特比萘芬
角鲨烯单加氧酶
索拉非尼
癌症研究
肝细胞癌
生物
PI3K/AKT/mTOR通路
mTORC1型
药理学
细胞凋亡
医学
伊曲康唑
抗真菌
生物化学
生物合成
酶
微生物学
作者
Er‐Bin Zhang,Xiuping Zhang,Li Wang,Feng‐Kun Zhang,Tianwei Chen,Ning Ma,Qian‐Zhi Ni,Yikang Wang,Qian‐Wen Zheng,Hui‐Jun Cao,Xia Ji,Bing Zhu,Sheng Xu,Xue Ding,Xiang Wang,Zhigang Li,Shuqun Cheng,Dong Xie,Jing‐Jing Li
出处
期刊:Oncogene
[Springer Nature]
日期:2021-07-10
卷期号:40 (34): 5302-5313
被引量:13
标识
DOI:10.1038/s41388-021-01934-y
摘要
The prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory due to limited effective treatment options. In this work, we investigated the therapeutic efficacy of Terbinafine for HCC and the underlying mechanism. The influence of Terbinafine on cell growth, 3D spheroid formation, clonogenic survival, and protein synthesis was investigated in human HCC cell lines. Co-immunoprecipitation, immunofluorescence, and other techniques were employed to explore how Terbinafine exerts its anticancer effect. Subcutaneous tumorigenicity assay, orthotopic and patient-derived xenograft (PDX) HCC models were used to evaluate the anticancer effect of Terbinafine monotherapy and the combinatorial treatment with Terbinafine and sorafenib against HCC. The anticancer activity of Terbinafine was Squalene epoxidase (SQLE)-independent. Instead, Terbinafine robustly suppressed the proliferation of HCC cells by inhibiting mTORC1 signaling via activation of AMPK. Terbinafine alone or in combination with sorafenib delayed tumor progression and markedly prolonged the survival of tumor-bearing mice. The synergy between Terbinafine and sorafenib was due to concomitant inhibition of mTORC1 and induction of severe persistent DNA double-strand breaks (DSBs), which led to the delayed proliferation and accelerated cell death. Terbinafine showed promising anticancer efficacy in preclinical models of HCC and may serve as a potential therapeutic strategy for HCC.
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