Anticancer effects of mifepristone on human uveal melanoma cells

Abstract Background Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical tri...

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Autores principales:	Prisca Bustamante Alvarez, Alexander Laskaris, Alicia A. Goyeneche, Yunxi Chen, Carlos M. Telleria, Julia V. Burnier
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Uveal melanoma Mifepristone Drug repurposing Cancer therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/b0b6ab0ef5404f77b77de73b8f023451
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spelling	oai:doaj.org-article:b0b6ab0ef5404f77b77de73b8f0234512021-11-21T12:39:34ZAnticancer effects of mifepristone on human uveal melanoma cells10.1186/s12935-021-02306-y1475-2867https://doaj.org/article/b0b6ab0ef5404f77b77de73b8f0234512021-11-01T00:00:00Zhttps://doi.org/10.1186/s12935-021-02306-yhttps://doaj.org/toc/1475-2867Abstract Background Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds. Methods The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 μM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR. Results MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. Conclusion This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.Prisca Bustamante AlvarezAlexander LaskarisAlicia A. GoyenecheYunxi ChenCarlos M. TelleriaJulia V. BurnierBMCarticleUveal melanomaMifepristoneDrug repurposingCancer therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCancer Cell International, Vol 21, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Uveal melanoma Mifepristone Drug repurposing Cancer therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Uveal melanoma Mifepristone Drug repurposing Cancer therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Prisca Bustamante Alvarez Alexander Laskaris Alicia A. Goyeneche Yunxi Chen Carlos M. Telleria Julia V. Burnier Anticancer effects of mifepristone on human uveal melanoma cells
description	Abstract Background Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds. Methods The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 μM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR. Results MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. Conclusion This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.
format	article
author	Prisca Bustamante Alvarez Alexander Laskaris Alicia A. Goyeneche Yunxi Chen Carlos M. Telleria Julia V. Burnier
author_facet	Prisca Bustamante Alvarez Alexander Laskaris Alicia A. Goyeneche Yunxi Chen Carlos M. Telleria Julia V. Burnier
author_sort	Prisca Bustamante Alvarez
title	Anticancer effects of mifepristone on human uveal melanoma cells
title_short	Anticancer effects of mifepristone on human uveal melanoma cells
title_full	Anticancer effects of mifepristone on human uveal melanoma cells
title_fullStr	Anticancer effects of mifepristone on human uveal melanoma cells
title_full_unstemmed	Anticancer effects of mifepristone on human uveal melanoma cells
title_sort	anticancer effects of mifepristone on human uveal melanoma cells
publisher	BMC
publishDate	2021
url	https://doaj.org/article/b0b6ab0ef5404f77b77de73b8f023451
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Anticancer effects of mifepristone on human uveal melanoma cells

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