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Review
. 2020 Feb:324:113121.
doi: 10.1016/j.expneurol.2019.113121. Epub 2019 Nov 21.

Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems

Nathan P Staff  1 , Jill C Fehrenbacher  2 , Martial Caillaud  3 , M Imad Damaj  3 , Rosalind A Segal  4 , Sandra Rieger  5
Affiliations
Review

Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems

Nathan P Staff et al. Exp Neurol. 2020 Feb.

Abstract

Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.

Keywords: Human genetic studies; Inflammation; Intraepidermal nerve endings; Neuropathic pain; Paclitaxel-induced peripheral neuropathy; Reactive oxygen species; Small fiber neuropathy.

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Conflict of interest statement

Conflict of interest

The authors declare no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Mechanisms of paclitaxel pathogenesis leading to axon degeneration and painful neuropathy based on mammalian studies.
Isolated rodent DRG neurons and patient-derived induced pluripotent stem cells have revealed acute and chronic changes in calcium signaling in vitro. In vivo studies using rodent models have shown various effects directly in sensory neurons and indirectly in skin cells, immune cells and glia. Genetic studies using patient data identified polymorphisms and mutations in various pathways associated with increased risk for paclitaxel-induced peripheral neuropathy (PIPN). Clinical trials for antioxidants have so far failed to prevent or reverse paclitaxel-neurotoxicity.
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References

    1. Abraham JE, Guo Q, Dorling L, Tyrer J, Ingle S, Hardy R, Vallier AL, Hiller L, Burns R, Jones L, Bowden SJ, Dunn JA, Poole CJ, Caldas C, Pharoah PP, Earl HM, 2014. Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel. Clinical cancer research: an official journal of the American Association for Cancer Research 20, 2466–2475. - PubMed
    1. Al-Massri KF, Ahmed LA, El-Abhar HS, 2018. Pregabalin and lacosamide ameliorate paclitaxel-induced peripheral neuropathy via inhibition of JAK/STAT signaling pathway and Notch-1 receptor. Neurochemistry International 120, 164–171. - PubMed
    1. Al-Massri KF, Ahmed LA, El-Abhar HS, 2019. Mesenchymal stem cells therapy enhances the efficacy of pregabalin and prevents its motor impairment in paclitaxel-induced neuropathy in rats: Role of Notch1 receptor and JAK/STAT signaling pathway. Behavioural Brain Research 360, 303–311. - PubMed
    1. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD, 2004. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24, 4444–4452. - PMC - PubMed
    1. André N, Carré M, Brasseur G, Pourroy B, Kovacic H, Briand C, Braguer D, 2002. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett 532, 256–260. - PubMed

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