Cerles Olivier, Benoit Evelyne, Chéreau Christiane, Chouzenoux Sandrine, Morin Florence, Guillaumot Marie-Anne, Coriat Romain, Kavian Niloufar, Loussier Thomas, Santulli Pietro, Marcellin Louis, Saidu Nathaniel E B, Weill Bernard, Batteux Frédéric, Nicco Carole
Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS, Gif-sur-Yvette, France.
Mol Cancer Ther. 2017 Feb;16(2):300-311. doi: 10.1158/1535-7163.MCT-16-0326. Epub 2016 Dec 15.
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 HO, thereby preventing cell death. In colon cancer cells, niclosamide enhanced oxaliplatin-mediated cell death through increased HO 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.
神经性疼痛是铂类化疗的一个限制因素。我们试图研究氯硝柳胺在外周神经病变中的神经保护潜力，该外周神经病变由奥沙利铂诱导。正常神经元样细胞和癌细胞在体外分别用奥沙利铂单独处理，或与STAT3和NF-κB的抑制剂氯硝柳胺联合处理。用2',7'-二氯二氢荧光素二乙酸酯和结晶紫测定细胞活性氧的产生和细胞活力。在小鼠中用奥沙利铂单独或与氯硝柳胺联合诱导外周神经病变。通过行为和电生理测试、表皮内神经支配以及使用共聚焦显微镜的免疫组织化学、组织学和形态学研究评估髓鞘形成，从而评估神经功能。在接种CT26结肠癌细胞的小鼠中评估对肿瘤生长的疗效。在神经元样细胞中，氯硝柳胺下调奥沙利铂介导的HO的产生，从而防止细胞死亡。在结肠癌细胞中，氯硝柳胺通过增加HO的产生增强奥沙利铂介导的细胞死亡。与正常细胞和神经元样细胞相比，癌细胞中谷胱甘肽的基础水平较低，这解释了这些观察结果。在神经性疼痛小鼠中，氯硝柳胺可预防触觉减退和热痛觉过敏，并消除膜兴奋性过高。在这种混合形式的外周神经病变中，该杀绦虫剂还可预防奥沙利铂小鼠的表皮内神经纤维密度降低和脱髓鞘。氯硝柳胺可预防奥沙利铂诱导的IL6、TNFα和晚期氧化蛋白产物水平升高。氯硝柳胺显示出抗肿瘤作用，同时不消除奥沙利铂的疗效。这些结果表明，氯硝柳胺通过限制奥沙利铂诱导的氧化应激和神经炎症在体外和体内发挥神经保护作用。这些发现表明氯硝柳胺是奥沙利铂化疗有前景的治疗辅助药物。《分子癌症治疗》；16(2)；300 - 311。©2016美国癌症研究协会
