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Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

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      Abstract

      Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

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      Most cited references 187

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      Apoptosis: a review of programmed cell death.

      The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
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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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          Cell-cycle checkpoints and cancer.

          All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000000086837370, GRID grid.214458.e, College of Literature, Sciences and the Arts, , University of Michigan-Ann Arbor, ; Ann Arbor, MI 48109 USA
            [2 ]Weill Cornell Medicine-Qatar, P.O.B. 24144, Doha, Qatar
            [3 ]ISNI 0000 0001 2176 9917, GRID grid.411327.2, Institute of Neuropathology, , Heinrich Heine University Düsseldorf, ; Moorenstraße 5, 40225 Düsseldorf, Germany
            Contributors
            ORCID: http://orcid.org/0000-0001-5196-3366, +974 33480728 , dib2015@qatar-med.cornell.edu
            Journal
            Apoptosis
            Apoptosis
            Apoptosis
            Springer US (New York )
            1360-8185
            1573-675X
            19 April 2017
            19 April 2017
            2017
            : 22
            : 7
            : 898-919
            28424988
            5486846
            1375
            10.1007/s10495-017-1375-1
            © The Author(s) 2017

            Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

            Funding
            Funded by: FundRef http://dx.doi.org/10.13039/100007458, Qatar Foundation;
            Award ID: 6-089-3-021
            Award Recipient :
            Categories
            Review
            Custom metadata
            © Springer Science+Business Media New York 2017

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