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      Targeting Nuclear Factor-Kappa B to Overcome Resistance to Chemotherapy

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          Abstract

          Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

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          Most cited references 138

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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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            Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.

            Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.
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              Death receptors: signaling and modulation.

              Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.
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                Author and article information

                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                19 March 2013
                16 May 2013
                2013
                : 3
                Affiliations
                1Department of Clinical Medicine, Thoracic Oncology Research Group, Trinity College Dublin, St. James’s Hospital Ireland Dublin, Ireland
                Author notes

                Edited by: Gerald Batist, Segal Cancer Centre, Jewish General hospital, McGill University, Canada

                Reviewed by: Olivier Micheau, INSERM, France; Marc Poirot, Institut National de la Santé et de la Recherche Médicale, France; Raquel Aloyz, Lady Davis Institute for Medical Research

                *Correspondence: K. Gately, Department of Clinical Medicine, Thoracic Oncology Research Group, Trinity College Dublin, St. James’s Hospital Ireland, Dublin 8, Ireland. e-mail: gatelyk@ 123456tcd.ie

                This article was submitted to Frontiers in Pharmacology of Anti-Cancer Drugs, a specialty of Frontiers in Oncology.

                Article
                10.3389/fonc.2013.00120
                3655421
                23720710
                Copyright © 2013 Godwin, Baird, Heavey, Barr, O’Byrne and Gately.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 133, Pages: 10, Words: 10074
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy

                nf-κb, cancer, cisplatin, chemotherapy, resistance, apoptosis, oncogene

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