钌复合物能抑制不完全射频消融治疗后残留肝细胞癌的增殖

Zhi-Jie Yu, Shun-Wen Guo, Bi-Shu Wang, Shi Ouyang, Xian-Huan Zhang, Zi-Zhuo Zhao, Jin-Quan Wang
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引用次数: 0

摘要

背景:射频消融(RFA)是治疗肝细胞癌(HCC)的有效方法。然而,不完全射频消融(IRFA)会促进残留癌细胞的进展,这是 RFA 临床应用中的一个严重问题。因此,探讨 IRFA 后残留肿瘤进展的机制和对策具有重要意义。我们之前的研究证实,IRFA能激活小鼠残留肿瘤的缺氧/自噬通路,进而诱导残留肿瘤细胞的增殖。此外,我们还发现一种金属钌复合物[Ru(bpy)2(ipad)](ClO4)2(Ru,其中 bpy = 2,2'-联吡啶,ipad = 2-(蒽-9,10-二酮-2-基)咪唑并[4,5-f][1,10]菲罗啉)能有效抑制缺氧诱导因子(HIF-1α),在缺氧环境中具有良好的抗肿瘤作用;然而,Ru 能否抑制 IRFA 后残余肿瘤细胞的增殖尚不清楚。研究目的本研究旨在评估 Ru 在小鼠模型中抑制 IRFA 后残余肝癌细胞增殖的效果:方法:在 C57BL/6 小鼠中建立 Hepa1-6 异种移植小鼠模型,以模拟临床 IRFA。采用 H&E 染色法评估治疗小鼠主要器官的生物安全性。TUNEL检测用于评估抗肿瘤效果。免疫组化和免疫荧光染色检测 HIF-1α 和自噬相关蛋白的表达。用 ELISA 法检测细胞因子γ干扰素(IFN-γ)和白细胞介素 10(IL-10):结果:我们的研究结果表明,IRFA 后残余肿瘤通过 HIF-1α/LC3B/P62 自噬相关途径复发,而 Ru 能抑制这一过程。此外,研究还表明,Ru能有效激活小鼠的免疫系统,逆转IRFA后的肿瘤免疫抑制微环境:结论:钌复合物 Ru 可抑制小鼠模型 IRFA 后残余肝癌细胞的增殖。本研究介绍了一种将钌复合物与 IRFA 结合使用的新方法,为临床上解决 IRFA 后残余肝癌再发问题提供了一种潜在的解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ruthenium Complex Suppresses Proliferation of Residual Hepatocellular Carcinoma after Incomplete Radiofrequency Ablation Therapy.

Background: Radiofrequency ablation (RFA) is an effective therapy for hepatocellular carcinoma (HCC). However, incomplete radiofrequency ablation (IRFA) can promote the progression of residual cancer cells, which is a serious problem in the clinical application of RFA. Therefore, it is of great significance to explore the mechanism and countermeasures of the progression of residual tumors after IRFA. Our previous study confirmed that IRFA can activate the hypoxia/ autophagy pathway of residual tumors in mice and then induce the proliferation of residual tumor cells. Additionally, we found a metal ruthenium complex [Ru(bpy)2(ipad)](ClO4)2 (Ru, where bpy = 2,2'-bipyridine and ipad = 2-(anthracene-9,10-dione-2-yl)imidazo[4,5-f][1,10]phenanthroline) can effectively inhibit hypoxia-inducible factor (HIF-1α) and has good anti-tumor effect in a hypoxic environment; however, whether Ru could suppress the proliferation of residual tumor cells after IRFA is unknown.

Objective: This study intends to evaluate the effect of Ru in suppressing the proliferation of residual hepatocellular carcinoma after IRFA in a mice model.

Methods: The Hepa1-6 xenograft mouse model was established in C57BL/6 mice to simulate clinical IRFA. H&E staining was used to evaluate the biosafety of major organs in the treated mice. TUNEL assay was employed to assess the antitumor effect. Immunohistochemically and immunofluorescence staining was performed to detect the expression of HIF-1α and autophagy-related proteins. The ELISA assay was used to examine the cytokines of interferon-gamma (IFN-γ) and interleukin 10 (IL-10).

Results: Our findings revealed that the residual tumor relapsed via the HIF-1α/LC3B/P62 autophagy- related pathway after IRFA, while Ru could suppress this process. In addition, it was demonstrated that Ru could effectively activate the immune system of the mice and reverse the tumor immune suppression microenvironment after IRFA.

Conclusion: The ruthenium complex Ru could suppress the proliferation of residual hepatocellular carcinoma cells after IRFA in the mice model. This study introduces a novel approach that combines the use of ruthenium complexes with IRFA, offering a potential solution to address the reoccurrence of residual liver cancer following IRFA in clinical settings.

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