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      In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis

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          Abstract

          The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers.

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          PI3K/Akt and apoptosis: size matters.

          Recent research has examined Akt and Akt-related serine-threonine kinases in signaling cascades that regulate cell survival and are important in the pathogenesis of degenerative diseases and in cancer. We seek to recapitulate the research that has helped to define the current understanding of the role of the Akt pathway under normal and pathologic conditions, also in view of genetic models of Akt function. In particular, we will evaluate the mechanisms of Akt regulation and the role of Akt substrates in Akt-dependent biologic responses in the decisions of cell death and cell survival. Here, we hope to establish the mechanisms of apoptosis suppression by Akt kinase as a framework for a more general understanding of growth factor-dependent regulation of cell survival.
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            Targeting PI3K Signaling in Combination Cancer Therapy.

            Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients.
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              The PI3K/Akt Pathway in Tumors of Endocrine Tissues

              The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a key driver in carcinogenesis. Defects in this pathway in human cancer syndromes such as Cowden’s disease and Multiple Endocrine Neoplasia result in tumors of endocrine tissues, highlighting its importance in these cancer types. This review explores the growing evidence from multiple animal and in vitro models and from analysis of human tumors for the involvement of this pathway in the following: thyroid carcinoma subtypes, parathyroid carcinoma, pituitary tumors, adrenocortical carcinoma, phaeochromocytoma, neuroblastoma, and gastroenteropancreatic neuroendocrine tumors. While data are not always consistent, immunohistochemistry performed on human tumor tissue has been used alongside other techniques to demonstrate Akt overactivation. We review active Akt as a potential prognostic marker and the PI3K pathway as a therapeutic target in endocrine neoplasia.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                21 January 2018
                January 2018
                : 19
                : 1
                : 312
                Affiliations
                [1 ]Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan; yingray.lee@ 123456gmail.com (Y.-R.L.); cych10472@ 123456gmail.com (S.-H.C.); jouyuan22@ 123456gmail.com (C.-Y.L.)
                [2 ]Department of Nursing, Min-Hwei College of Health Care Management, Tainan 736, Taiwan; april@ 123456mail.mhchcm.edu.tw
                [3 ]Department of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan; limyp@ 123456mail.cmu.edu.tw
                [4 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 600, Taiwan; 04490@ 123456cych.org.tw
                [5 ]Department of Biotechnology, Asia University, Taichung 404, Taiwan
                Author notes
                [* ]Correspondence: 02602@ 123456cych.org.tw ; Tel.: +886-5-276-5041 (ext. 7605)
                Author information
                https://orcid.org/0000-0002-0349-0960
                Article
                ijms-19-00312
                10.3390/ijms19010312
                5796256
                29361731
                7f730cc1-30a1-4949-97a8-ec0850171354
                © 2018 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 (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 November 2017
                : 17 January 2018
                Categories
                Article

                Molecular biology
                aloperine,thyroid cancer,apoptosis
                Molecular biology
                aloperine, thyroid cancer, apoptosis

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