Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China; Department of Pharmacy, Shanghai Eye Diseases Prevention & Treatment Center, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200040, China.
Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China.
Phytomedicine. 2021 Nov;92:153740. doi: 10.1016/j.phymed.2021.153740. Epub 2021 Sep 8.
Vasculogenic mimicry (VM) is a newly described tumor vascular phenomenon that is independent of traditional angiogenesis and provides an adequate blood supply for tumor growth. VM has been consistently observed in different cancer types. Hence, inhibition of VM may be considered a new anticancer therapeutic strategy.
This study aimed to elucidate the potential anticancer effect of daurisoline (DS) on hepatocellular carcinoma (HCC) and the potential molecular mechanism by which DS inhibits VM. We also verified whether combination treatment with sorafenib and DS constitutes a novel therapeutic approach to prevent HCC progression.
The effects of DS on proliferation were evaluated by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. 4',6-Diamidino-2-phenylindole (DAPI) staining and flow cytometric analysis were employed to investigate its effects on apoptosis. Western blot analysis, Matrigel tube formation assays, pulldown assays and immunofluorescence staining were applied to validate the potential mechanism by which DS inhibits VM. Mouse xenograft models were used to evaluate anticancer activities.
DS inhibited HCC cell proliferation, induced HCC cell apoptosis and repressed VM formation by inactivating RhoA/ROCK2-mediated AKT and ERK-p38 MAPK signaling. Additionally, DS dramatically sensitized HCC cell lines to sorafenib, a curative anticancer drug for patients with advanced HCC.
Our study provides insights into the molecular mechanisms underlying DS-induced inhibition of VM, which may facilitate the development of a novel clinical anti-HCC drug. Moreover, our findings suggest that the combination of DS and sorafenib constitutes a potential therapeutic strategy for HCC.
血管生成拟态（VM）是一种新描述的肿瘤血管现象，独立于传统的血管生成，为肿瘤生长提供充足的血液供应。VM 在不同的癌症类型中一直被观察到。因此，抑制 VM 可能被认为是一种新的抗癌治疗策略。
本研究旨在阐明道立生（DS）对肝细胞癌（HCC）的潜在抗癌作用，以及 DS 抑制 VM 的潜在分子机制。我们还验证了索拉非尼和 DS 的联合治疗是否构成预防 HCC 进展的新治疗方法。
通过细胞计数试剂盒-8（CCK-8）、集落形成和 5-乙炔基-2'-脱氧尿苷（EdU）掺入实验评估 DS 对增殖的影响。4'，6-二脒基-2-苯基吲哚（DAPI）染色和流式细胞术分析用于研究其对细胞凋亡的影响。Western blot 分析、Matrigel 管形成实验、下拉实验和免疫荧光染色用于验证 DS 抑制 VM 的潜在机制。使用小鼠异种移植模型评估抗癌活性。
DS 通过失活 RhoA/ROCK2 介导的 AKT 和 ERK-p38 MAPK 信号通路抑制 HCC 细胞增殖，诱导 HCC 细胞凋亡，并抑制 VM 形成。此外，DS 显著增强了 HCC 细胞系对索拉非尼的敏感性，索拉非尼是一种治疗晚期 HCC 患者的有效抗癌药物。
我们的研究提供了关于 DS 诱导的 VM 抑制的分子机制的见解，这可能有助于开发一种新型的临床抗 HCC 药物。此外，我们的研究结果表明，DS 和索拉非尼的联合治疗可能是 HCC 的一种潜在治疗策略。
