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Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

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      Abstract

      Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.

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      Guidelines for the use and interpretation of assays for monitoring autophagy.

      In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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        Regulation mechanisms and signaling pathways of autophagy.

        Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Autophagy is upregulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation, ER stress, and pathogen infection. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases. We present our current knowledge on the key genes composing the autophagy machinery in eukaryotes from yeast to mammalian cells and the signaling pathways that sense the status of different types of stress and induce autophagy for cell survival and homeostasis. We also review the recent advances on the molecular mechanisms that regulate the autophagy machinery at various levels, from transcriptional activation to post-translational protein modification.
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          Targeting multidrug resistance in cancer.

          Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.
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            Author and article information

            Affiliations
            [1 ]Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University , Hangzhou, China
            [2 ]Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University , Hangzhou, China
            [3 ]Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital , Hangzhou, China
            [4 ]Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province , Hangzhou, China
            Author notes
            [* ]Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University , Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6926; Fax: +86 571 8600 6926; E-mail: wangxzju@ 123456163.com
            [* ]Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University , Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6929; Fax: +86 571 8600 6929; E-mail: drhechao@ 123456yahoo.com.cn
            [* ]Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University , Hangzhou, Zhejiang 310016, China. Tel: +86 0571 8600 6926; Fax: +86 0571 8600 6926; E-mail: drpanhm@ 123456aliyun.com
            [5]

            These authors contributed equally to this work.

            Journal
            Cell Death Dis
            Cell Death Dis
            Cell Death & Disease
            Nature Publishing Group
            2041-4889
            October 2013
            10 October 2013
            1 October 2013
            : 4
            : 10
            : e838
            24113172
            3824660
            cddis2013350
            10.1038/cddis.2013.350
            Copyright © 2013 Macmillan Publishers Limited

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

            Categories
            Review

            Cell biology

            autophagy, chemotherapy resistance, cancer, therapy

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