Deng Youlin, Wang Zhongliang, Zhang Fugui, Qiao Min, Yan Zhengjian, Wei Qiang, Wang Jing, Liu Hao, Fan Jiaming, Zou Yulong, Liao Junyi, Hu Xue, Chen Liqun, Yu Xinyi, Haydon Rex C, Luu Hue H, Qi Hongbo, He Tong-Chuan, Zhang Junhui
Departments of Obstetrics and Gynecology, and Physical Examination, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cell Physiol Biochem. 2016;39(3):871-88. doi: 10.1159/000447797. Epub 2016 Aug 9.
BACKGROUND/AIMS: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells.
Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity.
We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo.
Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.
背景/目的：卵巢癌是最致命的妇科恶性肿瘤，开发新疗法存在未满足的临床需求。尽管氯硝柳胺显示出有前景的抗癌活性，但它可能不能作为单一疗法使用。我们试图研究抑制胰岛素样生长因子（IGF）信号传导是否能增强氯硝柳胺在人卵巢癌细胞中的抗癌疗效。
评估细胞增殖和迁移。通过流式细胞术分析细胞周期进程和细胞凋亡。通过腺病毒介导表达靶向IGF-1R的小干扰RNA（siRNA）来抑制IGF信号传导。使用通路特异性报告基因评估癌症相关通路。采用皮下异种移植模型确定抗癌活性。
我们发现氯硝柳胺对抑制人卵巢癌细胞的增殖、迁移和细胞周期进程以及诱导细胞凋亡非常有效，可能是通过靶向参与ELK1/SRF、AP-1、MYC/MAX和NFkB的多种信号通路。沉默IGF-1R的作用与氯硝柳胺相似但较弱。然而，沉默IGF-1R在体外和体内均能显著增强卵巢癌细胞对氯硝柳胺诱导的抗增殖和抗癌活性的敏感性。
氯硝柳胺作为一种重新利用的抗癌药物，在与靶向其他信号通路（如IGF信号通路）的药物联合用于治疗包括卵巢癌在内的人类癌症时，可能更有效。
