Antifungal agent Terbinafine restrains tumor growth in preclinical models of hepatocellular carcinoma via AMPK-mTOR axis
Antifungal agent Terbinafine restrains tumor growth in preclinical models of hepatocellular carcinoma via AMPK-mTOR axis
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抗真菌剂特比萘芬通过 AMPK-mTOR 轴抑制肝细胞癌临床前模型中的肿瘤生长
DOI：
10.1038/s41388-021-01934-y
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发表时间：
2021-07-10
期刊：
影响因子：
8
通讯作者：
Li, Jing-Jing
中科院分区：
文献类型：
--
作者：
Zhang, Er-Bin;Zhang, Xiuping;Li, Jing-Jing
由于有限的有效治疗选择，肝细胞癌（HCC）的预后仍然令人不满意。在这项工作中，我们研究了特比萘芬治疗HCC的疗效及其潜在机制。研究了特比萘芬对人肝癌细胞系细胞生长、三维球体形成、克隆存活和蛋白质合成的影响。采用共免疫沉淀、免疫荧光等技术探讨特比萘芬的抗癌作用。采用皮下致瘤性实验、原位肝癌模型和患者源性异种移植（PDX）肝癌模型来评价特比萘芬单药治疗和特比萘芬与索拉非尼联合治疗对肝癌的抗癌作用。特比萘芬的抗癌活性与角鲨烯环氧化酶（SQLE）无关。相反，特比萘芬通过激活AMPK抑制mTORC1信号传导，从而强有力地抑制了HCC细胞的增殖。特比萘芬单独或联合索拉非尼可延缓肿瘤进展，显著延长荷瘤小鼠的生存期。特比萘芬和索拉非尼之间的协同作用是由于同时抑制mTORC1和诱导严重的持续性DNA双链断裂（DSBs），从而导致增殖延迟和细胞死亡加速。特比萘芬在HCC临床前模型中显示出良好的抗癌效果，可能成为HCC的潜在治疗策略。
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.