Antiproliferative activity of contragestazol (DL111-IT) in murine and human tumor models in vitro and in vivo

Purposes: 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 μg/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.