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

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Xiong, Chenling ^[1] ; Chua, Katherina C. ^[1] ; Stage, Tore B. ^{[1, 2]} ; Priotti, Josefina ^[1] ; Kim, Jeffrey ^[1] ; Altman-Merino, Anne ^[1] ; Chan, Daniel ^[1] ; Saraf, Krishna ^[1] ; Canato Ferracini, Amanda ^{[3, 1]} ; Fattahi, Faranak ^[4] ; Kroetz, Deanna L. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 - USA

^[2] Univ Southern Denmark, Dept Publ Hlth Clin Pharmacol & Pharm, Odense - Denmark

^[3] Univ Estadual Campinas, Fac Med Sci, Sao Paulo - Brazil

^[4] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA - USA

• Tipo de documento: Artigo Científico
• Fonte: CTS-CLINICAL AND TRANSLATIONAL SCIENCE; v. 14, n. 2 DEC 2020.
• Citações Web of Science: 1

Resumo

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

• Processo FAPESP: 18/00070-2 - Avaliação do gene EPHA5 nos efeitos da neuropatia periférica induzida pelo paclitaxel em neurônios sensoriais derivados de células-tronco pluripotentes induzidas
• Beneficiário: Amanda Canato Ferracini
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado