Advanced assessment of migration and invasion of cancer cells in response to mifepristone therapy using double fluorescence cytochemical labeling

Ritch, Sabrina J.; Brandhagen, BreeAnn N.; Goyeneche, Alicia A.; Telleria, Carlos M.

doi:10.1186/s12885-019-5587-3

Cited by 38 publications

(32 citation statements)

References 44 publications

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“…One attractive candidate for repositioning is mifepristone, a synthetic steroid that serves as an abortifacient drug based on anti-progestational and anti-glucocorticoid action. Mifepristone reportedly has antiproliferative effects in breast ( 15 , 16 ), cervix ( 17 ), endometrium ( 18 ), ovary ( 19 ), and prostate cancer ( 20 ), can cross the BBB, and provides palliative effects on brain tumors such as meningiomas ( 21 ) and glioblastoma ( 22 ). Additionally, it is considered safe (with few adverse effects) and has a low cost.…”

Section: Introductionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60–70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

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Section: Introductionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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“…RU486 was found to decrease migration and invasion of glia (U87MG), ovary (SKOV-3), breast (MDA-MB231), and prostate (LNCaP) cancer cells (26). Moreover, it was also demonstrated that treatment with RU486 induces a distinct pattern of migration in these different cell lines, as well as for nuclear location during migration and the apparent redistribution of F-actin to the nucleus (26).…”

Section: Discussionmentioning

confidence: 98%

“…With regard to the effect on tumor growth, while the steroid antagonist treatment caused a significant retardation of tumor progression, a complete inhibition or prevention of tumor growth did not occur. However, RU486 could possibly act as regulator of tumor metastatic diffusion, since an inhibitory effect of the RU486 in vivo on cancer metastasis has been described (26). Moreover, RU486 may be used as an adjuvant or a chemo-sensitizing agent in association with more conventional anticancer drugs, as suggested by a number of reports.…”

Section: Discussionmentioning

confidence: 99%

“…A series of studies have shown an inhibitory effect of RU486 on the growth of tumor cell xenografts in nude mice, such as meningioma ( 14 , 33 ), glioma ( 9 ), prostate cancer ( 13 ), ovarian cancer metastasis ( 26 ), and melanoma ( 8 , 11 ). In this study, we also evaluated the effect of RU486 against SK-N-SH cells xenografted in vivo .…”

Section: Discussionmentioning

confidence: 99%

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Antiproliferative effect of mifepristone (RU486) on human neuroblastoma cells (SK-N-SH): in vitro and in vivo studies

Casulari

Dondi

Pratesi

et al. 2020

Braz J Med Biol Res

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RU486 (mifepristone), a glucocorticoid and progesterone receptor antagonist, has been reported to exert antiproliferative effects on tumor cells. Experiments were performed to analyze the effects of RU486 on the proliferation of the human neuroblastoma, both in vitro and in vivo, using the human neuroblastoma SK-N-SH cell line. The exposure in vitro of SK-N-SH cells to RU486 revealed a dose-dependent inhibition of 3 H-thymidine incorporation due to a rapid but persistent inhibition of MAPKinase activity and ERK phosphorylation. A significant decrease of SK-N-SH cell number was evident after 3, 6, and 9 days of treatment (up to 40% inhibition), without evident cell death. The inhibitory effect exerted by RU486 was not reversed by the treatment of the cells with dexamethasone or progesterone. Moreover, RU486 induced a shift in SK-N-SH cell phenotypes, with an almost complete disappearance of the neuronal-like and a prevalence of the epithelial-like cell subtypes. Finally, the treatment with RU486 of nude mice carrying a SK-N-SH cell xenograft induced a strong inhibition (up to 80%) of tumor growth. These results indicated a clear effect of RU486 on the growth of SK-N-SH neuroblastoma cells that does not seem to be mediated through the classical steroid receptors. RU486 acted mainly on the more aggressive component of the SK-N-SH cell line and its effect in vivo was achieved at a concentration already used to inhibit oocyte implantation.

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“…In the clinic, steroidal PR agonists have been used in oral contraception and postmenopasusal hormone therapy (Fensome et al, 2005;Afhüppe et al, 2009;Lee et al, 2020). In addition, PR antagonists are gaining attention as a potential anti-cancer treatment due to their inhibitory effects on cell growth in vitro, affecting ovarian, breast, prostate, and bone cancer cells (Tieszen et al, 2011;Zheng et al, 2017;Ponikwicka-Tyszko et al, 2019;Ritch et al, 2019;Trabert et al, 2019). However, recent clinical trials on ovarian cancer with a selective progesterone receptor modulator, such as mifepristone, have largely been unsuccessful, despite high in vitro antagonist activity in nuclear PR (Rocereto et al, 2010;Ponikwicka-Tyszko et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

DeepSnap-Deep Learning Approach Predicts Progesterone Receptor Antagonist Activity With High Performance

Matsuzaka

Uesawa

2020

Front. Bioeng. Biotechnol.

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The progesterone receptor (PR) is important therapeutic target for many malignancies and endocrine disorders due to its role in controlling ovulation and pregnancy via the reproductive cycle. Therefore, the modulation of PR activity using its agonists and antagonists is receiving increasing interest as novel treatment strategy. However, clinical trials using the PR modulators have not yet been found conclusive evidences. Recently, increasing evidence from several fields shows that the classification of chemical compounds, including agonists and antagonists, can be done with recent improvements in deep learning (DL) using deep neural network. Therefore, we recently proposed a novel DL-based quantitative structure-activity relationship (QSAR) strategy using transfer learning to build prediction models for agonists and antagonists. By employing this novel approach, referred as DeepSnap-DL method, which uses images captured from 3-dimension (3D) chemical structure with multiple angles as input data into the DL classification, we constructed prediction models of the PR antagonists in this study. Here, the DeepSnap-DL method showed a high performance prediction of the PR antagonists by optimization of some parameters and image adjustment from 3Dstructures. Furthermore, comparison of the prediction models from this approach with conventional machine learnings (MLs) indicated the DeepSnap-DL method outperformed these MLs. Therefore, the models predicted by DeepSnap-DL would be powerful tool for not only QSAR field in predicting physiological and agonist/antagonist activities, toxicity, and molecular bindings; but also for identifying biological or pathological phenomena.

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Advanced assessment of migration and invasion of cancer cells in response to mifepristone therapy using double fluorescence cytochemical labeling

Cited by 38 publications

References 44 publications

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Antiproliferative effect of mifepristone (RU486) on human neuroblastoma cells (SK-N-SH): in vitro and in vivo studies

DeepSnap-Deep Learning Approach Predicts Progesterone Receptor Antagonist Activity With High Performance

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