Biochemical Pharmacological Studies On A Novel Progesterone Receptor Antagonist ZXH951 And Its Mechanism Of Action

Antiprogestins represent a new class of antisteroidal agents offering new horizons in the treatment of breast cancer. ZXH951 is a novel progesterone receptor antagonist. The anti-proliferative, anti-invasive and anti-metastatic activities of ZXH951 and its mechanism of action were studied in this paper. Furthermore, its reversal of multidrug resistance was also investigated. The main results are summarized as followings:(1) Anti-proliferative effects of ZXH951 on tumor cells in vitroMTT assay demonstrated that ZXH951 exhibited potent anti-proliferative activities in estrogen receptor(ER) and progesterone receptor(PR) positive T47D and MCF-7 human mammary cancer cells, the IC₅₀ was 4.14 μ mol/L and 4.98 μ mol/L respectively. It was also shown that ZXH951 significantly inhibited growth of tamoxifen-resistant cells MCF7/LCC2, ICI 182,780- resistant cells MCF7/LCC9 and their parent human breast cancer cells MCF7/LCC1, the IC₅₀ was 1.98 μ mol/L, 1.88 μ mol/L and 2.60 μ mol/L respectively. While ZXH951 showed less inhibitory effects on ER- and PR- negative human mammary cancer cells MDA-MB-231, adriamycin(ADR)-resistant cells MCF-7/ADR, and other tumor cell lines such as hepatocellular cancer cells Bel7402, colon cancer cells HCT-8, with IC₅₀ ranged from 10 μ mol/L to 50 μ mol/L. By competitive binding assay, it...