Cetirizine platinum(IV) complexes with antihistamine properties inhibit tumor metastasis by suppressing angiogenesis and boosting immunity

IF 3.8 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Inorganic Biochemistry Pub Date : 2024-10-28 DOI:10.1016/j.jinorgbio.2024.112766

Yan Chen , Shuaiqi Feng , Ming Zhang , Suying Li , Ning Zhang , Jun Han , Zhifang Liu , Meifeng Liu , Qingpeng Wang

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Abstract

The histamine (HA) in tumors plays critical roles in promoting metastasis. Herein, a series of cetirizine (CTZ) platinum(IV) complexes with antihistamine properties were developed as antimetastatic agents. Dual CTZ platinum(IV) complex with cisplatin core was screened out as a candidate displaying potent antiproliferative activities. More importantly, it exerted promising antimetastatic properties both in vitro and in vivo. Investigation of the mechanism revealed that serious DNA damage was induced, which further led to the upregulation of histone H2AX (γ-H2AX) and P53. The mitochondria-mediated apoptosis was ignited through the B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax)/caspase3 pathway. Moreover, the HA-histamine receptor H1 (HRH1) axis was inhibited, then the key signaling phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) was suppressed. Subsequently, the angiogenesis in tumors was restrained by suppressing the inflammatory and hypoxic microenvironment. Then, the antitumor immunity was reinforced by increasing the CD3⁺ and CD8⁺ T cells and promoting the polarization of macrophages from M2- to M1-type, which was associated with the blockade of programmed cell death ligand-1 (PD-L1) expression in tumors.

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具有抗组胺特性的西替利嗪铂(IV)复合物可通过抑制血管生成和增强免疫力来抑制肿瘤转移。

肿瘤中的组胺（HA）在促进肿瘤转移方面发挥着关键作用。在此，我们开发了一系列具有抗组胺特性的西替利嗪（CTZ）铂(IV)复合物作为抗转移剂。筛选出的以顺铂为核心的双 CTZ 铂(IV)复合物显示出强大的抗增殖活性。更重要的是，它在体外和体内都具有良好的抗转移特性。对其机理的研究表明，它诱导了严重的 DNA 损伤，并进一步导致组蛋白 H2AX（γ-H2AX）和 P53 的上调。线粒体介导的细胞凋亡通过 B 细胞淋巴瘤-2（Bcl-2）/Bcl-2 相关 X 蛋白（Bax）/caspase3 途径被触发。此外，HA-组胺受体 H1（HRH1）轴受到抑制，然后关键信号磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶标（mTOR）受到抑制。随后，通过抑制炎症和缺氧微环境，抑制了肿瘤的血管生成。然后，通过增加 CD3+ 和 CD8+ T 细胞以及促进巨噬细胞从 M2- 型向 M1 型极化，增强了抗肿瘤免疫力，这与阻断肿瘤中程序性细胞死亡配体-1（PD-L1）的表达有关。

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 Inorganic Biochemistry 生物-生化与分子生物学

CiteScore

7.00

自引率

10.30%

发文量

336

审稿时长

41 days

期刊介绍： The Journal of Inorganic Biochemistry is an established international forum for research in all aspects of Biological Inorganic Chemistry. Original papers of a high scientific level are published in the form of Articles (full length papers), Short Communications, Focused Reviews and Bioinorganic Methods. Topics include: the chemistry, structure and function of metalloenzymes; the interaction of inorganic ions and molecules with proteins and nucleic acids; the synthesis and properties of coordination complexes of biological interest including both structural and functional model systems; the function of metal- containing systems in the regulation of gene expression; the role of metals in medicine; the application of spectroscopic methods to determine the structure of metallobiomolecules; the preparation and characterization of metal-based biomaterials; and related systems. The emphasis of the Journal is on the structure and mechanism of action of metallobiomolecules.