Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy

  1. Peter M LoCoco
  2. April L Risinger
  3. Hudson R Smith
  4. Teresa S Chavera
  5. Kelly A Berg
  6. William P Clarke  Is a corresponding author
  1. University of Texas Health Science Center at San Antonio, United States

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.

Article and author information

Author details

  1. Peter M LoCoco

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5678-791X
  2. April L Risinger

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4363-3268
  3. Hudson R Smith

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
  4. Teresa S Chavera

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
  5. Kelly A Berg

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    Kelly A Berg, Received funding to support some of this work by a grant from Calico Life Sciences LLC.
  6. William P Clarke

    Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    For correspondence
    clarkew@uthscsa.edu
    Competing interests
    William P Clarke, Received funding to support some of this work by a grant from Calico Life Sciences LLC..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8861-8256

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The animal study protocol (#20130051AR) was approved by the Institutional Animal Care and Use Committee of the University of Texas Health Science Center at San Antonio and conformed to International Association for the Study of Pain (IASP) and federal guidelines.

Reviewing Editor

  1. David D Ginty, Harvard Medical School, United States

Publication history

  1. Received: June 14, 2017
  2. Accepted: November 3, 2017
  3. Accepted Manuscript published: November 10, 2017 (version 1)
  4. Version of Record published: November 24, 2017 (version 2)

Copyright

© 2017, LoCoco et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Peter M LoCoco
  2. April L Risinger
  3. Hudson R Smith
  4. Teresa S Chavera
  5. Kelly A Berg
  6. William P Clarke
(2017)
Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy
eLife 6:e29626.
https://doi.org/10.7554/eLife.29626

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