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

Abstract

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 Ca 2+ influx in response to capsaicin, ,-meATP and glutamate. iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with IC 50 values of 38.1 M (95% CI: 22.9 -70.9 M) for 48 hr exposure and 9.3 M (95% CI: 5.7 -16.5 M) for 72 hr treatment. Paclitaxel causes dose-and time-dependent changes in neurite network complexity detected by III-tubulin staining and high content imaging. The IC 50 for paclitaxel reduction of neurite area was 1.4 M (95% CI: 0.3 -16.9 M) for 48 hr exposure and 0.6 M (95% CI: 0.09 -9.9 M) for 72 hr 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.

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents

“…PTX has been shown to damage peripheral sensory neurons, including dorsal root ganglions, and dorsal root ganglions axons, as shown by a number of studies in PTX-induced peripheral neuropathy [38,39]. In the current study, PTX treatment induced damage in isolated DRGs from mice, as demonstrated by decreased neurite outgrowths and the quantity of neurites carrying cells, as well as a change in neuron morphology.…”

Mechanistic insights into the pathogenesis of microtubule‐targeting agent‐induced peripheral neuropathy from pharmacogenetic and functional studies

“…The sensory neurons also showed reduced mitochondrial transport, altered mitochondrial membrane potential and changes in glutamate‐induced Ca 2+ influx in response to paclitaxel. Overall, these iPSC‐derived sensory neurons show similar nociceptive responses to MTA exposure as human sensory neurons 91 . Their utility in investigating GWAS findings was demonstrated by functional validation of a role for S1P signalling in paclitaxel‐induced neurotoxicity 63 .…”

“…Sensory neurons derived from a single iPSC line could be used to investigate the role of selected genes and pathways in MTA‐induced neurotoxicity. The authors have recently described the use of the iPSC line WTC11 to differentiate sensory neurons with a homogeneous genetic background 91 . This well‐characterized pluripotent cell line is used worldwide for the derivation of various cell types.…”

Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy

“…Recently, we and others have shown that paclitaxel exposure is associated with morphological signs of axonal damage in hiPSC-DSN, a dose-and time-dependent decrease of hiPSC-DSN viability and an upregulation of neuronal injury markers as well as differentially expressed metabolic pathways (12,13). As NFL is an axonal protein and CIPN leads to a primarily axonal polyneuropathy, we hypothesized that injured peripheral neurons release NFL, which subsequently leads to increased NFL concentrations.…”