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      Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma

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          Abstract

          Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvβ5. In addition, our results demonstrate that integrin αvβ5 expression is modulated by the PI3K/Akt and NF-κB signaling cascade. Nimbolide has potential as an anti-tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS.

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          Most cited references47

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          Cell migration in tumors.

          Invasion of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix. Recent advances in intravital imaging and the development of an in vivo invasion assay have provided new insights into how cancer cell migration is regulated by elements of the local microenvironment, including the extracellular matrix architecture and other cell types found in primary tumors. These results, combined with new findings from in vitro studies, have led to new insights into the molecular mechanisms of cell protrusive activity and chemotactic migration during invasion and metastasis.
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            The glucose-regulated proteins: stress induction and clinical applications.

            Amy S. Lee (2001)
            A protective mechanism used by cells to adapt to stress of the endoplasmic reticulum (ER) is the induction of members of the glucose-regulated protein (Grp) family. The induction of mammalian Grp proteins in response to ER stress involves a complex network of regulators and novel mechanisms. The elucidation of Grp function and regulation opens up new therapeutic approaches to diseases associated with ER stress and cancer.
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              ROS, stress-activated kinases and stress signaling in cancer.

              Anticancer therapy is frequently efficient in early stages of the disease, whereas advanced tumors are usually resistant to the same treatments. The molecular basis for this change is not entirely understood. Many anticancer agents are DNA- or cytoskeleton-damaging drugs that show some specificity towards dividing cells. However, recent studies show that these agents also activate stress-signaling cascades that may play a role in eliciting the observed therapeutic effects. We discuss recent findings that suggest that induction of stress signaling in oncogenically transformed cells is integrated into apoptotic pathways. Reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), which are potentiated in recently transformed cells, emerge as key effectors of cell death. In advanced tumors, however, these agents are downregulated and, consequently, death signaling is suppressed. Such changes in ROS and SAPK activity levels during the course of tumor development may underlie the changes in responsiveness to anticancer therapy.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 September 2015
                October 2015
                : 16
                : 10
                : 23405-23424
                Affiliations
                [1 ]Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan; E-Mail: anti0822@ 123456hotmail.com
                [2 ]Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei 10617, Taiwan; E-Mails: chhou@ 123456ntu.edu.tw (C.-H.H.); m102094011@ 123456tmu.edu.tw (Y.-T.T.)
                [3 ]Department of Dermatology, Sijhih Cathay General Hospital, Taipei 22174, Taiwan; E-Mail: lavande213@ 123456gmail.com
                [4 ]Department of Orthopedic Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, No. 95, Wenchang Road, Shilin District, Taipei 11101, Taiwan
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: shengmou@ 123456ms.skh.org.tw ; Tel.: +886-2-2833-2211 (ext. 9420); Fax: +886-2-2835-3547.
                Article
                ijms-16-23405
                10.3390/ijms161023405
                4632706
                26426012
                8ecbf2cd-f892-4c74-a9d9-9767d34d0891
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 June 2015
                : 21 September 2015
                Categories
                Article

                Molecular biology
                osteosarcoma,apoptosis,endoplasmic reticulum stress,reactive oxygen species,migration

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