Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Paige, Mikell; Kosturko, George W.; Bulut, Güllay; Miessau, Matthew; Rahim, Said; Toretsky, Jeffrey A.; Brown, Milton L.; Üren, Aykut

doi:10.1016/j.bmc.2013.11.003

Cited by 24 publications

(22 citation statements)

References 34 publications

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“…However, the effectiveness of this therapy has achieved little improvement in the past 20 years. Recent evidence has shown that pulmonary metastasis is the leading cause of death among osteosarcoma patients, and toxic side effects as well as multidrug resistance to traditional agents were too pronounced to provide any benefit to some patients [9]. Therefore, it is extremely urgent to develop new anti-osteosarcoma drugs.…”

Section: Introductionmentioning

confidence: 99%

Artesunate Decreases β-Catenin Expression, Cell Proliferation and Apoptosis Resistance in the MG-63 Human Osteosarcoma Cell Line

Chen

Gong

et al. 2017

Cell Physiol Biochem

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Background: This study aims to determine the effects of artesunate on proliferation, apoptosis and β-catenin expression in the human osteosarcoma cell line MG-63. Methods: MG-63 cells in the logarithmic growth phase were collected and cultured with different concentrations of artesunate (12.5 µg/mL, 25 µg/mL and 50 µg/mL) for 24 h, 48 h and 72 h. The total number of MG-63 cells and the morphological changes were observed under an inverted microscope. The MTT assay was adopted to test the inhibition rate (IR) of cell growth. The apoptosis rate was detected using annexin V/propidium iodide (PI) staining. Cell cycle distribution was identified by flow cytometry (FCM), and the expression levels of β-catenin, cyclins and cyclin dependent kinases (CDKs) were measured using Western blotting. Results: The results of the MTT assay indicated that artesunate could remarkably inhibit MG-63 cell proliferation compared with the rates in the untreated control group (0 µg/mL artesunate), and the inhibitory effect was dose-dependent. The apoptosis rate of MG-63 cells was elevated as the concentration of artesunate increased, and all the rates were significantly higher than that in the control group. Additionally, as the artesunate concentration increased, the proportion of MG-63 cells in G0/G1 phase gradually declined whereas that of cells in the G2/M and S phases increased. Western blotting confirmed that a higher concentration of artesunate reduced the expression levels of β-catenin, cyclin A, cyclin D1 and CDK1 and increased the expression levels of cyclin B1; however, artesunate had no impact on CDK2 expression in MG-63 cells. Conclusion: These results demonstrated that artesunate can inhibit β-catenin expression and cell proliferation as well as promote cell apoptosis in MG-63 cells, which indicates that artesunate may serve as a promising drug in the clinical treatment of osteosarcoma.

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Section: Introductionmentioning

confidence: 99%

Artesunate Decreases β-Catenin Expression, Cell Proliferation and Apoptosis Resistance in the MG-63 Human Osteosarcoma Cell Line

Chen

Gong

et al. 2017

Cell Physiol Biochem

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“…What is more, the molecule NSC 668394, identified by Paige at al. [20], binds to ezrin resulting in inhibition of in vitro and in vivo cell migration, invasion, and metastatic colony survival. Wang et al [38] showed AU1751 to be the most effective target site of ezrin mRNA for DNAzymes.…”

Section: Discussionmentioning

confidence: 99%

“…In osteosarcoma, high ezrin expression is linked to pulmonary metastasis and a more aggressive course of disease [18]. There is evidence that suppression of ezrin expression in experimental models results in inhibition of cell growth and reduction of metastatic spread [19,20]. Accordingly, there is a clinical need to validate ezrin expression in patients with osteosarcoma and to assess whether monitoring of changes in levels over the course of treatment predicts treatment response and influences patient survival.…”

Section: Introductionmentioning

confidence: 97%

The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults

Ługowska

Mierzejewska²,

Lenarcik³

et al. 2016

Tumor Biol.

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Ezrin is a protein that functions as a cross-linker between actin cytoskeleton and plasma membrane. Its clinical role in osteosarcoma is unclear. The aim of this study was to investigate, in osteosarcoma, the prognostic value of ezrin expression at biopsy and changes in expression levels after preoperative chemotherapy. Thirty-eight newly diagnosed osteosarcoma patients aged 6-23 years were included. At diagnosis, 20 patients had localized disease, the others had distant metastases. Median follow-up was 75 months (range 13-135). Ezrin expression was assessed immunohistochemically in biopsy tissue and primary tumour specimens resected after chemotherapy. The influence on survival of changes in ezrin expression after chemotherapy was analysed. Ezrin expression was significantly higher after preoperative chemotherapy and changes compared to biopsy tissue were significantly lower in patients with early progression than in patients with relapse or no further evidence of disease (p = 0.006 and p = 0.002, respectively). Similarly, ezrin expression was higher after preoperative chemotherapy and exhibited less change in expression in deceased patients compared to patients surviving more than 5 years (both p = 0.001). Ezrin expression at biopsy was significantly associated with both histopathological aggressiveness (p < 0.001) and tumour size (p = 0.037). The results of this study provide evidence that changes in overexpression of ezrin due to preoperative chemotherapy could be a useful predictive and prognostic marker in patients with osteosarcoma.

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“…This effect was observed for infected and uninfected HEp-2 cells ( Figures 6C-6E). It has been shown for NSC668394 that it binds to ezrin (Paige et al, 2014). To assess whether disorazoles also bind to ezrin, a binding experiment using surface plasmon resonance (SPR) was performed by using human recombinant ezrin as the ligand and the disorazoles as analytes.…”

Section: Ezrin Is Targeted By Disorazolesmentioning

confidence: 99%

Disorazoles Block Group A Streptococcal Invasion into Epithelial Cells Via Interference with the Host Factor Ezrin

Rohde

Chhatwal

Müller

2017

Cell Chemical Biology

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Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin. Overall, our study suggests ezrin as a new factor in two different GAS invasion pathways, independent of the already known CD44 pathway, and that disorazoles are promising "pathoblocker" compounds aimed at this additional invasion mechanism.

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Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Cited by 24 publications

References 34 publications

Artesunate Decreases β-Catenin Expression, Cell Proliferation and Apoptosis Resistance in the MG-63 Human Osteosarcoma Cell Line

Artesunate Decreases β-Catenin Expression, Cell Proliferation and Apoptosis Resistance in the MG-63 Human Osteosarcoma Cell Line

The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults

Disorazoles Block Group A Streptococcal Invasion into Epithelial Cells Via Interference with the Host Factor Ezrin

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