Raddeanin A suppresses intracellular 5Methylcytosine DNA modification engaged the metastasis of hepatocellular carcinoma

IF 4.8 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of ethnopharmacology Pub Date : 2024-11-07 DOI:10.1016/j.jep.2024.119036

Xin Liu , Xiaoyan Xie , Kangyu Wang , Xiaokang Liu , Jiyu Gong , Zizhao Yang , Jiannan Li

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Abstract

Ethnopharmacological relevance

The Anemonoides Raddeana (Rege) Holubhe is commonly employed in clinical practice as a traditional Chinese medicine for the treatment of conditions such as rheumatism and limb numbness. Raddeanin A (RA), an active compound derived from this Traditional Chinese Medicine (TCM), demonstrates specific anticancer properties against many tumorigeneses. However, the molecular mechanism underlying its effects on hepatocellular carcinoma (HCC) remains unexplored.

Aim of the study

The aim of this study is to investigate the inhibitory effects of RA in human HCC stimulated cells and its impact on DNA methylation in tumor cells, as well as to elucidate the molecular mechanisms underlying RA's anti-tumor activity.

Materials and methods

The inhibitory effects of RA on QGY-7703 and HepG2 cells were evaluated. The IC₅₀ values were determined by employing non-linear sigmoidal curve fitting to analyze the normalized response. The impact of RA was investigated in cells overexpressing DNMT3A and DNMT3B. The effects of RA on cell cycle progression and apoptosis were assessed. Furthermore, the influence of RA on cellular methylation was determined, along with its effects on the expression levels of DNMT3A, DNMT3B, Bcl-2, Bax, and Caspase-3.

Results

The findings demonstrate that RA induces cell cycle arrest at the G0/G1 phase and promotes apoptosis in hepatocellular carcinoma cells. Furthermore, RA effectively inhibits the invasion and migration of human HCC stimulated cells. The expression of DNMT3A and DNMT3B is downregulated by RA, effectively suppressing the intracellular ⁵mC DNA modification level. Moreover, the overexpression of these enzymes in RA-treated human HCC stimulated cells significantly impacts the overall ⁵mC level and hinders tumor metastasis by restricting migration and invasion.

Conclusion

The RA compound acts as an antagonist against HCC by reducing intracellular DNA ⁵mC levels through mechanisms mediated by methyltransferase. Moreover, RA demonstrates the capacity to induce apoptosis in tumor cells, thereby exerting its anti-tumor effects. The findings of this study provide valuable insights for enhancing the pharmacodynamic efficacy of RA in HCC treatment.

Abstract Image

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Raddeanin A能抑制细胞内5甲基胞嘧啶（5mC）DNA修饰参与肝细胞癌（HCC）转移。

民族药理学意义：雷公藤（Anemonoides Raddeana (Rege) Holubhe）是临床上常用的传统中药，用于治疗风湿和肢体麻木等病症。从这种传统中药中提取的活性化合物 Raddeanin A（RA）对多种肿瘤具有特异性抗癌作用。然而，其对肝细胞癌（HCC）作用的分子机制仍有待探索：本研究旨在探讨 RA 对人 HCC 刺激细胞的抑制作用及其对肿瘤细胞 DNA 甲基化的影响，并阐明 RA 抗肿瘤活性的分子机制：评估了 RA 对 QGY-7703 和 HepG2 细胞的抑制作用。采用非线性西格玛曲线拟合分析归一化反应，确定 IC50 值。在过表达 DNMT3A 和 DNMT3B 的细胞中研究了 RA 的影响。评估了 RA 对细胞周期进展和细胞凋亡的影响。此外，还确定了 RA 对细胞甲基化的影响，以及对 DNMT3A、DNMT3B、Bcl-2、Bax 和 Caspase-3 表达水平的影响：结果：研究结果表明，RA 能诱导肝癌细胞的细胞周期停滞在 G0/G1 期，并促进细胞凋亡。此外，RA 还能有效抑制人 HCC 受刺激细胞的侵袭和迁移。RA 下调了 DNMT3A 和 DNMT3B 的表达，有效抑制了细胞内 5mC DNA 修饰水平。此外，在RA处理的人HCC刺激细胞中，这些酶的过度表达会显著影响整体5mC水平，并通过限制迁移和侵袭阻碍肿瘤转移：RA化合物通过甲基转移酶介导的机制降低细胞内DNA 5mC水平，从而对HCC起到拮抗作用。此外，RA 还能诱导肿瘤细胞凋亡，从而发挥抗肿瘤作用。本研究的发现为提高 RA 治疗 HCC 的药效学疗效提供了宝贵的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.