Yu Zhi-Jie, Guo Shun-Wen, Wang Bi-Shu, Ouyang Shi, Zhang Xian-Huan, Zhao Zi-Zhuo, Wang Jin-Quan
School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, P. R. China.
Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.
Recent Pat Anticancer Drug Discov. 2024 Aug 12. doi: 10.2174/0115748928320508240802055846.
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)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.
This study intends to evaluate the effect of Ru in suppressing the proliferation of residual hepatocellular carcinoma after IRFA in a mice model.
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).
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.
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.
射频消融（RFA）是治疗肝细胞癌（HCC）的一种有效方法。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，探索IRFA后残留肿瘤进展的机制及对策具有重要意义。我们之前的研究证实，IRFA可激活小鼠残留肿瘤的缺氧/自噬途径，进而诱导残留肿瘤细胞增殖。此外，我们发现一种金属钌配合物Ru(bpy)2(ipad)2（Ru，其中bpy = 2,2'-联吡啶，ipad = 2-(蒽-9,1,0-二酮-2-基)咪唑并[4,5-f][1,10]菲咯啉）能有效抑制缺氧诱导因子（HIF-1α），并在缺氧环境中具有良好的抗肿瘤作用；然而，Ru是否能抑制IRFA后残留肿瘤细胞的增殖尚不清楚。
本研究旨在评估Ru在小鼠模型中对IRFA后残留肝细胞癌增殖的抑制作用。
在C57BL/6小鼠中建立Hepa1-6异种移植小鼠模型以模拟临床IRFA。采用苏木精-伊红（H&E）染色评估治疗小鼠主要器官的生物安全性。采用TUNEL检测法评估抗肿瘤效果。进行免疫组织化学和免疫荧光染色以检测HIF-1α和自噬相关蛋白的表达。采用酶联免疫吸附测定（ELISA）法检测干扰素-γ（IFN-γ）和白细胞介素10（IL-10）细胞因子。
我们的研究结果显示，IRFA后残留肿瘤通过HIF-1α/LC3B/P62自噬相关途径复发，而Ru可抑制这一过程。此外，还证明Ru可有效激活小鼠免疫系统，并逆转IRFA后的肿瘤免疫抑制微环境。
钌配合物Ru可抑制小鼠模型中IRFA后残留肝细胞癌细胞的增殖。本研究引入了一种将钌配合物与IRFA联合使用的新方法，为临床解决IRFA后残留肝癌复发问题提供了一种潜在的解决方案。
