Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response

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-B, 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 n...

Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Cerles, O., Benoit, E., Chereau, C., Chouzenoux, S., Morin, F., Guillaumot, M.-A., Coriat, R., Kavian, N., Loussier, T., Santulli, P., Marcellin, L., Saidu, N. E. B., Weill, B., Batteux, F., Nicco, C. Tags: Small Molecule Therapeutics Source Type: research