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.
Highlights
The microtubule stabilizer, paclitaxel (PTX), is widely used for the treatment of breast, ovarian, lung, and pancreatic cancer (Rivera and Cianfrocca, 2015)
P7C3-A20 did not interfere with the antitumor activity of PTX nor promote tumor growth. These results suggest that enhancement of nicotinamide phosphoribosyltransferase (NAMPT) activity with P7C3-A20 may be a promising new therapeutic strategy to protect peripheral afferent sensory neurons against anticancer drug-induced peripheral neurotoxicity
To further test the hypothesis that the neuroprotective effect of P7C3-A20 is dependent on its ability to enhance NAMPT activity, we evaluated the effect of supplementation of an ineffective dose of P7C3-A20 with the NAMPT substrate, nicotinamide (NAM), on PTX-induced allodynia and intraepidermal nerve fibers (IENFs) degeneration (Figure 5D and Figure 5—figure supplement 2A)
Summary
The microtubule stabilizer, paclitaxel (PTX), is widely used for the treatment of breast, ovarian, lung, and pancreatic cancer (Rivera and Cianfrocca, 2015). Chemotherapy-induced peripheral neuropathy (CIPN) is the most common nonhematologic side effect of anticancer pharmacotherapy that affects up to 90% of cancer patients (Grisold et al, 2012; Miltenburg and Boogerd, 2014; Windebank and Grisold, 2008). As there are no effective treatments or preventions for CIPN, potentially life-saving cancer treatment must often be dose-reduced or discontinued, adversely affecting cancer prognosis and survival (Rivera and Cianfrocca, 2015). P7C3-A20 did not interfere with the antitumor activity of PTX nor promote tumor growth These results suggest that enhancement of NAMPT activity with P7C3-A20 may be a promising new therapeutic strategy to protect peripheral afferent sensory neurons against anticancer drug-induced peripheral neurotoxicity
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