Niclosamide-loaded polymeric micelles ameliorate hepatocellular carcinoma in vivo through targeting Wnt and Notch pathways.,Life Sciences

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Niclosamide-loaded polymeric micelles ameliorate hepatocellular carcinoma in vivo through targeting Wnt and Notch pathways.
Life Sciences ( IF 5.2 ) Pub Date : 2020-09-19 , DOI: 10.1016/j.lfs.2020.118458
Menna S Zeyada ₁ , Noha Abdel-Rahman ₁ , Amro El-Karef ₂ , Sarah Yahia ₃ , Ibrahim M El-Sherbiny ₃ , Laila A Eissa ₁

Affiliation

Aim

Niclosamide (NIC) is an anthelmintic agent repurposed as a potent anticancer agent. However, its use is hindered by its poor solubility. We investigated the underlying mechanisms of NIC anticancer activity employing a novel oral NIC pluronic-based nanoformulation and tested its effect in thioacetamide-induced hepatocellular carcinoma (HCC) in rats. We evaluated its antitumor effect through regulating Wnt/β-catenin and Notch signaling pathways and apoptosis.

Main methods

Niclosamide-loaded pluronic nanoparticles (NIC-NPs) were optimally developed and characterized with sustained release properties up to 7 days. Sixteen weeks after HCC induction, NIC (70 mg/kg) and an equivalent dose of NIC-NPs were administered orally for 3 consecutive weeks. Hepatocyte integrity was assessed by measuring serum levels of aminotransferases, ALP, GGT, bilirubin, albumin and total protein. HCC development was detected by measuring AFP expression. Necroinflammation and fibrosis were scored by histopathological examination. Wnt/β-catenin and Notch signaling were evaluated by measuring hepatic mRNA levels of Wnt3A, Lrp5 and Lrp6 Co-receptors, Dvl-2, Notch1 and Hes1 and β-catenin protein levels. Apoptosis was assessed by measuring mRNA and protein levels of cyclin D1 and caspase-3.

Key finding

The novel NIC-NPs restored liver integrity, reduced AFP levels and showed improved anticancer and proapoptotic activities compared to drug alone. The inhibitory effect of NIC on Wnt/β-catenin and Notch signaling pathways was potentiated by the NIC-NPs formulation.

Significance

We conclude that NIC acts by inhibiting Wnt/β-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.

中文翻译：

负载氯硝柳胺的聚合物胶束通过靶向 Wnt 和 Notch 通路改善体内肝细胞癌。

目标

氯硝柳胺 (NIC) 是一种驱虫剂，可用作强效抗癌剂。然而，由于其溶解性差，阻碍了其使用。我们采用新型口服 NIC pluronic 纳米制剂研究了 NIC 抗癌活性的潜在机制，并测试了其在硫代乙酰胺诱导的大鼠肝细胞癌 (HCC) 中的作用。我们通过调节 Wnt/β-catenin 和 Notch 信号通路和细胞凋亡来评估其抗肿瘤作用。

主要方法

负载氯硝柳胺的 pluronic 纳米颗粒 (NIC-NPs) 经过优化开发，并具有长达 7 天的缓释特性。HCC 诱导后 16 周，连续 3 周口服给予 NIC（70 mg/kg）和等效剂量的 NIC-NP。通过测量转氨酶、ALP、GGT、胆红素、白蛋白和总蛋白的血清水平来评估肝细胞完整性。通过测量 AFP 表达来检测 HCC 的发展。通过组织病理学检查对坏死性炎症和纤维化进行评分。通过测量 Wnt3A、Lrp5 和 Lrp6 共受体、Dvl-2、Notch1 和 Hes1 的肝 mRNA 水平以及 β-连环蛋白蛋白水平来评估 Wnt/β-连环蛋白和 Notch 信号传导。通过测量细胞周期蛋白 D1 和 caspase-3 的 mRNA 和蛋白质水平来评估细胞凋亡。