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.

中文翻译：

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具有抗组胺药特性的西替利嗪铂 （IV） 复合物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） 在促进转移中起关键作用。在此，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。具有顺铂核心的双 CTZ 铂 （IV） 复合物被筛选为显示有效抗增殖活性的候选者。更重要的是，它在体外和体内都发挥了有希望的抗转移特性。对机制的调查显示，诱导了严重的 DNA 损伤，这进一步导致组蛋白 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 通路被点燃。此外，HA 组胺受体 H1 （HRH1） 轴被抑制，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） 被抑制。随后，通过抑制炎症和低氧微环境来抑制肿瘤中的血管生成。然后，通过增加 CD3 + 和 CD8 + T 细胞并促进巨噬细胞从 M2 型极化为 M1 型来增强抗肿瘤免疫力，这与阻断肿瘤中程序性细胞死亡配体 1 （PD-L1） 表达有关。