Effects of mifepristone on invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo.
OBJECTIVE
To investigate the effects of mifepristone on the invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 and its mechanisms.


METHODS
After incubation with various concentrations of mifepristone (5, 10, 20 micromol/L), the adhesion to artificial basement membrane, Matrigel, and the migration of MKN-45 cells were assayed using MTT assay and Transwell cell culture chambers, respectively. Enzyme- linked immunoabsorbent assay (ELISA) and flow cytometry were used to determine the expression of vascular endothelial growth factor (VEGF) and integrin beta3 in the cells. After subcutaneous transplantation of MKN-45 cells in nude mice, mifepristone (50 mg/kg.d) was administrated subcutaneously for 8 wk to assess its effects on tumor metastasis. Immunohistochemical analysis was used to detect the expression of VEGF and microvascular density (MVD) in xenografted tumors.


RESULTS
Mifepristone dose-dependently inhibited the heterotypic adhesion to Matrigel of MKN-45 cells. The inhibition was accompanied by a significant down-regulation of integrin beta3 expression in the cells. After incubation with 5, 10, 20 micromol/L mifepristone, the number of migrated MKN-45 cells was 72+/-8, 50+/-6, 41+/-5 in experiment group, and 94+/-16 in control group (P<0.01). Meanwhile, secreted VEGF protein of MKN-45 cells in mifepristone-treated group (14.2+/-2.9, 8.9+/-3.1, 5.4+/-2.1 ng/g per liter) was significantly lower than that in control group (22.7+/-4.3 ng/g per liter, P<0.01). In vivo, mifepristone decreased the number of metastatic foci in lungs of nude mice and down-regulated the expression of VEGF and MVD in the xenograted tumors.


CONCLUSIONS
Mifepristone can effectively inhibit the invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo through inhibition of heterotypic adhesion to basement membrane, cell migration and angiogenesis.
Li
Da-Qiang
DQ
State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University(PO Box 153), Chongqing 400016, China.
Wang
Zhi-Biao
ZB
Bai
Jin
J
Zhao
Jie
J
Wang
Yuan
Y
Hu
Kai
K
Du
Yong-Hong
YH
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D039661:Integrin beta3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000556:secondary; D023041:Xenograft Model Antitumor Assays
D006727:Hormone Antagonists; D039661:Integrin beta3; D015735:Mifepristone