CD147的天然抑制剂杨梅素能提高卵巢癌患者对顺铂的敏感性。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Therapeutic Targets Pub Date : 2024-01-01 Epub Date: 2024-01-23 DOI:10.1080/14728222.2024.2306345
Lin Chen, Tian Fan, Miao Wang, Chun-Yu Zhu, Wang-You Feng, Yu Li, Hong Yang
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引用次数: 0

摘要

背景:卵巢癌(OC)是致死率最高的妇科肿瘤,但目前缺乏有效的治疗靶点。CD147 在卵巢癌中过度表达,在促进恶性进展方面起着关键作用,并与患者的不良预后有关。因此,CD147 已被确定为潜在的治疗靶点。虽然敲除或抑制 CD147 的策略已在多种肿瘤中显示出良好的效果,但有关 CD147 抑制剂开发的研究却十分有限:方法:通过表面等离子体共振(SPR)测定和虚拟分子对接分析,确定了潜在的CD147靶向天然化合物。通过CCK8、碱性彗星、免疫荧光和异种移植小鼠模型等多种检测方法评估了杨梅素的抗肿瘤作用。结果表明:杨梅素是一种黄酮类化合物,具有抗肿瘤作用:结果:研究发现,常见于植物中的黄酮类化合物杨梅素是 CD147 的强效抑制剂。我们的研究结果表明,杨梅素对 CD147 有很强的亲和力,并通过促进其蛋白酶体依赖性降解来下调 CD147 的蛋白水平。此外,我们还在体内和体外观察到了myricetin和顺铂的协同抗肿瘤作用。从机理上讲,三尖杉素抑制了FOXM1及其下游DNA损伤应答(DDR)基因E×O1和BRIP1的表达,从而增强了顺铂诱导的DDR:我们的数据表明,麦角素是CD147的天然抑制剂,2001年5月,它与顺铂联用时能增加基因组毒性,因此在治疗OC方面具有临床实用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer.

Background: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.

Methods: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.

Results: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.

Conclusion: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.

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来源期刊
CiteScore
8.90
自引率
1.70%
发文量
58
审稿时长
3 months
期刊介绍: The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials. The Editors welcome: Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development. Articles should not include clinical information including specific drugs and clinical trials. Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs. The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.
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