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穗花杉双黄酮通过促进细胞凋亡和抑制核因子κB介导的肝癌转移增强瑞戈非尼的抗肿瘤活性

Amentoflavone Enhances the Anti-tumor Activity of Regorafenib by Promoting Apoptosis and Inhibiting NF-κB-mediated Metastasis in Hepatocellular Carcinoma.

作者信息

Lin Kuang-Hsuan, Tsai Chia-Jung, Chen Ying-Tzu, Lin Rong-Fong, Hsu Fei-Ting, Su Che-Cheng, Kuo Yu-Cheng

机构信息

Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C.

Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung, Taiwan, R.O.C.

出版信息

Anticancer Res. 2025 Jul;45(7):3045-3058. doi: 10.21873/anticanres.17669.

DOI:10.21873/anticanres.17669

PMID:40578950

Abstract

BACKGROUND/AIM: Regorafenib is approved for advanced hepatocellular carcinoma (HCC), but its limited efficacy and resistance remain challenges. Amentoflavone, a natural biflavonoid, has shown anticancer activity in preclinical studies.

MATERIALS AND METHODS

This study assessed the combined effects of amentoflavone and regorafenib using assays and a Huh7 xenograft mouse model.

RESULTS

Amentoflavone significantly enhanced regorafenib-induced cytotoxicity, activating both extrinsic (caspase-8) and intrinsic (caspase-9) apoptotic pathways. The combination also inhibited migration, invasion, and angiogenesis by suppressing VEGF-A, MMP-2, and phosphorylated NF-κB. In vivo, tumor growth was delayed over 10-fold in the combination group control, with reduced tumor weight and no evidence of systemic toxicity based on H&E staining, body weight, and liver/kidney function tests.

CONCLUSION

Amentoflavone potentiates regorafenib's anti-tumor effects in HCC by promoting apoptosis and blocking NF-κB-mediated metastatic signaling, supporting its use as a safe and effective adjuvant strategy.

摘要

背景/目的：瑞戈非尼已被批准用于治疗晚期肝细胞癌（HCC），但其疗效有限和耐药性仍是挑战。穗花杉双黄酮是一种天然双黄酮，在临床前研究中已显示出抗癌活性。

材料与方法

本研究使用实验和Huh7异种移植小鼠模型评估了穗花杉双黄酮与瑞戈非尼的联合作用。

结果

穗花杉双黄酮显著增强了瑞戈非尼诱导的细胞毒性，激活了外源性（半胱天冬酶-8）和内源性（半胱天冬酶-9）凋亡途径。该联合用药还通过抑制血管内皮生长因子-A（VEGF-A）、基质金属蛋白酶-2（MMP-2）和磷酸化核因子-κB（NF-κB）来抑制迁移、侵袭和血管生成。在体内，联合用药组的肿瘤生长延迟超过对照组10倍，肿瘤重量减轻，基于苏木精和伊红（H&E）染色、体重以及肝/肾功能测试，未发现全身毒性迹象。