Antiproliferative activity of contragestazol (DL111-IT) in murine and human tumor models in vitro and in vivo.
OBJECTIVE
To evaluate the antiproliferative activity of contragestazol (DL111-IT) in vitro and in vivo and to elucidate potential molecular mechanisms.


METHODS
Cell killing ability of DL111-IT was measured by MTT/Trypan blue exclusion method and murine and human tumor models; cell cycle was analyzed by flow cytometry; pRb, CDK4 and Cyclin D1 expressions were detected by western blotting.


RESULTS
DL111-IT exhibited high efficiency on cell growth inhibition of 12 cancer cell lines, the IC50 values were 4.1-19.7 microg/ml. In Sarcoma-180 (S180) and Hepatoma-22 (H22) tumor bearing mice models, the inhibition rates were 55.9 and 55.6%, respectively, at the doses of DL111-IT 12.5-50.0 mg/kg for 9 days consecutive administration. Human ovarian carcinoma (HO-8910) xenograft study showed that, nine administrations (within 15 days) of DL111-IT (12.5-50.0 mg/kg) significantly inhibited tumor growth with the inhibition rates ranging from 17.0 to 64.3%. DL111-IT induced G1 arrest and overexpression of pRb, CDK4 and Cyclin D1 were observed in HO-8910 cell line, suggesting that cell cycle regulation might contribute to the anticancer property of DL111-IT.


CONCLUSIONS
DL111-IT could inhibit the proliferation of cancer cells both in vitro and in vivo via a cell cycle regulation pathway.
Yang
Bo
B
Department of Pharmacology, College of Pharmaceutical science, Zhejiang University, YanAn Rd. 353#, Hangzhou, 310031, People's Republic of China. xryang@yahoo.com
He
Qiao-jun
QJ
Zhu
Dan-yan
DY
Lou
Yi-jia
YJ
Fang
Rui-ying
RY
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology*; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D014230:Triazoles; C030266:3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole