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    • Mechanisms underlying CIPN include direct and indirect

    2018-10-24

    Mechanisms underlying CIPN include direct and indirect effects on sensory nerves such as damage to neuronal cell bodies in the dorsal root ganglion, alteration of the amplitude of the sglt or conduction velocity (Argyriou et al., 2012; Sisignano et al., 2014). Whereas CIPN may be reversible for some cytotoxic drugs (e.g. taxanes), for other agents (e.g. cisplatin), the persistence of CIPN is well documented (Argyriou et al., 2012; Avan et al., 2015). Wide ranges in incidence rates likely reflect not only differences in study populations, drug-related factors (e.g. dose-intensity) and potential confounders, but also genetic susceptibility (Argyriou et al., 2012; Bhatia, 2011). Patients at high risk could consider alternative chemotherapy regimens with similar efficacy or a treatment strategy that mitigates risk by limiting the cumulative dose of the neurotoxic drug. For the treatment of painful neuropathies, most drugs fall short of providing adequate relief (Sisignano et al., 2014). A systematic evaluation of 48 randomized controlled trials concluded that there are no agents that can be recommended for the prevention of CIPN (Hershman, et al., 2014). With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (Smith, et al., 2013). Goshajinkigan (GJG), a traditional Japanese herbal medicine, has been shown to inhibit the progression of neuropathy or alleviate symptoms of nerve pain resulting from chemotherapy treatment with paclitaxel/carboplatin for ovarian and endometrial cancer patients (Kaku et al., 2012), docetaxel in breast cancer patients (Abe et al., 2013), nab-paclitaxel for breast cancer patients (Ohno et al., 2014) and oxaliplatin in colorectal cancer patients (Nishioka et al., 2011; Hosokawa et al., 2012; Yoshida et al., 2013). In animal models, GJG has been shown to suppress various transient receptor potential channels that may mitigate the pain responses in the patient (Mizuno et al., 2014; Kato et al., 2014; Matsumura et al., 2014). Given the paucity of available treatments and increasing number of cancer survivors living with CIPN, there is an urgent need to identify a reasonable model system to identify more effective compounds supporting multiple targets and providing relief to patients undergoing treatment. Previously, we have demonstrated that induced-pluripotent stem cell (iPSC) derived neurons can be used as a preclinical model system to study CIPN (Wheeler et al., 2015). In the present manuscript, we extend these studies by: 1) evaluating additional platinating agents (oxaliplatin, carboplatin) and taxane analogs (docetaxel, nab-paclitaxel), a proteasome inhibitor (bortezomib), an antiangiogenic (thalidomide), and a chemotherapeutic that does not cause neuropathy (5-fluorouracil); 2) determining the effect of paclitaxel treatment on electrical activity of neurons; 3) comparing drug sensitivity in iPSC- derived cortical versus peripheral neurons; 4) and testing GJG, as a potential neuroprotectant to counteract the effects of paclitaxel, cisplatin and oxaliplatin by evaluating in neurons and cancer cell lines.
    Methods
    Results
    Discussion We have demonstrated that induced pluripotent stem cell derived cortical and peripheral neurons provide new opportunities to evaluate neurotoxicity associated with chemotherapeutic agents. Differences in sensitivity to various classes of chemotherapeutics and different drugs within a class are evident. For example, platinating agents (at ≥10μM) cause a dramatic increase in caspase 3/7 activation in neurons concomitant with a decrease in both cell viability and neurite outgrowth suggesting apoptotic cell death as a mechanism for neurotoxicity. In contrast to platinating agents, other chemotherapeutics evaluated (paclitaxel, nab-paclitaxel, docetaxel, thalidomide and 5-fluorouracil) do not exhibit effects on cell viability through an increase in caspase 3/7 activation. Taxanes had minimal effect on cell viability, yet resulted in a gradual dose dependent inhibition of neurite outgrowth parameters. Bortezomib, a targeted drug, showed the most dramatic effects with increased sensitivity as measured by neurite outgrowths and cellular viability but not in activation of caspase 3/7. Chemotherapeutic drugs not known to cause CIPN, such as 5-fluorouracil and hydroxyurea caused little, to no effect, on neurite formation or cell viability in iPSC-derived cortical neurons. Comparable results as measured by cell viability and neurite outgrowth were observed using either sensory or peripheral neurons for various neurotoxic chemotherapeutics (cisplatin, paclitaxel, vincristine and bortezomib); however peripheral neurons tended to be more sensitive to the effects of chemotherapy. GJG demonstrated some promise as a neuroprotectant for use with paclitaxel, but not with cisplatin or oxaliplatin.