Abstract
Purpose :
Uveal melanoma (UM), a neoplasm of melanocytic origin in the uveal tract, is a highly metastatic and drug resistant disease. Current therapies provide excellent local control of UM; regardless, 50% of patients will develop metastases. Mifepristone (MF), an antiprogestin abortifacient, seems to provide a promising solution for metastatic lesions by impeding proliferation while simultaneously targeting the migratory capacity of tumor cells. Recent studies have confirmed cytotoxic anti-metastatic effects of MF on various cancer cell lines and in clinical trials involving meningioma, colon, breast and ovarian cancers. This study aims to investigate the ability of MF to induce cytotoxicity and inhibit pro-metastatic behaviour in UM cell lines.
Methods :
Cellular viability, following 72-hour treatment of human UM cells (Mel270, 92.1, mp41, mp46, and OMM2.5) with MF (0, 5, 10, 20, 40μM), was assessed by CCK8 and Trypan Blue exclusion. Proliferation and morphology were investigated at the aforementioned MF doses over a period of 72-hours using the IncuCyte live-cell analysis system. Scratch-wound healing assays were conducted to examine dose-dependent effects of MF on cell migration. Cell cycle analysis with propidium iodide staining by flow cytometry was performed at various time points following treatment. One- and two-way ANOVA tests were used for statistical analysis (significance P<0.05).
Results :
Cytotoxic effects of MF on UM cell lines were observed at concentrations of 20 and 40μM. Significant morphological alterations began at doses of 20μM in all cell lines. The IncuCyte phase contrast mask revealed a dose-dependent reduction in cell confluency over time, validating the influence of MF treatment on UM proliferation (P<0.0001). UM cells showed a decreased migratory capacity in the wound healing assay, with inhibition of migration at doses of 40μM. Finally, cell cycle analysis demonstrated a trend indicative of cellular death at higher MF doses (20 and 40μM) while lower doses suggested an absence of G2 cell cycle arrest after 72 hours.
Conclusions :
This study demonstrates the propensity of MF to induce cytotoxic effects in UM cell lines and discusses the inhibitory capacity of this drug on cell proliferation and migration. As metastatic lesions account for nearly 90% of cancer related deaths, there remains an urgency to repurpose safe and effective drugs such as mifepristone as preventative treatment for metastasis.
This is a 2020 ARVO Annual Meeting abstract.