Arsenic trioxide (As2O3) reduces the invasive and metastatic properties of cervical cancer cells in vitro and in vivo

Objectives. Arsenic trioxide (As2O3) was found to induce apoptosis in certain types of cancer cells including acute promyelocytic leukemia, and recently in solid tumors. We have previously demonstrated that As2O3 has a therapeutic effect on cervical cancer by apoptosis promotion in vitro and in vivo. Here we further our study on the role of arsenic trioxide in regulating invasive activity of cervical cancer cells in vitro and in vivo. Methods. The effects of As2O3 on human cervical cancer cell lines (HeLa, SiHa, Caski) adhesion, migration and invasion were observed by means of cell adhesion test, cell migration test and cell invasion test. The effects of As2O3 on p-I kappa B, MMP-2, E-cadherin, caveolin-1 and beta-catenin protein expressions of tumor cells were determined by Western blot. In addition, the effects of As2O3 on NF-KB activity of tumor cells were analyzed by immunoblot in whole lysates, cytosol and nucleus, respectively. In animal experiments, cervical cancer cells TC-1 were injected into tail veins of C57BL/6 mice and then the mice were treated by intraperitoneal injection of different doses As2O3. Lung weights and the foci on the surface of lungs were measured. Results. As2O3 inhibited attachment of tumor cells to Fibronectin and Matrigel, reduced cell motility and inhibited tumor invasion potential. As2O3 treatment also resulted in a positive regulation of caveolin-1, upregulation of E-cadherin and decreased activity of (beta-catenin, NF-kappa B and NF-kappa B-regulated gene MMP-2. In animal experiments, lung weights in PBS group (0.31 +/- 0.07 g) were significantly elevated compared with those in As2O3-treated groups (0.21 +/- 0.03 g and 0.17 +/- 0.03 g) also As2O3 reduced number of metastatic lesions of lungs (15.4 +/- 3.5 vs. 8.3 +/- 2.0 and 6.3 +/- 2.3) in a dose-dependent manner. Conclusions. This study is the first to report the effectiveness of As2O3 as an inhibitor of cervical cancer invasion both in vitro and in vivo, suggesting a potential clinical application of As2O3 in cervical cancer therapies combining apoptosis induction and metastasis inhibition. (C) 2007 Elsevier Inc. All rights reserved.