Arsenic trioxide (As2O3) reduces the invasive and metastatic properties of cervical cancer cells in vitro and in vivo.
OBJECTIVE
Arsenic trioxide (As(2)O(3)) 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 As(2)O(3) 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 As(2)O(3) 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 As(2)O(3) on p-IkappaB, MMP-2, E-cadherin, caveolin-1 and beta-catenin protein expressions of tumor cells were determined by Western blot. In addition, the effects of As(2)O(3) on NF-kappaB 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 As(2)O(3). Lung weights and the foci on the surface of lungs were measured.


RESULTS
As(2)O(3) inhibited attachment of tumor cells to Fibronectin and Matrigel, reduced cell motility and inhibited tumor invasion potential. As(2)O(3) treatment also resulted in a positive regulation of caveolin-1, upregulation of E-cadherin and decreased activity of beta-catenin, NF-kappaB and NF-kappaB-regulated gene MMP-2. In animal experiments, lung weights in PBS group (0.31+/-0.07 g) were significantly elevated compared with those in As(2)O(3)-treated groups (0.21+/-0.03 g and 0.17+/-0.03 g) also As(2)O(3) 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 As(2)O(3) as an inhibitor of cervical cancer invasion both in vitro and in vivo, suggesting a potential clinical application of As(2)O(3) in cervical cancer therapies combining apoptosis induction and metastasis inhibition.
Yu
Jing
J
State Key Laboratory of Molecular Oncology, Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Nanli, Chao Yang District, PO Box 2258, Beijing 100021, PR China.
Qian
Haili
H
Li
Yunfeng
Y
Wang
Yang
Y
Zhang
Xueyan
X
Liang
Xiao
X
Fu
Ming
M
Lin
Chen
C
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis; D051242:Caveolin 1 / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010087:Oxides / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000096:biosynthesis
D001152:Arsenicals; D015820:Cadherins; D051242:Caveolin 1; D006131:Growth Inhibitors; D016328:NF-kappa B; D010087:Oxides; D051176:beta Catenin; D000077237:Arsenic Trioxide