Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

作者: Chenling Xiong , Katherina C. Chua , Tore B. Stage , Jeffrey Kim , Anne Altman-Merino

DOI: 10.1101/2020.06.04.134262

关键词:

摘要: Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment paclitaxel and other chemotherapeutic agents. The prevention of CIPN are limited by lack understanding the molecular mechanisms underlying this toxicity. In current study, human induced pluripotent stem cell–derived sensory neuron (iPSC-SN) model was developed for study chemotherapy-induced neurotoxicity. iPSC-SNs express proteins characteristic nociceptor, mechanoreceptor proprioceptor neurons show Ca2+ influx in response to capsaicin, α,β-meATP glutamate. relatively resistant cytotoxic effects paclitaxel, IC50 values 38.1 μM (95% CI: 22.9 – 70.9 μM) 48 hr exposure 9.3 5.7 16.5 72 treatment. Paclitaxel causes dose- time-dependent changes neurite network complexity detected βIII-tubulin staining high content imaging. reduction area 1.4 0.3 - 16.9 0.6 0.09 9.9 exposure. Decreased mitochondrial membrane potential, slower movement mitochondria down neurites glutamate-induced neuronal excitability were also observed sensitive docetaxel, vincristine bortezomib. Collectively, these data support use detailed mechanistic investigations genes pathways implicated neurotoxicity identification novel therapeutic approaches its

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