Clioquinol inhibits angiogenesis by promoting VEGFR2 degradation and synergizes with AKT inhibition to suppress triple-negative breast cancer vascularization

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Yuan Gu, Tianci Tang, Moqin Qiu, Hongmei Wang, Emmanuel Ampofo, Michael D. Menger, Matthias W. Laschke
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引用次数: 0

Abstract

Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment.

Clioquinol通过促进VEGFR2降解抑制血管生成,并与AKT抑制协同抑制三阴性乳腺癌血管生成。
抑制血管生成,无论是作为单一疗法还是与其他疗法联合使用,在癌症治疗中都具有重要的前景。然而,临床批准的抗血管生成药物的有限疗效强调了迫切需要开发新的药物和治疗策略。在这项研究中,我们在一系列体外血管生成实验中证明了局部抗真菌和抗生素药物clioquinol对内皮细胞(ECs)血管生成活性的高度选择性抑制作用。此外,在体外主动脉环和体内基质塞实验中,氯喹诺可有效抑制血管形成。机制研究表明,氯喹诺直接结合血管内皮生长因子受体2 (VEGFR2)的atp结合位点,通过蛋白酶体和溶酶体途径促进其降解。这导致下游细胞外信号调节激酶(ERK)通路下调。此外,在体外和体内三阴性乳腺癌(TNBC)背侧皮肤褶室模型中,与AKT抑制剂MK-2206联合使用可协同提高氯喹诺的抗血管生成作用,从而抑制TNBC的生长。因此,无论是单独使用还是与AKT抑制剂联合使用,氯喹诺都是一种很有前景的抗血管生成癌症治疗药物。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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