A novel human neuronal model of chemotherapyinduced peripheral neuropathy
K. M., W. H.E., W. C., D. S., and D. M.E..
Clinical Pharmacology and Therapeutics (2014)

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting toxicity for several anti-cancer drugs, whereas there are no effective biomarkers or treatment for CIPN. We utilized human neurons derived from induced pluripotent stem cells (iCell Neurons) to evaluate the effect of various chemotherapeutics in efforts to create a human neuronal model to study CIPN. METHODS: Morphological changes were evaluated in iCell neurons following treatment with paclitaxel, vincristine, cisplatin and hydroxyurea (0.001-100 $\mu$M), using high-content imaging of neurite outgrowth. In addition, we measured cellular viability using CellTiterGlo. To determine whether the model could be used for evaluation of genes important in CIPN, we used siRNA to decrease expression of TUBB2A, a gene known to be associated with paclitaxel-induced neuropathy. RESULTS: Upon treatment of iCell Neurons with paclitaxel, vincristine or cisplatin for 72 hours, we identified reproducible decreases in cell median neurite process length of 12-14\%, 6-18\% and 2-4\%, respectively. No decrease in neurite length was observed with hydroxyurea, an agent that does not cause neuropathy. The morphological changes differed across drugs, with vincristine treatment showing the most dramatic effect on neurite outgrowth at low doses, paclitaxel showing an intermediate effect, and cisplatin showing little effect until micromolar doses. Transient knockdown of TUBB2A caused decreases of mean neurite process length (interaction P = 2.2 × 10 -8 ) and total neurite outgrowth (interaction P = 1.8 × 10 -10 ) of iCell neurons 48 hours post-paclitaxel treatment. CONCLUSION: This model system may provide a means to elucidate the mechanisms of CIPN and functionally validate candidate genes contributing to neuropathy.
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