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      Systems biology of cisplatin resistance: past, present and future

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          Abstract

          The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            The Hallmarks of Aging

            Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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              The Hallmarks of Cancer

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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                May 2014
                29 May 2014
                1 May 2014
                : 5
                : 5
                : e1257
                Affiliations
                [1 ]Gustave Roussy , Villejuif, France
                [2 ]Université Paris Descartes/Paris V, Sorbonne Paris Cité , Paris, France
                [3 ]Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris, France
                [4 ]Regina Elena National Cancer Institute , Rome, Italy
                [5 ]National Institute of Health , Rome, Italy
                [6 ]INSERM, U848 , Villejuif, France
                [7 ]INSERM, UMRS 769; LabEx LERMIT , Châtenay Malabry, France
                [8 ]Faculté de Pharmacie, Université de Paris Sud/Paris XI , Châtenay Malabry, France
                [9 ]Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London , London, UK
                [10 ]Department of Biomedical Sciences, Università Degli Studi di Padova , Padova, Italy
                [11 ]Laboratoire Epigenetique et Cancer, Université de Paris Sud/Paris XI , Gif-Sur-Yvette, France
                [12 ]CNRS, FRE3377 , Gif-Sur-Yvette, France
                [13 ]Commissariat à l'Energie Atomique (CEA) , Saclay, France
                [14 ]Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP , Paris, France
                [15 ]Metabolomics and Cell Biology Platforms, Gustave Roussy , Villejuif, France
                Author notes
                [* ]Université Paris Descartes/Paris V, INSERM, U848, Gustave Roussy , PR1, 39, rue Camille Desmoulins, Villejuif F-94805, France. Tel: +33 1 4211 4516; Fax: 33 1 4211 6665; E-mail: deadoc@ 123456vodafone.it
                [* ]INSERM, U848, Gustave Roussy, PR1, 39, rue Camille Desmoulins , Villejuif F-94805, France. Tel: +33 1 4211 6046; Fax: +33 1 4211 6047; E-mail: kroemer@ 123456orange.fr
                [16]

                Share senior co-authorship.

                Article
                cddis2013428
                10.1038/cddis.2013.428
                4047912
                24874729
                5e773452-497f-4dc0-b92a-c7ef2ef8f5cb
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 02 September 2013
                : 23 September 2013
                : 26 September 2013
                Categories
                Review

                Cell biology
                bcl-2,carboplatin,ctr1,dna damage response,oxaliplatin,p53
                Cell biology
                bcl-2, carboplatin, ctr1, dna damage response, oxaliplatin, p53

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