Improvements in anticancer pharmacotherapy over the past 40 years have led to a steady increase in the number of cancer survivors worldwide. The clinical effectiveness of anticancer agents like the microtubule-stabilizing agent, paclitaxel, ultimately led to their adoption into standard of care regimens for most cancers. What makes these drugs so effective is how they bind to their respective targets to disrupt fundamental cellular processes. For example, by binding to β-tubulin, paclitaxel induces polymerization and stabilization of cellular microtubules, leading to impairments in cellular functions like mitosis and intracellular transport. While an ingenious approach to kill cancer cells, microtubules are ubiquitous in all cell types. Consequently, paclitaxel has a burdensome side effect profile due to its effects on noncancerous cells. The most prevalent nonhematologic side effect is chemotherapy-induced peripheral neuropathy, which arises due to paclitaxel-induced damage to peripheral afferent sensory neurons. Cancer patients with peripheral neuropathy often develop debilitating neuropathic pain and numbness that diminish everyday quality of life. Symptoms intensify as treatment progresses and can persist for months and years beyond treatment. There is no effective treatment or prevention for chemotherapy-induced peripheral neuropathy. Instead, patients must dose de-escalate or discontinue life-saving chemotherapy, which subsequently worsens cancer prognosis. Thus, there is a compelling need to identify novel therapeutic options to prevent or treat chemotherapy-induced peripheral neuropathy so to improve both anticancer treatment and patient quality of life. The goal of this dissertation is to evaluate the neuroprotective efficacy of a first-in-class stimulator of nicotinamide phosphoribosyltransferase, P7C3-A20, against paclitaxel-induced peripheral neurotoxicity. Nicotinamide phosphoribosyltransferase is the rate-limiting enzyme in the salvage pathway for nicotinamide adenine dinucleotide, an indispensable redox biomolecule that drives energy production. We first developed an aggressive model of paclitaxel-induced peripheral neuropathy in adult male rats. Treatment with a near maximally-tolerated dose of paclitaxel produced significant, but recoverable weight loss and leukopenia. Paclitaxel-treated rats exhibited differentially altered nociceptive thresholds to noxious stimuli, including the development of persistent allodynia to mechanical and cold stimulation as well as transient hyposensitivity to heat stimulation. Toxicity associated with paclitaxel treatment required that 25% of the rats be removed from the study. Histological analysis determined that paclitaxel triggered degeneration of intraepidermal nerve fibers and up-regulated expression of activating transcription factor 3 in nuclei of neuron cell bodies residing in the lumbar dorsal root ganglia. Remarkably, daily treatment with P7C3-A20 prevented mechanical allodynia and heat hypoalgesia, and reduced the cold allodynia associated with paclitaxel treatment. P7C3-A20 also prevented intraepidermal nerve fiber degeneration and partially decreased activating transcription factor 3 expression in lumbar dorsal root ganglia neurons. A randomized, double-blind trial determined that P7C3-A20, and another analogue, P7C3-S321, dose-dependently decreased paclitaxel-induced neuropathic pain and intraepidermal nerve fiber loss. Furthermore, P7C3-A20 improved indices of general health and prevented premature death that normally arose because of overt toxicity caused by paclitaxel. P7C3-A20 displayed superior neuroprotective efficacy, while an inhibitor of poly(adenosine diphosphate-ribose) polymerase was completely ineffective. P7C3-A20 stimulated nicotinamide adenine dinucleotide production in vitro following induction of damage with either hydrogen peroxide or paclitaxel, but not under normal conditions. Additionally, P7C3-A20 in vivo stimulated nicotinamide adenine dinucleotide recovery in the hindpaw and sciatic nerve of rats treated with paclitaxel. FK866 blocked P7C3-A20-mediated nicotinamide adenine dinucleotide production in vitro and the neuroprotective effects on peripheral nociceptive neurons in vivo. Although treatment with either nicotinamide or a subthreshold dose of P7C3-A20 alone was ineffective, the combination produced neuroprotection against paclitaxel that was equivalent to that of a maximal dose of P7C3-A20. We also investigated the effects of P7C3-A20 on cancer cell proliferation and on the anticancer efficacy of paclitaxel. Only MDA-MB-231 breast cancer cells demonstrated a slight increase in proliferation by P7C3-A20, but enhanced growth of implanted MDA-MB-231 tumor xenografts was not observed. Furthermore, P7C3-A20 did not diminish the antiproliferative effects of paclitaxel, despite preventing the development of mechanical allodynia in the tumored mice. In conclusion, these studies discovered robust neuroprotective efficacy of P7C3-A20 against paclitaxel -induced peripheral neurotoxicity, likely through the enhancement of nicotinamide phosphoribosyltransferase-mediated recovery of nicotinamide adenine dinucleotide. Based on these results, clinical investigation of P7C3-A20 as a potential treatment option for chemotherapy-induced peripheral neuropathy may be warranted.
|Advisor:||Clarke, William P.|
|Commitee:||Hargreaves, Kenneth M., Mooberry, Susan L., Schmidt, Brian L., Weitman, Steven D.|
|School:||The University of Texas Health Science Center at San Antonio|
|School Location:||United States -- Texas|
|Source:||DAI-B 79/02(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Pharmacology, Oncology|
|Keywords:||Nad, Nampt, Neuroprotection, P7c3, Paclitaxel, Peripheral neuropathy|
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