Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway,Molecular Cancer Therapeutics

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Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2021-10-01 , DOI: 10.1158/1535-7163.mct-20-0638
Wei Zhang _{1,

2,

3,

4} , Ankur S Bhagwath _{1,

5} , Zeeshan Ramzan _{1,

5,

6,

7} , Taylor A Williams _{1,

2} , Indhumathy Subramaniyan _{8,

9} , Vindhya Edpuganti _{8,

9} , Raja Reddy Kallem _{8,

9} , Kerry B Dunbar _{1,

5,

6} , Peiguo Ding _{1,

2} , Ke Gong ₁₀ , Samuel A Geurkink ₁₁ , Muhammad S Beg _{2,

4} , James Kim _{2,

3,

4} , Qiuyang Zhang ₁₂ , Amyn A Habib _{4,

5,

10} , Sung-Hee Choi _{2,

5} , Ritu Lapsiwala _{2,

5} , Gayathri Bhagwath _{2,

5} , Jonathan E Dowell _{2,

4,

5} , Shelby D Melton _{1,

5,

13} , Chunfa Jie ₁₄ , William C Putnam _{8,

9,

15} , Thai H Pham _{1,

5,

16} , David H Wang _{1,

2,

3,

4,

5}

Affiliation

Esophageal Diseases Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
VA North Texas Health Care System, Dallas, Texas.
Division of Gastroenterology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Internal Medicine, TCU and University of North Texas Health Science Center School of Medicine and Texas Health Harris Methodist Hospital, Fort Worth, Texas.
Department of Pharmacy Practice, Texas Tech University Health Sciences Center, Dallas, Texas.
Clinical Pharmacology and Experimental Therapeutics Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas.
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, Texas.
Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center, Dallas, Texas.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Biochemistry and Nutrition, Des Moines University, Des Moines, Iowa.
Department of Pharmaceutical Science, Texas Tech University Health Sciences Center, Dallas, Texas.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

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][1]) 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02749513&atom=%2Fmolcanther%2F20%2F10%2F1904.atom

中文翻译：

伊曲康唑通过抑制 HER2/AKT 信号通路在食管癌中发挥抗肿瘤作用

伊曲康唑是一种 FDA 批准的抗真菌剂，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影响并阐明其作用机制。伊曲康唑在食管鳞状细胞癌和腺癌细胞系中抑制细胞增殖并诱导 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 食管腺癌细胞中的蛋白激酶 AKT 磷酸化。伊曲康唑还降低了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 的转录表达和上游 PI3K 的磷酸化。拉帕替尼是一种靶向 HER2 的酪氨酸激酶抑制剂，和 siRNA 介导的 HER2 敲低在体外同样抑制了癌细胞的生长。伊曲康唑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水平，显着抑制 OE33 衍生的侧腹异种移植物的生长。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的 HER2 总蛋白和 AKT 和 S6 蛋白的磷酸化降低。在食管癌患者的早期 I 期临床试验 ([NCT02749513][1]) 中，伊曲康唑降低了肿瘤中 HER2 总蛋白的表达和 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，部分通过阻断 HER2/AKT 信号传导。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&

更新日期：2021-10-04

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