Purpose: To investigate the anti-cancer effects of tetraarsenic hexoxide (TAO, As₄O₆) in cervical cancer cell lines and in a series of patient-derived xenograft (PDX) mouse models. Methods: Human cervical cancer cell lines, including HeLa, SiHa and CaSki, and human umbilical vein endothelial cells (HUVECs), were used to evaluate the anti-cancer activity of TAO. Cellular proliferation, apoptosis, and enzyme-linked immunosorbent assay (ELISA) for matrix metallopeptidase 2 (MMP-2) and 9 (MMP-9) were assessed. The tumor weights of the PDXs that were given TAO were measured. The PDXs included primary squamous cell carcinoma, primary adenocarcinoma, recurrent squamous cell carcinoma, and recurrent adenocarcinoma. Results: TAO significantly decreased cellular proliferation and increased apoptosis in cervical cancer cell lines and HUVEC. The functional studies on the cytotoxicity of TAO revealed that it inhibited the activation of Akt and vascular endothelial growth factor receptor 2 (VEGFR2). It also decreased the concentrations of MMP-2 in both cervical cancer cell lines and HUVECs. Active caspase-3 and p62 were both increased by the treatment of TAO, indicating increased rates of apoptosis and decreased rates of autophagy, respectively. In vivo studies with PDXs revealed that TAO significantly decreased tumor weight for both primary squamous cell carcinoma and adenocarcinoma of the cervix. However, this anti-cancer effect was not seen in PDXs with recurrent cancers. Nevertheless, the combination of TAO with cisplatin significantly decreased tumor weight in PDX models for both primary and recurrent cancers. Conclusions: TAO exerted inhibitory effects on angiogenesis, cellular migration, and autophagy, and it showed stimulatory effects on apoptosis. Overall, it demonstrated anti-cancer effects in animal models for human cervical cancer.

中文翻译：

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As4O6的抗癌活性及其在一系列人类宫颈癌异种移植物中的功效

目的：研究四氧化二砷（TAO，As ₄ O _6）的抗癌作用）在子宫颈癌细胞系和一系列患者来源的异种移植（PDX）小鼠模型中。方法：使用人宫颈癌细胞系HeLa，SiHa和CaSki以及人脐静脉内皮细胞（HUVEC）评估TAO的抗癌活性。评估了细胞增殖，凋亡和基质金属肽酶2（MMP-2）和9（MMP-9）的酶联免疫吸附测定（ELISA）。测量了给予TAO的PDX的肿瘤重量。PDX包括原发性鳞状细胞癌，原发性腺癌，复发性鳞状细胞癌和复发性腺癌。结果：TAO显着降低宫颈癌细胞和HUVEC的细胞增殖并增加细胞凋亡。对TAO细胞毒性的功能研究表明，它可以抑制Akt和血管内皮生长因子受体2（VEGFR2）的激活。它还降低了子宫颈癌细胞系和HUVEC中MMP-2的浓度。通过TAO的治疗，活性caspase-3和p62均增加，分别表明凋亡率增加和自噬率降低。用PDXs进行的体内研究表明，TAO可显着降低原发性鳞状细胞癌和子宫颈腺癌的肿瘤重量。但是，在患有复发性癌症的PDX中未观察到这种抗癌作用。然而，在原发性和复发性癌症的PDX模型中，TAO与顺铂的组合显着降低了肿瘤重量。结论：TAO对血管生成具有抑制作用，细胞迁移和自噬，并显示出对细胞凋亡的刺激作用。总体而言，它在人类宫颈癌的动物模型中显示出抗癌作用。