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  • Previously in vitro studies of CIPN were

    2018-10-24

    Previously, in vitro studies buy 5z of CIPN were performed in rat pheochromocytoma or SK-N-SH human neuroblastoma cell lines as model systems to evaluate decreases in neurite outgrowth in response to neurotoxic chemotherapy drugs, such as paclitaxel, vincristine, oxaliplatin and cisplatin (Rovini et al., 2010; Verstappen et al., 2004; Wheeler, et al., 2013; Takeshita et al., 2011; Mendonca et al., 2013). Our knowledge of the mechanisms of CIPN has also been enhanced through studies using primary rat and mouse dorsal root ganglion neurons (Xiao et al., 2012; Xiao et al., 2011; Cavaletti et al., 1995; Zheng et al., 2012; Staff et al., 2013). Other models used by researchers include behavioral tests in rodents to assess sensory thresholds to nociceptive stimuli; however, the results, especially regarding cold/heat and mechanical sensitivity, have been, at times, contradictory (Authier et al., 2009). There is a lack of consensus regarding which behaviors best represent human manifestations of sensory peripheral neuropathy. Although insights into the mechanism of CIPN have been made through animal models, these studies have not yielded effective drugs to prevent or treat CIPN (Hershman, et al., 2014). This is likely because rodent models do not reflect the complex genetic interactions that result in CIPN in humans; however they are complementary to neurons because animal studies allow an evaluation of behavior that cannot be studied in vitro. In efforts to create more relevant models, human neurons have become available through reprogramming skin or blood buy 5z into a state in which the cells have the capability to self-replicate indefinitely and differentiate into many cell types including neurons (Karagiannis and Yamanaka, 2014). Previously, human iPSC-derived neurons have been evaluated to screen for neurotoxic compounds (Ryan et al., 2016). Our laboratory has used commercially available iPSC-derived cortical neurons to evaluate their potential as a model of neurotoxicity (Wheeler et al., 2015) and to functionally validate genes identified in human clinical genome wide association studies of peripheral neuropathy following treatment with paclitaxel (Wheeler et al., 2015; Komatsu et al., 2015), vincristine (Diouf et al., 2015) and docetaxel (Hertz et al., 2016). Our work reported here extends previous studies to evaluate mechanistically distinct chemotherapeutics in iPSC-derived cortical and peripheral neurons, for effects on morphological characteristics and electrical activity. Our data suggest that this model has potential for screening neuroprotectants, a much needed area of research. A limitation of our study is that measures of cell viability, neurite outgrowth and apoptosis could be indicators of cellular response to chemotherapeutics, thus other phenotypes such as effects on neuronal hyperexcitability (increased firing in response to a noxious stimulus) may better represent clinical manifestations of peripheral neuropathy. In support of this, studies utilizing rodent sensory neurons suggest that neuronal hyperexcitability is phenotypically linked with CIPN, potentially due to potassium channel dysfunction (Zhang and Dougherty, 2014). Large-scale implementation of these human cells for high throughput characterization will require further optimization experiments. For example, the development of patient derived neurons from individuals who have experienced severe neuropathy after chemotherapeutics to identify in vitro characteristics that recapitulate clinical manifestations of peripheral neuropathy (motor, sensory, pain) would be highly beneficial for the development of appropriate preclinical assays that represent CIPN and to use in drug development. Previous work using patient-specific human iPSC-derived cardiomyocytes in which cellular consequences of drugs were shown to recapitulate the sensitivity and insensitivity to doxorubicin induced cardiotoxicity of individual patients supports this concept (Burridge et al., 2016).