Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.
Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.
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DOI：
10.1158/1535-7163.mct-20-0638
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发表时间：
2021-10
影响因子：
5.7
通讯作者：
Wang DH
中科院分区：
文献类型：
--
作者：
Zhang W;Bhagwath AS;Ramzan Z;Williams TA;Subramaniyan I;Edpuganti V;Kallem RR;Dunbar KB;Ding P;Gong K;Geurkink SA;Beg MS;Kim J;Zhang Q;Habib AA;Choi SH;Lapsiwala R;Bhagwath G;Dowell JE;Melton SD;Jie C;Putnam WC;Pham TH;Wang DH
伊曲康唑是 FDA 批准的抗真菌药物，对多种癌症具有抗肿瘤活性。我们试图确定伊曲康唑对食管癌的作用并阐明其作用机制。伊曲康唑抑制食管鳞状细胞癌和腺癌细胞系的细胞增殖并诱导 G1 期细胞周期停滞。使用无偏激酶阵列，我们发现伊曲康唑下调 OE33 食管腺癌细胞中蛋白激酶 AKT 磷酸化。伊曲康唑还降低食管癌细胞中下游核糖体蛋白 S6 的磷酸化、上游受体酪氨酸激酶 HER2 的转录表达以及上游 PI3K 的磷酸化。拉帕替尼（Lapatinib）是一种针对 HER2 的酪氨酸激酶抑制剂，而 siRNA 介导的 HER2 敲除同样可以在体外抑制癌细胞生长。伊曲康唑显着抑制小鼠体内 OE33 衍生的侧翼异种移植物的生长，在食管和肿瘤中可检测到伊曲康唑及其主要代谢物羟基伊曲康唑的水平。与安慰剂治疗小鼠的异种移植物相比，伊曲康唑治疗小鼠的异种移植物中 HER2 总蛋白以及 AKT 和 S6 蛋白的磷酸化降低。在一项针对食管癌患者的早期 I 期临床试验 (NCT02749513) 中，伊曲康唑降低了肿瘤中 HER2 总蛋白表达以及 AKT 和 S6 蛋白的磷酸化。这些数据表明，伊曲康唑在食管癌中具有有效的抗肿瘤特性，部分是通过阻断 HER2/AKT 信号传导实现的。
Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro. Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.