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      Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

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          Abstract

          Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “ cytotoxicity” to be synonymous with “ anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms.

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          Protein prenylation: molecular mechanisms and functional consequences.

          Prenylation is a class of lipid modification involving covalent addition of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoids to conserved cysteine residues at or near the C-terminus of proteins. Known prenylated proteins include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins (G proteins), the subunits of trimeric G proteins, protein kinases, and at least one viral protein. Prenylation promotes membrane interactions of most of these proteins, which is not surprising given the hydrophobicity of the lipids involved. In addition, however, prenylation appears to play a major role in several protein-protein interactions involving these species. The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance of prenylation in cellular events. Several other recent reviews provide more detailed coverage of aspects of prenylation that receive limited attention here owing to length restrictions (1-4).
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            Apoptosis and cancer: the genesis of a research field.

            In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.
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              Anoikis resistance and tumor metastasis.

              As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed "anoikis". Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in anoikis and anoikis resistance and how targeting defects in these pathways can restore sensitivity to anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                19 June 2015
                June 2015
                : 13
                : 6
                : 3950-3991
                Affiliations
                [1 ]ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; E-Mails: goncalomortagua@ 123456hotmail.com (N.G.M.G.); ankijjoa@ 123456icbas.up.pt (A.K.)
                [2 ]Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal
                [3 ]Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium; E-Mail: florence.lefranc@ 123456erasme.ulb.ac.be
                [4 ]Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Campus de la Plaine, CP205/1, Boulevard du Triomphe, 1050 Brussels, Belgium
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: rkiss@ 123456ulb.ac.be ; Tel.: +32-477-622-083.
                Article
                marinedrugs-13-03950
                10.3390/md13063950
                4483665
                26090846
                42eb511a-6bf3-484a-bb6e-50a6d3385b18
                © 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
                : 15 April 2015
                : 09 June 2015
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                marine fungi,natural products,anticancer,chemotherapeutic,cytotoxic,multidrug resistance,in vivo antitumor,non-apoptotic,pro-apoptotic,preclinical

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