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

LoCoco, Peter M.; Risinger, April L.; Smith, Hudson R.; Chavera, Teresa A.; Berg, Kelly A.; Clarke, William P.

doi:10.7554/elife.29626

Cited by 39 publications

(29 citation statements)

References 99 publications

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“…Such a strategy has been shown to alleviate paclitaxel-induced pain where cellular NAD + levels were augmented either via supplementation of its precursor 19 or enhancement of its synthesis. 20 These studies further support aerobic glycolysis as the principle mechanism that sustains CIPN.…”

Section: Discussionmentioning

confidence: 71%

Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

Ludman

Melemedjian

2019

Mol Pain

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Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.

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Section: Discussionmentioning

confidence: 71%

Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

Ludman

Melemedjian

2019

Mol Pain

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“…The potentially protective activity of P7C3 in peripheral neurons has also been tested by the laboratory of William Clarke in a rat model of taxol-induced peripheral neuropathy. Robustly favorable measures of compound-mediated protection from both allodynia and nerve fiber degeneration were reported for this model of chemotherapy-induced peripheral neuropathy (LoCoco et al 2017).…”

Section: P7c3 Compounds Are Neuroprotectivementioning

confidence: 69%

Benefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve Cells

Pieper

McKnight

2018

Cold Spring Harb Symp Quant Biol

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“…Given the mode of action we have described, with Carba1 facilitating the accumulation of PTX in MTs, we can bet that the combination should diminish MT-independent adverse events. Interestingly, it has been shown that a compound sharing the same carbazole scaffold protects against PTX-induced peripheral neuropathy [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Peronne

Denarier

Rai

et al. 2020

Cancers

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Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

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

Cited by 39 publications

References 99 publications

Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

Benefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve Cells

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

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