| Authors |
Lisse TS, Middleton LJ, Pellegrini AD, Martin PB, Spaulding EL, Lopes O, Brochu
EA, Carter EV, Waldron A, Rieger S
|
| Submitted By |
Sandra Rieger on 2/7/2018 |
| Status |
Published |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Year |
2016 |
| Date Published |
4/12/2016 |
| Volume : Pages |
113 : E2189 - 98 |
| PubMed Reference |
27035978 |
| Abstract |
Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely
used in cancer treatment and in a number of curative and palliative regimens.
Despite its beneficial effects on cancer, paclitaxel also damages healthy
tissues, most prominently the peripheral sensory nervous system. The mechanisms
leading to paclitaxel-induced peripheral neuropathy remain elusive, and
therapies that prevent or alleviate this condition are not available. We
established a zebrafish in vivo model to study the underlying mechanisms and to
identify pharmacological agents that may be developed into therapeutics. Both
adult and larval zebrafish displayed signs of paclitaxel neurotoxicity,
including sensory axon degeneration and the loss of touch response in the distal
caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel
rapidly promotes epithelial damage and decreased mechanical stress resistance of
the skin before induction of axon degeneration. Moreover, injured
paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes
(HEK001) display reduced healing capacity. Epithelial damage correlated with
rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal
keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13
(MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in
contrast, largely rescued paclitaxel-induced epithelial damage and
neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the
skin vulnerable to injury under mechanical stress conditions. Thus, our studies
provide evidence that the epidermis plays a critical role in this condition, and
we provide a previously unidentified candidate for therapeutic interventions.
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