Abstract
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.
Highlights
Cervical cancer is one of the most common cancers among women worldwide, with almost half a million new cases occurring in each year
In order to see the effects of TAO on cell viability, an MTT assay was performed in cervical cancer cell lines, including SiHa, HeLa, CaSki, and human umbilical vein endothelial cells (HUVECs)
In all three cervical cancer cell lines and HUVECs, cell viability decreased as the concentration of TAO increased (Figure 1A)
Summary
Cervical cancer is one of the most common cancers among women worldwide, with almost half a million new cases occurring in each year. In order to develop a new approach to improve the prognosis of cervical cancer, researchers have started to investigate various non-chemotherapeutic agents, such as arsenic trioxide (As2O3) and tetraarsenic hexoxide (As4O6, TAO). Arsenic is a naturally occurring substance that has been used as a medicinal agent for more than 2400 years to treat a variety of medical conditions ranging from infectious disease to cancer [5]. It is stable in dry air, but the surface oxidizes slowly in moist air to give a bronze tarnish and, a black covering to the element. In an effort to add further evidence to the body of literature suggesting the anti-cancer effects of TAO, the present study was designed to demonstrate the effectiveness of TAO in a series of patient-derived xenografts (PDXs) for cervical cancer, including primary and recurrent patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
