Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response

被引：34

作者：

Cerles, Olivier ^{[1
]}

Benoit, Evelyne ^{[2
,3
]}

Chereau, Christiane ^{[1
]}

Chouzenoux, Sandrine ^{[1
]}

Morin, Florence ^{[1
,4
]}

Guillaumot, Marie-Anne ^{[1
,5
]}

Coriat, Romain ^{[1
,5
]}

Kavian, Niloufar ^{[1
,4
]}

Loussier, Thomas ^{[1
]}

Santulli, Pietro ^{[1
,6
]}

Marcellin, Louis ^{[1
,6
]}

Saidu, Nathaniel E. B. ^{[1
]}

Weill, Bernard ^{[1
,4
]}

Batteux, Frederic ^{[1
,4
]}

Nicco, Carole ^{[1
]}

机构：

[1] Paris Descartes Univ, Dept Dev Reprod & Canc, Inst Cochin, Sorbonne Paris Cite,INSERM U1016, Paris, France

[2] CNRS, Inst Neurosci Paris Saclay, UMR 9197, Gif Sur Yvette, France

[3] CEA Saclay, Mol Engn Prot Unit DRF iBiTec S SIMOPRO, Gif Sur Yvette, France

[4] Cochin Teaching Hosp, AP HP, Dept Immunol, Paris, France

[5] Paris Descartes Univ, Cochin Teaching Hosp, Dept Gastroenterol, Paris, France

[6] Cochin Teaching Hosp, Dept Gynecol Obstet & Reprod Med 2, Paris, France

来源：

MOLECULAR CANCER THERAPEUTICS | 2017年 / 16卷 / 02期

关键词：

INDUCED PERIPHERAL NEUROPATHY; OXIDATIVE STRESS; PAINFUL; CHEMOTHERAPY; ANTIOXIDANT; GLUTATHIONE; ROS; PHOSPHORYLATION; MITOCHONDRIA; EXCITABILITY;

D O I：

10.1158/1535-7163.MCT-16-0326

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-kB, niclosamide. Cell production of reactive oxygen species and viability were measured by 20,70-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, niclo-samide 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, 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 oxaliplatininduced oxidative stress and neuroinflammation. These findings identify niclosamide as a promising therapeutic adjunct to oxaliplatin chemotherapy.

引用

页码：300 / 311

页数：12

共 59 条

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