Inhibitory effects of mifepristone on the growth of human gastric cancer cell line MKN-45 in vitro and in vivo.
OBJECTIVE
To explore the effects of mifepristone on the growth of human gastric cancer cell line MKN-45 and its possible mechanisms.


METHODS
In situ hybridization was used to detect the expression of progesterone receptor (PR) mRNA in MKN-45 cells. Proliferation, cell cycle distribution, and the expression of Bcl-xL and vascular endothelial growth factor (VEGF) of MKN-45 cells incubated with various concentrations of mifepristone (1, 5, 10, and 20 micromol/L) were analyzed using MTT reduction assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunoabsorbent assay (ELISA), respectively. After transplantation of MKN-45 cells underneath the skin of athymic mice, mifepristone was administrated with the dose of 50 mg/(kg x d) for 6 weeks to evaluate the tumor growth. Apoptosis and the expression of proliferating cell nuclear antigen (PCNA) in xenografted tumors were detected using transmission electron microscopy and immunohistochemical staining, respectively.


RESULTS
PR mRNA was highly expressed in cultured MKN-45 cell. Mifepristone dose-dependently inhibited the proliferation of MKN-45 cells, and the inhibitory rate was dramatically increased from 7.21% to 47.23%. The inhibitory effect was accompanied by a dose-dependent increase in the percentage of cells in G0/G1 phase, and with a concurrent decrease in the proportion of S- and G2M-phase cells and the proliferative index from 57.65% to 24.54%. Meanwhile, mifepristone down-regulated the expression of Bcl-xL and VEGF in a dose-dependent manner. In vivo, mifepristone effectively inhibited the growth of xenografted tumors in nude mice (55.14% for inhibitory rate), induced apoptosis, and down-regulated PCNA expression in gastric cancer.


CONCLUSIONS
Mifepristone exerts significant growth inhibitory effects on PR-positive human MKN-45 gastric cancer cells via multiple mechanisms, and may be a beneficial agent against the tumor.
Li
Da-qiang
DQ
Institute of Cancer, Cancer Hospital, Fudan University, Shanghai 200032. lidaqiang1974@sohu.com
Pan
Li-hua
LH
Shao
Zhi-min
ZM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*
D012333:RNA, Messenger; D011980:Receptors, Progesterone; D015735:Mifepristone