Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response

Olivier Cerles (1) , Evelyne Benoit (2, 3) , Christiane Chéreau (1) , Sandrine Chouzenoux (1) , Florence Morin (1) , Marie-Anne Guillaumot (1) , Romain Coriat (1) , Niloufar Kavian (1) , Thomas Loussier (1) , Pietro Santulli (4, 1) , Louis Marcellin (1) , Nathaniel E.B. Saidu (1) , Bernard Weill (1) , Frédéric Batteux (5, 1) , Carole Nicco (1)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
3 NeuroPSI - Institut des Neurosciences Paris-Saclay
4 Service de Gynécologie Obstétrique II et Médecine de la Reproduction
5 Laboratoire d'Immunologie Biologique

Neuropathic pain is a limiting factor of platinum-based che-motherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxali-platin. Normal neuron-like and cancer cells were treated $in\ vitro$ with oxaliplatin associated or not with an inhibitor of STAT3 and NF-$k$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 immuno-histochemical, histologic, and morphologic studies using confo-cal microscopy. Efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. In neuron-like cells, niclo-samide downregulated the production of oxaliplatin-mediated H$_2$ O$_2$ , thereby preventing cell death. In colon cancer cells, niclo-samide enhanced oxaliplatin-mediated cell death through increased H$_2$ O$_2$ 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, niclo-samide prevented tactile hypoesthesia and thermal hyperalgesia and abrogated membrane hyperexcitability. The teniacide also prevented intraepidermal nerve fiber density reduction and demy-elination in oxaliplatin mice in this mixed form of peripheral neuropathy. Niclosamide prevents oxaliplatin-induced increased levels of IL6, TNF$\alpha$, 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 oxa-liplatin chemotherapy.

Domaines: Sciences du Vivant [q-bio]; Cancer; Médecine humaine et pathologie

Olivier Cerles, Evelyne Benoit, Christiane Chéreau, Sandrine Chouzenoux, Florence Morin, et al.. Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response. Molecular Cancer Therapeutics, 2017, 16 (2), pp.300-311. ⟨10.1158/1535-7163.MCT-16-0326⟩. ⟨cea-02121953⟩