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      C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells

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          Abstract

          Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.

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          Most cited references36

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          Cell death: critical control points.

          Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics.
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            Morphologic and biochemical hallmarks of apoptosis.

            Apoptosis is characterised by a series of typical morphological features, such as shrinkage of the cell, fragmentation into membrane-bound apoptotic bodies and rapid phagocytosis by neighbouring cells. This paper reviews the current knowledge on the molecular mechanisms of apoptosis as they relate to the morphologic hallmarks and their implications for the detection of apoptosis in cardiac tissue. Activation of cysteine proteases called caspases plays a major role in the execution of apoptosis. These proteases selectively cleave vital cellular substrates, which results in apoptotic morphology and internucleosomal fragmentation of DNA by selectively activated DNases. In response to several pro-apoptotic signals, mitochondria release caspase activating factors, that initiate an escalating caspase cascade and commit the cell to die. Members of the Bcl-2 oncoprotein family control mitochondrial events and are able to prevent, or induce, both apoptotic and non-apoptotic types of cell death. This suggests that different types of cell death share common mechanisms in the early phases, whereas activation of caspases determines the phenotype of cell death. Detection of apoptotic cells in tissue samples currently relies on the TUNEL assay. TUNEL-positive cardiomyocytes show morphological features of apoptosis and the typical ladder pattern in DNA electrophoresis. Thus, provided that the staining protocol is carefully standardised, this quantitative methodology provides reproducible results of the occurrence of cardiomyocyte apoptosis in cardiac samples. Recently, potentially more specific assays based on analysis of DNA fragmentation or demonstration of caspase activation have been developed. Applicability of these assays to demonstrate cardiomyocyte apoptosis should be tested.
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              Mechanisms of action of Bcl-2 family proteins.

              The Bcl-2 family of proteins controls a critical step in commitment to apoptosis by regulating permeabilization of the mitochondrial outer membrane (MOM). The family is divided into three classes: multiregion proapoptotic proteins that directly permeabilize the MOM; BH3 proteins that directly or indirectly activate the pore-forming class members; and the antiapoptotic proteins that inhibit this process at several steps. Different experimental approaches have led to several models, each proposed to explain the interactions between Bcl-2 family proteins. The discovery that many of these interactions occur at or in membranes as well as in the cytoplasm, and are governed by the concentrations and relative binding affinities of the proteins, provides a new basis for rationalizing these models. Furthermore, these dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.
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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
                14 February 2020
                February 2020
                : 21
                : 4
                : 1298
                Affiliations
                [1 ]Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; jin4477@ 123456hanmail.net (H.-J.K.); sbk6427@ 123456naver.com (B.-G.S.); kdkim88@ 123456gnu.ac.kr (K.D.K.); yooj@ 123456gnu.ac.kr (J.Y.)
                [2 ]Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
                [3 ]Department of Animal Bioscience, College of Agriculture and Life Sciences, Gyeongsang National University, Jinju 52828, Korea; sbxjhl@ 123456gnu.ac.kr
                [4 ]College of Pharmacy, Catholic University of Daegu, Daegu 38430, Korea; bsmin@ 123456cu.ac.kr
                [5 ]Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Korea
                Author notes
                [* ]Correspondence: jhlee36@ 123456kangwon.ac.kr (J.-H.L.); chwangbo@ 123456gnu.ac.kr (C.H.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6505-3080
                Article
                ijms-21-01298
                10.3390/ijms21041298
                7072863
                32075108
                a4f609fc-d1bb-4941-9aa5-68704d4e459b
                © 2020 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
                : 22 January 2020
                : 12 February 2020
                Categories
                Article

                Molecular biology
                c5 (3β-acetyl-nor-erythrophlamide),apoptosis,extrinsic pathways,bcl-2,caspase-8
                Molecular biology
                c5 (3β-acetyl-nor-erythrophlamide), apoptosis, extrinsic pathways, bcl-2, caspase-8

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