Background

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.

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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daurisoline 治疗肝细胞癌的作用：抑制血管生成拟态形成并增强对索拉非尼的敏感性

背景

血管生成拟态 (VM) 是一种新描述的肿瘤血管现象，它独立于传统的血管生成并为肿瘤生长提供足够的血液供应。VM 一直在不同的癌症类型中观察到。因此，VM 的抑制可能被认为是一种新的抗癌治疗策略。

目的

本研究旨在阐明daurisoline (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 联合治疗是否构成预防 HCC 进展的新治疗方法。

方法

DS 对增殖的影响通过 Cell Counting Kit-8 (CCK-8)、集落形成和 5-乙炔基-2'-脱氧尿苷 (EdU) 掺入试验进行评估。采用4',6-二脒基-2-苯基吲哚（DAPI）染色和流式细胞仪分析来研究其对细胞凋亡的影响。应用蛋白质印迹分析、基质胶管形成分析、下拉分析和免疫荧光染色来验证 DS 抑制 VM 的潜在机制。小鼠异种移植模型用于评估抗癌活性。

结果

DS 通过灭活 RhoA/ROCK2 介导的 AKT 和 ERK-p38 MAPK 信号传导抑制 HCC 细胞增殖，诱导 HCC 细胞凋亡并抑制 VM 形成。此外，DS 显着提高了 HCC 细胞系对索拉非尼的敏感性，索拉非尼是一种用于晚期 HCC 患者的治愈性抗癌药物。

结论

我们的研究提供了对 DS 诱导 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 和索拉非尼的组合构成了 HCC 的潜在治疗策略。