Figure S1. In Vivo Effects Of Oxaliplatin And Niclosamide On Mouse Motor Excitability from Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response
Excitability waveforms (means {plus minus} SD) were recorded at the plantar muscle in response to motor sciatic nerve stimulation of mice treated for 5 weeks with vehicle (black circles, n = 6), oxaliplatin (white circles, n = 7), oxaliplatin plus niclosamide (white squares, n = 9) or niclosamide alone (black squares, n = 7). (A) Strength-duration relationship. (B) Current-threshold relationship. (C) Threshold electrotonus in response to constant depolarizing (up) and hyperpolarizing (down) long-duration currents applied at sub-threshold intensity ({plus minus} 40%). (D) Recovery cycle. The oxaliplatin-induced effects are highlighted in grey with the corresponding parameter number beside. Note the absence of effect of oxaliplatin plus niclosamide and niclosamide alone on excitability waveforms, versus vehicle.
Funding
Institut National de la Santé et de la Recherche Médicale
Institut Cochin
History
ARTICLE ABSTRACT
Neuropathic pain is a limiting factor of platinum-based chemotherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxaliplatin. Normal neuron-like and cancer cells were treated in vitro with oxaliplatin associated or not with an inhibitor of STAT3 and NF-κB, niclosamide. Cell production of reactive oxygen species and viability were measured by 2′,7′-dichlorodihydrofluorescein diacetate and crystal violet. Peripheral neuropathies were induced in mice by oxaliplatin with or without niclosamide. Neurologic functions were assessed by behavioral and electrophysiologic tests, intraepidermal innervation, and myelination by immunohistochemical, histologic, and morphologic studies using confocal microscopy. Efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. In neuron-like cells, niclosamide downregulated the production of oxaliplatin-mediated H2O2, thereby preventing cell death. In colon cancer cells, niclosamide enhanced oxaliplatin-mediated cell death through increased H2O2 production. These observations were explained by inherent lower basal levels of GSH in cancer cells compared with normal and neuron-like cells. In neuropathic mice, niclosamide prevented tactile hypoesthesia and thermal hyperalgesia and abrogated membrane hyperexcitability. The teniacide also prevented intraepidermal nerve fiber density reduction and demyelination in oxaliplatin mice in this mixed form of peripheral neuropathy. Niclosamide prevents oxaliplatin-induced increased levels of IL6, TNFα, and advanced oxidized protein products. Niclosamide displayed antitumor effects while not abrogating oxaliplatin efficacy. These results indicate that niclosamide exerts its neuroprotection both in vitro and in vivo by limiting oxaliplatin-induced oxidative stress and neuroinflammation. These findings identify niclosamide as a promising therapeutic adjunct to oxaliplatin chemotherapy. Mol Cancer Ther; 16(2); 300–11. ©2016 AACR.Usage metrics
