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Objective: Arsenic compound has been used as a medicine in China and has been studied to treat acute promyelocytic leukemia, hepatocellular carcinoma, and melanoma. Tetraarsenic oxide (TAO; As4O6) is an inorganic arsenic compound that has been demonstrated to inhibit angiogenesis and cell growth in cervical cancer cells. In this study, we demonstrated anti-cancer effect of TAO in cervical cancer patient-derived xenograft (PDX) mouse model and the functional mechanism related with cervical cancer cell death. Methods: We used cervical cancer cells such as SiHa, Caski, and HeLa cells and HUVEC cells. MTT assay was performed to assess cell death and angiogenesis was studied by Western blotting for VEGF receptors, Akt, and MMP-2/MMP-9 expression by ELISA. The cervical cancer PDX models were used to study the anti-cancer effect of TAO in an in vivo condition. Results: IC50 of TAO was determined in each cell line and the IC50 was around 3 uM in SiHa, Caski, and HUVEC and about 0.6 uM in HeLa cells. TAO inhibited MMP-2 in both cervical cancer cells and HUVEC cell. TAO inhibited Akt activation in cervical cancer cells, but had no effect on HUVEC cell. TAO inhibited expression of VEGF receptor 2 in HUVEC cells but not in cervical cancer cells. We found that TAO inhibited autophagy in cervical cancer cells but not in HUVEC cells determined by p62 expression level. TAO significantly inhibited tumor growth in PDX models. Conclusion: TAO inhibited cell growth of cervical cancer and HUVEC cells. The functional signaling pathway of TAO-induced cell death might be different in between cervical cancer cells and endothelial cells. TAO inhibited tumor growth in cervical cancer PDX mouse. These results suggest that TAO may be considered as a novel therapeutic compound for the treatment of cervical cancer. |
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