In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines

Navo, Marisa A.; Smith, Judith A.; Gaikwad, Anjali; Burke, Thomas W.; Brown, Jubilee; Ramondetta, Lois M.

doi:10.1007/s00280-007-0628-z

Cited by 27 publications

(23 citation statements)

References 25 publications

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“…Since the first clinical trial in 1982, RU486 has been used in many clinical studies in the gynecologic fields including endometrial cancer (Schneider et al 1998). Navo et al (2008) have tested RU486 in Hec-1-A and Ishikawa cell lines and upon treatment with RU486, PR expression increased in Hec-1-A cells with no change in ERa/b levels. Moreover, the expression of p53 and Cox-2 increased and Bcl-2 decreased in this set of experiments.…”

Section: Progesterone and Progesterone Receptorsmentioning

confidence: 99%

Resistance to chemotherapy and hormone therapy in endometrial cancer

Chaudhry¹,

Asselin²

2009

Endocrine-Related Cancer

112

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Endometrial cancer is the most common gynecological malignancy in developed countries and represents the eighth leading cause of cancer related death in women. The growing incidence of endometrial cancer leads scientists and oncologists to identify effective preventive measures and also molecular markers for diagnosis and prognosis. Chemotherapy and hormone therapy is the mainstay treatment option for advanced and recurrent endometrial cancer and response to therapy is one of the most important factor which favors prognosis and overall survival. In recent years, there have been major advances in the treatment of patients with endometrial cancer. Despite advances made in the treatment of this cancer, the overall survival of patients has not significantly improved because considerable number of patients harbor tumor refractory to these therapies and the majority of the initially responsive tumors become refractory to treatments. Therefore, determination of sensitivity/resistance is becoming increasingly important for individualization of endometrial cancer therapy. The aim of this review is to present the existing knowledge about the molecular markers that could play a crucial role in determining resistance to chemo-and hormone therapy. Extensive literature search for the cell signaling pathways and factors responsible for chemoresistance have been performed and reviewed. Several recent studies suggest that deregulations in the apoptotic pathways (such as p53, Fas/FasL, Bcl-2 family proteins, inhibitor of apoptosis proteins), survival pathways (PI3K/AKT, MAPK), hormone receptor signaling pathways (progesterone receptor), Cyclooxygenase-2 and Her-2 are considered as key factors involved in the onset and maintenance of therapeutic resistance, suggesting that resistance is a multi-factorial phenomenon.

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Section: Progesterone and Progesterone Receptorsmentioning

confidence: 99%

Resistance to chemotherapy and hormone therapy in endometrial cancer

Chaudhry¹,

Asselin²

2009

Endocrine-Related Cancer

112

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“…Mifepristone was also found to increase the sensitivity of chemotherapies for gastric cancer, breast cancer, endometrial cancer, and leukemia (Gaddy et al, 2004;Li et al, 2004;Check et al, 2007;Navo et al, 2008). Its mechanisms may include: 1) blocking ceramide glycosylation and promoting cell apoptosis; 2) reducing exocytosis of MDR-associated proteins and P-glycoprotein while elevating the intracellular drug concentration; 3) enhancing the DNA repair capacity and changing the activity of topoisomerase II and the expression of tumor suppressor genes such as p53.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Duan²,

Zuo³

2014

Genet. Mol. Res.

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ABSTRACT. We examined the ability of mifepristone to reverse the in vitro drug resistance of human cervical cancer cells resistant to mitomycin-C (HeLa/MMC) cells and investigated the mechanism of this effect. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the drug resistance of HeLa/ MMC cells and the reversed drug resistance in vitro. Expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and glucosylceramide synthase (GCS) were measured in HeLa and HeLa/ MMC cells. The resistance index of HeLa/MMC cells on MMC was reduced from 5.02 to 1.46 after 10 mg/mL mifepristone exposure. A combination of mifepristone upregulated the Bax/Bcl-2 protein expression ratio and apoptosis in HeLa/MMC cells. GCS expression was significantly higher in HeLa/MMC cells than in HeLa cells (P < 0.01), but distinctly declined in both cell lines after mifepristone application (P < 0.01). Mifepristone reversed the resistance of HeLa/MMC cells to MMC in vitro; the overexpression of the GCS gene and the increased expression of apoptosis-related protein Bcl-2 may play important roles

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“…It has been demonstrated that mifepristone has a dose-dependent in vitro inhibitory effect on endometrial cancer cell lines and can reduce the myometrial volume in benign leiomyoma. [14][15][16][17] Although, the mechanism of inhibition is unknown, the regulation of PR concentration through vascular alterations of the endometrium and manipulation of p53 have been reported. 15,18,19 This, this information served as a basis for the design of the current trial.…”

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confidence: 99%

“…25,26 This SPRM action partially explains the growth-inhibitory effect of mifepristone on endometrial cancer cell lines. 15,16 Its primary abortifacient effect, however, is caused by the antiprogesterone and associated prostaglandin (PG)-inducing effects. It is believed that mifepristone sensitizes the uterus to PGs and, when administered in the first trimester of pregnancy at a single dose of 600 mg, causes pregnancy termination.…”

mentioning

confidence: 99%

“…29 Since the design of this study, we have completed an in vitro investigation, and the results suggest that mifepristone also may work through an apoptotic effect to alter p53 and bcl-2. 15 Others also have suggested that the combination of mifepristone with a PG synthesis inhibitor further increases the number of apoptotic, degenerative, and vascular changes induced by the drug in addition to the hormone mode of action noted in benign endometrium. 27 Patients with recurrent uterine cancer, especially those burdened with high tumor volume and chemotherapy-resistant disease, often prefer less toxic regiments to Original Article aggressive chemotherapy, which has a minimal chance of producing long-term response rates.…”

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confidence: 99%

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Phase 2 trial of mifepristone (RU‐486) in advanced or recurrent endometrioid adenocarcinoma or low‐grade endometrial stromal sarcoma

Ramondetta

Johnson

Sun

et al. 2009

Cancer

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BACKGROUND:The objective of this study was to determine the efficacy of mifepristone (RU‐486) in women with advanced or recurrent endometrioid adenocarcinoma or low‐grade endometrial stromal sarcoma (LGESS).METHODS:Mifepristone (RU‐486; 200 mg orally) was given daily to patients with progesterone receptor‐positive advanced or recurrent endometrioid adenocarcinoma or LGESS. Patients were evaluated every 4 weeks for toxicity and response. Quality‐of‐life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy.RESULTS:Twelve of 13 enrolled patients were evaluable in the first phase of accrual. Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and ≥77 weeks, respectively), and the median time to disease progression was 48 days. Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS. No partial or complete responses were observed. The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50%, 50%, and 58% of patients, respectively. The most common grade 3 toxicities were fatigue and dyspnea observed in 25% and 17% of patients, respectively. One patient experienced grade 4 dyspnea. Thirty‐three percent of patients had asymptomatic elevations of corticotropin. No serious treatment‐related adverse events occurred. There were no significant changes in quality of life.CONCLUSIONS:Single‐agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25%. One patient who had a biopsy‐positive disease recurrence remained stable at 77 weeks. Although mifepristone was tolerated well, as a single agent, it provided limited response as a single agent in women with progesterone receptor‐positive uterine tumors. Recently, was been recognized that biologic agents used as single agents may result only in stable disease unless they are combined with cytotoxic agents. The authors concluded that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed. Cancer 2009. © 2009 American Cancer Society.

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In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines

Cited by 27 publications

References 25 publications

Resistance to chemotherapy and hormone therapy in endometrial cancer

Resistance to chemotherapy and hormone therapy in endometrial cancer

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

Phase 2 trial of mifepristone (RU‐486) in advanced or recurrent endometrioid adenocarcinoma or low‐grade endometrial stromal sarcoma

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