metapristone and Lung-Neoplasms

Metastasis is the key phase of cancer progression that characterizes a more advanced stage and a poorer prognosis. The majority of cancer fatalities occur as a consequence of metastasis.. Mifepristone (RU486), a chemical abortifacient, has recently been used in clinical trials for psychotic depression and cancer chemotherapy. As the most predominant biological active metabolite of mifepristone, metapristone is being developed as a novel cancer metastasis chemopreventive agent by us. However, there is no information available to address the effects of metapristone on non-small cell lung cancer (NSCLC). The aim of our study was to investigate the inhibitory effect of metapristone on the proliferation and metastasis of NSCLC cells.. In the present study, we evaluated the efficacy of metapristone on the growth, migration and invasion in different kinds of NSCLC cells (A549, H1975 and H1299), and further investigated the underlying mechanism of metapristone by real time PCR and western blot assay.. Metapristone could significantly inhibit the proliferation, migration and invasion of NSCLC cells through suppressing RAS/RAF/MEK/MAPK and PI3K/AKT signaling pathways. Moreover, metapristone could effectively inhibit the formation of NSCLC cells' cytoskeleton in a concentration-dependent manner, which possibly led to the inhibition of NSCLC cells' migration.. Overall, it was preliminarily demonstrated that metapristone could be developed as a useful agent to show anti-metastasis activity for NSCLC.

Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mifepristone; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras); raf Kinases; Signal Transduction

Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Metapristone is the primary metabolite of mifepristone (RU486) and shows biological activities similar to RU486. In the present study, we comprehensively investigated the efficacy of metapristone as a metastatic chemopreventive against melanoma B16F10 cells in vitro and in vivo, and evaluated the safety profile of both drugs in mice. Metapristone showed less cytostatic effect in vitro and in vivo in comparison with mifepristone. However, metapristone interfered the adhesion of B16F10 cells to fibronectin by down-regulating cellular expression of integrin α4. Chemopreventive pretreatment followed by oral administration of metapristone and mifepristone (2.5, 10, 50 mg/kg/day for 35 days) to melanoma C57BL/6 mouse model showed significant attenuation of pulmonary metastatic development. Oral administration of high doses of metapristone and mifepristone to normal mice for 35 days (25, 100, 250 mg/kg/day) resulted in a dose-dependent increase in mouse liver weight that was more severe with mifepristone than metapristone. The long-term toxicity study revealed more changes by mifepristone in counts of erythrocytes, leukocytes and platelets than by metapristone. In conclusion, metapristone may fit into a new class of cancer metastatic chemopreventive agents. It showed a safety and efficacy profile better than mifepristone.

Topics: Animals; Anticarcinogenic Agents; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemoprevention; Disease Models, Animal; Female; Integrin alpha4; Liver; Lung Neoplasms; Melanoma, Experimental; Mice, Inbred C57BL; Mifepristone; Treatment Outcome