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      Marine Compounds Selectively Induce Apoptosis in Female Reproductive Cancer Cells but Not in Primary-Derived Human Reproductive Granulosa Cells

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          Abstract

          Anticancer properties of tyrindoleninone and 6-bromoisatin from Dicathais orbita were tested against physiologically normal primary human granulosa cells (HGC) and reproductive cancer cell lines. Tyrindoleninone reduced cancer cell viability with IC 50 values of 39 µM (KGN; a tumour-derived granulosa cell line), 39 μM (JAr), and 156 μM (OVCAR-3), compared to 3516 μM in HGC. Apoptosis in HGC’s occurred after 4 h at 391 µM tyrindoleninone compared to 20 µM in KGN cells. Differences in apoptosis between HGC and KGN cells were confirmed by TUNEL, with 66 and 31% apoptotic nuclei at 4 h in KGN and HGC, respectively. These marine compounds therefore have potential for development as treatments for female reproductive cancers.

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          Most cited references53

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          Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor.

          We established a steroidogenic human ovarian granulosa-like tumor cell line, designated KGN, from a patient with invasive ovarian granulosa cell carcinoma. KGN had a relatively long population doubling time of about 46.4 h and had an abnormal karyotype of 45,XX, 7q-, -22. A steroid analysis of the cultured medium by RIA performed 5 yr after the initiation of culture showed that KGN was able to secrete pregnenolone and progesterone, and both dramatically increased after stimulation with (Bu)(2)cAMP. However, little or no secretion of 17alpha-hydroxylated steroids, dehydroepiandrosterone, androstenedione, or estradiol was observed. The aromatase activity of KGN was relatively high and was further stimulated by (Bu)(2)cAMP or FSH. These findings showed a pattern similar to that of steroidogenesis in human granulosa cells, thus allowing analysis of naturally occurring steroidogenesis in human granulosa cells. Fas-mediated apoptosis of KGN was also observed, which mimicked the physiological regulation of apoptosis in normal human granulosa cells. Based on these findings, this cell line is considered to be a very useful model for understanding the regulation of steroidogenesis, cell growth, and apoptosis in human granulosa cells.
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            Marine natural products.

            This review covers the literature published in 2007 for marine natural products, with 948 citations(627 for the period January to December 2007) referring to compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, cnidarians,bryozoans, molluscs, tunicates, echinoderms and true mangrove plants. The emphasis is on new compounds (961 for 2007), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.1 Introduction, 2 Reviews, 3 Marine microorganisms and phytoplankton, 4 Green algae, 5 Brown algae, 6 Red algae, 7 Sponges, 8 Cnidarians, 9 Bryozoans, 10 Molluscs, 11 Tunicates (ascidians),12 Echinoderms, 13 Miscellaneous, 14 Conclusion, 15 References.
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              A review of trabectedin (ET-743): a unique mechanism of action.

              Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer. (c) 2010 AACR.
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                Author and article information

                Journal
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                10 January 2012
                January 2012
                : 10
                : 1
                : 64-83
                Affiliations
                [1 ] Department of Medical Biotechnology, School of Medicine, Flinders University, GPO Box 2100, Adelaide, S.A. 5001, Australia; Email: edwa0223@ 123456flinders.edu.au (V.E.); Fiona.young@ 123456flinders.edu.au (F.Y.)
                [2 ] School of Biological Sciences, Flinders University, GPO Box 2100, Adelaide, S.A. 5001, Australia
                [3 ] School of Environmental Sciences and Management, Southern Cross University, PO Box 157, Lismore, NSW 2480, Australia
                Author notes
                [* ] Author to whom correspondence should be addressed; Email: kirsten.benkendorff@ 123456scu.edu.au ; Tel.: +61-2-6620-3755; Fax: +61-2-6621-2669.
                Article
                marinedrugs-10-00064
                10.3390/md10010064
                3280530
                22363221
                be40fc29-dcd7-4dc5-af57-1bc9a17d9e05
                © 2012 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/3.0/).

                History
                : 16 November 2011
                : 19 December 2011
                : 30 December 2011
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                brominated indoles,apoptosis,gynaecological cancers,marine mollusc

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