The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.
%0 Journal Article
%1 C.2017
%A C., Wing
%A M., Komatsu Krause
%A S.M., Delaney
%A M., Komatsu Krause
%A H.E., Wheeler
%A M.E., Dolan
%A Wing, Claudia
%A Komatsu, Masaaki
%A Delaney, Shannon M
%A Krause, Matthew
%A Wheeler, Heather E
%A Dolan, M Eileen
%D 2017
%J Stem Cell Research
%K A-549_cell_line Cell_Differentiation Humans Induced_Pluripotent_Stem_Cells Neurons Peripheral_Nervous_System_Diseases adenosine_triphosphate antineoplastic_agent apoptosis article bicuculline bortezomib brain_cell carboplatin caspase_3 caspase_7 cell_differentiation cell_structure cell_viability chemosensitivity chemotherapy cisplatin concentration_response controlled_study cytology docetaxel electric_activity enzyme_activation fluorouracil genetics goshajinkigan herbaceous_agent human human_cell hydroxyurea induced_pluripotent_stem_cell metabolism nerve_cell_network neural_stem_cell neurite neurite_outgrowth neuroprotection neuroprotective_agent neurotoxicity ovarian_cancer_cell_line oxaliplatin paclitaxel peripheral_neuropathy priority_journal thalidomide unclassified_drug vincristine
%R 10.1016/j.scr.2017.06.006 LK - http://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=18767753&id=doi:10.1016%2Fj.scr.2017.06.006&atitle=Application+of+stem+cell+derived+neuronal+cells+to+evaluate+neurotoxic+chemotherapy&stitle=Stem+Cell+Res.&title=Stem+Cell+Research&volume=22&issue=&spage=79&epage=88&aulast=Wing&aufirst=Claudia&auinit=C.&aufull=Wing+C.&coden=&isbn=&pages=79-88&date=2017&auinit1=C&auinitm=
%T Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy
%X The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.
@article{C.2017,
abstract = {The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell{\textregistered} Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.},
added-at = {2019-06-17T23:34:05.000+0200},
author = {C., Wing and M., Komatsu Krause and S.M., Delaney and M., Komatsu Krause and H.E., Wheeler and M.E., Dolan and Wing, Claudia and Komatsu, Masaaki and Delaney, Shannon M and Krause, Matthew and Wheeler, Heather E and Dolan, M Eileen},
biburl = {https://www.bibsonomy.org/bibtex/260e101e2464d0b67fc895affc45cac99/fcdi},
doi = {10.1016/j.scr.2017.06.006 LK - http://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=18767753&id=doi:10.1016%2Fj.scr.2017.06.006&atitle=Application+of+stem+cell+derived+neuronal+cells+to+evaluate+neurotoxic+chemotherapy&stitle=Stem+Cell+Res.&title=Stem+Cell+Research&volume=22&issue=&spage=79&epage=88&aulast=Wing&aufirst=Claudia&auinit=C.&aufull=Wing+C.&coden=&isbn=&pages=79-88&date=2017&auinit1=C&auinitm=},
interhash = {61584df42b4dde72555e4de9ff672747},
intrahash = {60e101e2464d0b67fc895affc45cac99},
issn = {1876-7753},
journal = {Stem Cell Research},
keywords = {A-549_cell_line Cell_Differentiation Humans Induced_Pluripotent_Stem_Cells Neurons Peripheral_Nervous_System_Diseases adenosine_triphosphate antineoplastic_agent apoptosis article bicuculline bortezomib brain_cell carboplatin caspase_3 caspase_7 cell_differentiation cell_structure cell_viability chemosensitivity chemotherapy cisplatin concentration_response controlled_study cytology docetaxel electric_activity enzyme_activation fluorouracil genetics goshajinkigan herbaceous_agent human human_cell hydroxyurea induced_pluripotent_stem_cell metabolism nerve_cell_network neural_stem_cell neurite neurite_outgrowth neuroprotection neuroprotective_agent neurotoxicity ovarian_cancer_cell_line oxaliplatin paclitaxel peripheral_neuropathy priority_journal thalidomide unclassified_drug vincristine},
pmid = {28645005},
timestamp = {2019-06-18T22:58:44.000+0200},
title = {{Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy}},
year = 2017
}