grant 1F31-NS-095628-01A1] (to L.D.S.) and, in part, by a Massey Cancer Center Pilot Project Grant (to D.A.G. and M.I.D.). Microscopy was performed at the VCU Microscopy Facility, and flow cytometry analysis was conducted at the VCU Massey Cancer Center Flow Cytometry Shared Resource, which were supported, in part, with funding by NIH-National Cancer Institute Cancer Center Support Grant P30-CA-016059. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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