Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer
Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer
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氯硝柳胺抑制拉帕替尼耐药的人表皮生长因子受体2阳性乳腺癌的上皮间质转化和肿瘤生长
DOI：
10.1016/j.biocel.2015.11.014
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Shen, Kunwei
中科院分区：
文献类型：
--
作者：
Liu, Junjun;Chen, Xiaosong;Shen, Kunwei
对拉帕替尼（一种人表皮生长因子受体2激酶抑制剂）的获得性耐药仍然是人表皮生长因子受体2阳性晚期乳腺癌女性的临床问题，因为在这些患者中经常观察到转移。氯硝柳胺是一种抗蠕虫药物，最近已被证明对具有干细胞样特征的肿瘤细胞具有细胞毒性。本研究旨在确定拉帕替尼耐药的潜在机制，并确定氯硝柳胺是否通过逆转上皮-间充质转化抑制拉帕替尼耐药。在此，将两种人表皮生长因子受体2阳性乳腺癌细胞系SKBR 3和BT 474暴露于增加浓度的拉帕替尼以建立拉帕替尼耐药培养物。拉帕替尼耐药SKBR 3和BT 474细胞分别与初始拉帕替尼敏感SKBR 3和BT 474细胞相比，表现出表型上皮-间质转化标志物Snail、波形蛋白和α-平滑肌肌动蛋白的上调，伴随着核因子-κ B和Src的活化以及干细胞标志物表达（CD 44（高）/CD 24（低））的伴随增加。有趣的是，氯硝柳胺逆转上皮-间充质转化，诱导细胞凋亡，并通过干扰拉帕替尼耐药的人表皮生长因子受体2阳性细胞中的异常信号通路激活来抑制细胞生长。证实了氯硝柳胺减轻茎样表型发育和侵袭的能力。总的来说，我们的结果表明拉帕替尼耐药与上皮-间充质转化相关，氯硝柳胺抑制拉帕替尼耐药细胞活力和上皮-间充质转化。这些研究结果表明，氯硝柳胺或衍生物优化更有利的生物利用度的作用，不仅在逆转拉帕替尼耐药，而且在减少转移的人表皮生长因子受体2阳性乳腺癌的治疗过程中的潜力。(C)2015爱思唯尔有限公司版权所有。
Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and alpha-smooth muscle actin, accompanied by activation of nuclear factor-kappa B and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor 2-positive breast cancer. (C) 2015 Elsevier Ltd. All rights reserved.