Mechanism of the reversal effect of mifepristone on drug resistance of the human cervical cancer cell line HeLa/MMC

Chen, H; Duan, Jie; Zuo, Fang

doi:10.4238/2014.february.27.14

Cited by 12 publications

(12 citation statements)

References 19 publications

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“…2009 ). More recently, a reversal of the resistance to mitomycin-C by mifepristone has been described in HeLa cells ( Chen et al . 2014 ).…”

Section: Cervical Cancermentioning

confidence: 99%

“…In the endometrial cell line EM42, mifepristone stimulated the activity of the transcription factor nuclear factor kappa B (NFkB) and induced apoptosis mediated by the induction of pro-apoptotic Bax and downregulation of antiapoptotic Bcl2, in a NFkB-dependent manner ( Han & Sidell 2003 ). In HeLa cervical adenocarcinoma cells resistant to mitomycin C, mifepristone increased BAX expression while decreasing expression of BCL2 ( Chen et al . 2014 ).…”

Section: Mechanisms Of Growth Inhibition Driven By Antiprogestinsmentioning

confidence: 99%

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Antiprogestins in gynecological diseases

Goyeneche

Telleria

2015

Reproduction

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Antiprogestins constitute a group of compounds, developed since the early 1980s, that bind progesterone receptors (PR) with different affinities. The first clinical uses for antiprogestins were in reproductive medicine: e.g. menstrual regulation, emergency contraception, and termination of early pregnancies. These initial applications, however, belied the capacity for these compounds to interfere with cell growth. Within the context of gynaecological diseases, antiprogestins can block the growth of and kill gynaecological-related cancer cells, such as those originating in the breast, ovary, endometrium, and cervix. They also can interrupt the excessive growth of cells giving rise to benign gynaecological diseases such as endometriosis and leiomyomata (uterine fibroids). In this article, we present a review of the literature providing support for the anti-growth activity antiprogestins command over cells from various gynaecological diseases. We also provide a summary of the cellular and molecular mechanisms reported for these compounds that lead to cell growth-inhibition and death. The preclinical knowledge gained during the past few years provides robust evidence to encourage using antiprogestins in order to alleviate the burden of gynaecological diseases, either as monotherapies or as adjuvants of other therapies with the perspective of allowing for long-term treatments with tolerable side effects. The key to the clinical success of antiprogestins in this field, likely lies in selecting those patients who will benefit from this therapy. This can be achieved by defining the genetic makeup required—within each particular gynaecological disease—for attaining an objective response to antiprogestin-driven growth-inhibition therapy.

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“…2009 ). More recently, a reversal of the resistance to mitomycin-C by mifepristone has been described in HeLa cells ( Chen et al . 2014 ).…”

Section: Cervical Cancermentioning

confidence: 99%

Section: Mechanisms Of Growth Inhibition Driven By Antiprogestinsmentioning

confidence: 99%

Antiprogestins in gynecological diseases

Goyeneche

Telleria

2015

Reproduction

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“…Studies by Chen et al and by Jurado et al both reported that MIF could reverse the drug resistance of HeLa cells by increasing Bcl-2 protein expression and reducing Bax protein expression. In addition, the overexpression of glucosylceramide synthase may play a crucial role in the development of MDR in cervical cancer cells and can be induced by MIF [19,20]. Additional studies have shown that by altering the expression of Bcl-2 and Bax, MIF changes the mitochondrial permeability and causes release of Omi/HtrA2 protein, which subsequently antagonizes inhibitor of apoptosis proteins (IAPs).…”

Section: Discussionmentioning

confidence: 99%

Mifepristone regulates the multidrug resistance via miR-758/MEPE of Hela cell lines

Hong¹,

Zhang²,

Liu³

et al. 2020

EJGO

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Background:In cervical cancer, matrix extracellular phosphoglycoprotein (MEPE) plays an important role of multidrug resistance, which is associated with miR-758. Mifepristone has anti-drug resistance effects, but whether mifepristone regulates the expression of multidrug resistance proteins via the pathway mediated by miR-758/MEPE is still unclear. Hela cells were induced by mifepristone (named as Hela/MIF cells). Then, matrix extracellular phosphoglycoprotein siRNA, and miR-758 mimics were transfected into HeLa/MIF cells. The sensitivity, clone forming ability, migration, and level of apoptosis of the cells in each group were respectively measured by CCK-8 assays, clone forming assays, transwell assays, and flow cytometry analysis. The targeting of miR-758 to MEPE was verified by dual-luciferase assay. At last, the expression of MDR-1, MRP-1, and GST-π were detected by qPCR and western blot assays. Results: The induction by mifepristone not only decreased the sensitivity of Hela cells, but also up-regulated the expression of multidrug resistance proteins. On this basis, by increasing the expression of miR-758 or downregulating the expression of MEPE, the expression of multidrug resistance proteins decreased, while the sensitivity of Hela cells to mifepristone were improved and the level of Hela cells proliferation, colony forming, and invasion further decreased. Conclusions: The induction by mifepristone inhibited the proliferation of Hela cells, but the sensitivity of Hela cells increased. The mechanism may depend on the expression of multidrug resistance protein. This study shows that regulating the expression of miR-758 and MEPE can reduce the resistance of Hela cells to mifepristone, enhance the sensitivity, and further improve the inhibitory effect of mifepristone.

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“…Similarly, metapristone (RU42633) is the primary metabolite of mifepristone (RU486) [14], which is used to terminate pregnancy in the rst month in clinic [15]. Some reports had showed that metapristone could inhibit lots of cancer cell proliferation [16,17]. However, there were few reports that indicated that whether metapristone could treat endometrial cancer.…”

Section: Introductionmentioning

confidence: 99%

Metapristone (RU486 derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

Chang

Hao

Jia

et al. 2020

Preprint

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Background: Endometrial cancer is the prevalent invasive gynecological cancer in the world. The pathogenesis of endometrial cancer involves many signaling pathways which are related with transcription factors or microRNAs. Metapristone is a hormone related drug and widely used in endometrial cancer clinical therapeutics. However, the deep regulatory mechanism of metapristone is not clear. In this research, we aimed to figure out the specific molecular mechanism during the treatment of endometrial cancer with metapristone.Methods: In this study, RL95-2 cells and Ishikawa cells were used as the endometrial cancer cell models. miR-492 was transfected into RL95-2 cells and Ishikawa cells. The miRNA expression was measured by qRT-PCR. Moreover, the mice tumor model was used to confirm the function of metapristone and the regulating process by miR-492/Klf5/Nrf1 axis in vivo. The protein expression was measured by western blot. Cell proliferation and apoptosis was monitored using the MTT assay, cell colony formation assay and EdU assay.Results: Firstly, the results indicated that metapristone as a kind of hormone-related drugs could significantly inhibit the endometrial cancer cell growth through regulating cell apoptosis-related gene expression. Meanwhile, miR-492 was detected to be highly expressed in the endometrial cancer cell lines. Overexpression of miR-492 could promote the cell proliferation and inhibit the cell apoptosis. Furthermore, the results demonstrated that the downstream target genes of miR-492 were Klf5 and Nrf1, which were inhibited by metapristone. At the animal level, metapristone also inhibited the endometrial cancer cell growth through down-regulating the expression of miR-492 and decreasing the protein level of Klf5 and Nrf1. Conclusion: Taken together, this study indicated that metapristone inhibited the endometrial cancer cell growth through regulating the cell apoptosis related signaling pathway and the expression of miR-492 and its downstream target genes (Klf5 and Nrf1), which provided the theoretical basis of endometrial cancer in clinical treatment.

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Mechanism of the reversal effect of mifepristone on drug resistance of the human cervical cancer cell line HeLa/MMC

Cited by 12 publications

References 19 publications

Antiprogestins in gynecological diseases

Antiprogestins in gynecological diseases

Mifepristone regulates the multidrug resistance via miR-758/MEPE of Hela cell lines

Metapristone (RU486 derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

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