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.
%0 Journal Article
%1 M.2014
%A M., Komatsu
%A H.E., Wheeler
%A C., Wing
%A S., Delaney
%A M.E., Dolan
%D 2014
%J Clinical Pharmacology and Therapeutics
%K antineoplastic_agent biological_marker cell_viability chemotherapy cisplatin clinical_pharmacology gene human hydroxyurea imaging low_drug_dose model nerve_cell neurite neurite_outgrowth neuropathy paclitaxel peripheral_neuropathy pluripotent_stem_cell small_interfering_RNA society therapy toxicity vincristine
%R 10.1038/clpt.2013.245 LK - http://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=00099236&id=doi:10.1038%2Fclpt.2013.245&atitle=A+novel+human+neuronal+model+of+chemotherapyinduced+peripheral+neuropathy&stitle=Clin.+Pharmacol.+Ther.&title=Clinical+Pharmacology+and+Therapeutics&volume=95&issue=&spage=S9&epage=&aulast=Komatsu&aufirst=M.&auinit=M.&aufull=Komatsu+M.&coden=&isbn=&pages=S9-&date=2014&auinit1=M&auinitm=
%T A novel human neuronal model of chemotherapyinduced peripheral neuropathy
%X 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.
@article{M.2014,
abstract = {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.},
added-at = {2019-06-18T22:58:43.000+0200},
author = {M., Komatsu and H.E., Wheeler and C., Wing and S., Delaney and M.E., Dolan},
biburl = {https://www.bibsonomy.org/bibtex/20613c6acd8c5f342840432e576eec651/fcdi},
doi = {10.1038/clpt.2013.245 LK - http://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=00099236&id=doi:10.1038%2Fclpt.2013.245&atitle=A+novel+human+neuronal+model+of+chemotherapyinduced+peripheral+neuropathy&stitle=Clin.+Pharmacol.+Ther.&title=Clinical+Pharmacology+and+Therapeutics&volume=95&issue=&spage=S9&epage=&aulast=Komatsu&aufirst=M.&auinit=M.&aufull=Komatsu+M.&coden=&isbn=&pages=S9-&date=2014&auinit1=M&auinitm=},
interhash = {3156ccba1e1ee7645e716f27d3535979},
intrahash = {0613c6acd8c5f342840432e576eec651},
issn = {0009-9236},
journal = {Clinical Pharmacology and Therapeutics},
keywords = {antineoplastic_agent biological_marker cell_viability chemotherapy cisplatin clinical_pharmacology gene human hydroxyurea imaging low_drug_dose model nerve_cell neurite neurite_outgrowth neuropathy paclitaxel peripheral_neuropathy pluripotent_stem_cell small_interfering_RNA society therapy toxicity vincristine},
timestamp = {2019-06-18T22:58:43.000+0200},
title = {{A novel human neuronal model of chemotherapyinduced peripheral neuropathy}},
year = 2014
}