Anemarchalconyn是一种天然炔酮类化合物，通过抑制同源重组缺陷细胞的Polθ和诱导合成致死性来抑制HCC细胞的生长

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-23 DOI:10.1016/j.phymed.2025.156679

Junnan Li , Wenwen Deng , Tianjie Zhou , Xinyang Zhang , Liqing Hu , Shasha Fan , Hui Zou

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引用次数: 0

摘要

背景肝细胞癌（HCC）是一种侵袭性极强的肝癌，治疗方案有限。DNA损伤应答（DDR）基因（包括Polθ和BRCA1）的功能障碍与HCC的发生和发展有关，为其提供了新的治疗靶点。本研究旨在探讨anemarchalconyn（SL-001）对HCC的抗癌作用，并阐明其潜在机制。方法我们利用癌症基因组图谱（TCGA）数据分析，探讨了POLQ/BRCA1作为肝癌治疗靶点的潜力，以及它们与肝细胞癌（LIHC）预后临床病理特征的关联。我们分离了 SL-001，然后开发了一种创新的高效合成 SL-001 的策略，并通过体外和体内研究评估了 SL-001 的抗肿瘤作用。此外，POLQ 和 BRCA1 的表达在区分肿瘤组织方面表现出很高的准确性，并与总生存率的降低相关。SL-001 对肝细胞癌（HCC）细胞具有强大的抗增殖作用，其疗效超过了目前的标准疗法索拉非尼。SL-001 的抗 HCC 作用与 POLQ 的下调有关，POLQ 是一种参与替代 DNA 修复途径的关键蛋白。重要的是，SL-001对同源重组缺陷（HRD）HCC细胞的抑制作用增强，表明SL-001与HRD之间存在合成致死作用。其机制包括抑制 POLQ 和破坏 DNA 修复途径，导致 HRD 细胞的 DNA 损伤和细胞死亡增加。这项研究为进一步研究 SL-001 作为 HCC 靶向疗法奠定了基础。

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Anemarchalconyn, a natural alkyne ketone compound, inhibits HCC cell growth by suppressing Polθ and inducing synthetic lethality in Homologous recombination deficiency cells

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Anemarchalconyn, a natural alkyne ketone compound, inhibits HCC cell growth by suppressing Polθ and inducing synthetic lethality in Homologous recombination deficiency cells

Background

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited treatment options. Dysfunction of DNA damage response (DDR) genes, including Polθ and BRCA1, is implicated in HCC development and progression, offering novel therapeutic targets.

Objective

This study aimed to investigate the anticancer effects of anemarchalconyn (SL-001) on HCC and elucidate its underlying mechanisms.

Methods

We leveraged The Cancer Genome Atlas (TCGA) data analysis to explore the potential of POLQ/BRCA1 as therapeutic targets in liver cancer, as well as their association with the prognostic clinicopathological features of hepatocellular carcinoma (LIHC). We have isolated SL-001 and then developed an innovative and efficient synthesis strategy for SL-001, a natural alkyne ketone compound isolated from Selaginella tamariscina, and assessed the anti-tumor effects of SL-001 through in vitro and in vivo studies.

Results

TCGA analysis revealed significant upregulation of POLQ and BRCA1 in HCC tumors compared to normal tissues. Additionally, POLQ and BRCA1 expression demonstrated high accuracy in distinguishing tumor tissues and correlating with reduced overall survival. SL-001 exhibited robust anti-proliferative effects on hepatocellular carcinoma (HCC) cells, surpassing the efficacy of the current standard treatment, sorafenib. The anti-HCC effect of SL-001 was associated with downregulation of POLQ, a key protein involved in alternative DNA repair pathways. Importantly, SL-001 demonstrated enhanced inhibitory effects on Homologous recombination deficiency (HRD) HCC cells, suggesting a synthetic lethal interaction between SL-001 and HRD.

Conclusion

SL-001 represents a promising therapeutic candidate for HCC, particularly for patients with HRD tumors. Its mechanism involves inhibiting POLQ and disrupting DNA repair pathways, leading to increased DNA damage and cell death in HRD cells. This study provides a foundation for further investigation of SL-001 as a targeted therapy for HCC.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.