GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

Fister, Stefanie; Günthert, Andreas R.; Aicher, Babette; Paulini, Klaus; Emons, Günter; Gründker, Carsten

doi:10.1158/0008-5472.can-08-4657

Cited by 52 publications

(57 citation statements)

References 42 publications

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“…In numerous cell types, JNK and p38 MAPK contribute to the induction of apoptosis, whereas ERK inhibits apoptotic processes (30)(31)(32). In the present study, treatment with quercetin enhanced the protein levels of phosphorylated ERK1/2, whereas it reduced the protein levels of phosphorylated JNK.…”

Section: Discussionsupporting

confidence: 51%

Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase pathway in MC3T3-E1 cells

Wang

Zhao

Guo

et al. 2014

Molecular Medicine Reports

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Abstract. Quercetin, a flavonoid found in onions and other vegetables, has potential inhibitory effects on bone resorption in vivo and in vitro. In our previous study it was identified that quercetin triggered the apoptosis of lipopolysaccharide (LPS)-induced osteoclasts and inhibited bone resorption. Currently, little information is available detailing the effect of quercetin on osteoblast differentiation and bone formation in bacteria-induced inflammatory diseases. The present study aimed to investigate the effect of quercetin on osteoblast differentiation in MC3T3-E1 osteoblasts stimulated with LPS. LPS significantly downregulated the mRNA expression of osteoblast-related genes in the MC3T3-E1 cells. By contrast, quercetin significantly restored the LPS-suppressed mRNA expression of osteoblast-related genes in a dose-dependent manner. Quercetin also restored the protein expression of Osterix in MC3T3-E1 cells suppressed by LPS. Furthermore, quercetin selectively triggered the activation of the mitogen-activated protein kinase (MAPK) pathway by enhancing the expression of extracellular signal-regulated kinase and reducing the expression of c-Jun N-terminal kinase. These data suggest that quercetin reversed the inhibition of osteoblast differentiation induced by LPS through MAPK signaling. These findings suggest that quercetin may be of potential use as a therapeutic agent to restore osteoblast function in bacteria-induced bone diseases. IntroductionBone is a dynamic tissue that constantly undergoes remodeling. Bone remodeling is a coupled process of bone formation mediated by osteoblasts and resorption regulated by osteoclasts, which continues throughout life (1). An imbalance between bone formation and resorption may result in excessive bone loss, which is a feature of chronic inflammatory diseases, including rheumatoid arthritis, osteomyelitis, bacterial arthritis and infection of orthopedic implants (2).Lipopolysaccharide (LPS), a component of the outer membranes of all gram-negative bacteria, has been demonstrated to be capable of inducing bone resorption in vivo and in vitro (3-8). Furthermore, LPS is able to inhibit osteoblast differentiation and function in cell culture (9-12). However, effective therapies against bacteria-induced bone destruction are limited to antibiotic regimens and surgical strategies in chronic inflammatory diseases. Therefore, the investigation and development of potential drugs that restore osteoblast function remains a major goal in the prevention of bone destruction in infective bone diseases.Quercetin, a dietary flavonoid, has been highlighted as a bioactive substance, due to its biological, pharmacological and medicinal activities. Evidence suggests that quercetin inhibits bone loss by affecting osteoclastogenesis and regulating a variety of systemic and local factors, including hormones and inflammatory cytokines (13-15). By contrast, the effect of quercetin on osteoblastogenesis remains a matter of controversy (16-17).Mitogen-activated protein kinases (MAPK) pathways, inclu...

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Section: Discussionsupporting

confidence: 51%

Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase pathway in MC3T3-E1 cells

Wang

Zhao

Guo

et al. 2014

Molecular Medicine Reports

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“…Previous work showed that nanomolar concentrations of GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells in vitro and in vivo via stress-induced MAPKs p38-and JNK-induced activation of the proapoptotic protein Bax, loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 [16][17][18]. Furthermore, we demonstrated that GnRH-II antagonists bind to the GnRH-I receptor and are clear antagonists at the GnRH-I receptor [17]. Recently, we showed that invasion of breast cancer cells through an artificial basement membrane was increased when they were cocultured with human primary osteoblasts (hOB) [19].…”

Section: Introductionmentioning

confidence: 99%

Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo

Schubert

Hawighorst

Emons

et al. 2011

Breast Cancer Res Treat

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Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the HER2-neu gene, so called triple-negative breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about 74% of triple-negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a therapeutic target. Recently, we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by GnRH analogs. In the present study, we have analyzed whether GnRH analogs are able to reduce metastases of triple-negative breast cancers in vivo. In addition, we have evaluated the effects of GnRH analogs on tumor growth. To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers, we used a real-time PCR method based on detection of human-specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs. To analyze tumor growth, the volumes of breast cancer xenotransplants into nude mice were measured. We could demonstrate that GnRH analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo. In addition, we could show that GnRH analogs significantly inhibited the growth of breast cancer into nude mice. Side effects were not detectable. In conclusion, GnRH analogs seem to be suitable drugs for an efficacious therapy for triple-negative, GnRH receptor-positive human breast cancers to prevent metastasis formation.

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“…17,28,29 Now we could show that the combination of both glycolysis inhibition and GnRH receptor-targeted chemotherapy using AESZ-108 results in a significantly increased antiproliferative effect compared with the single agents. Combination of glycolysis inhibitor 2DG and GnRH receptor-targeted hormone therapy using GnRH-II antagonist [Ac-D2Nal 1 , D-4Cpa 2 , D-3Pal 3,6 , Leu 8 , D-Ala 10 ]GnRH-II which induces apoptosis in vitro and in vivo 18,19 gave comparable results. However, due to the smaller antitumor effect of a GnRH-II antagonist compared with cytotoxic AESZ-108, the additive effect was more moderate as expected.…”

Section: Discussionmentioning

confidence: 99%

“…The GnRH-II antagonist [Ac-D2Nal 1 , D-4Cpa 2 , D-3Pal 3,6 , Leu 8 , D-Ala 10 ]GnRH-II was developed by us and synthesized by Peptide Specialty Laboratories GmbH (Heidelberg, Germany). 19 The cytotoxic GnRH agonist AEZS-108 (AN-152), which consists of 1 molecule of doxorubicin-14-0-hemiglutarate linked covalently to the D-amino group of the D-Lys 6 moiety of [D-Lys 6 ]GnRH, 26 was a gift from Aeterna Zentaris GmbH (Frankfurt, Germany).…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

“…GnRH-II antagonists couple to the GnRH-I receptor and exert antitumor effects in human endometrial and ovarian cancer cells by inducing apoptosis through the caspase cascade. 18,19 In the present study, we have analyzed whether inhibition of glycolysis can reduce the viability of human endometrial and ovarian cancer cells in vitro. In addition, we tested whether inhibition of glycolysis can enhance the antitumor efficacy of GnRH receptor-targeted therapies using cytotoxic GnRH-I analog AEZS-108 or GnRH-II antagonist [Ac-D2Nal 1 , D-4Cpa 2 , D-3Pal 3,6 , Leu 8 , D-Ala 10 ]GnRH-II.M…”

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confidence: 99%

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Starving Tumors: Inhibition of Glycolysis Reduces Viability of Human Endometrial and Ovarian Cancer Cells and Enhances Antitumor Efficacy of GnRH Receptor-Targeted Therapies

Reutter

Emons

Gründker

2013

Int J Gynecol Cancer

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GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

Cited by 52 publications

References 42 publications

Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase pathway in MC3T3-E1 cells

Quercetin reversed lipopolysaccharide-induced inhibition of osteoblast differentiation through the mitogen-activated protein kinase pathway in MC3T3-E1 cells

Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo

Starving Tumors: Inhibition of Glycolysis Reduces Viability of Human Endometrial and Ovarian Cancer Cells and Enhances Antitumor Efficacy of GnRH Receptor-Targeted Therapies

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