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      Mechanisms underlying the antiproliferative effects of a series of quinoxaline-derived chalcones

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          Abstract

          The present study aimed to characterize the effects of quinoxaline-derived chalcones, designed on the basis of the selective PI3Kγ inhibitor AS605240, in oral cancer cells. Three lead compounds, namely N9, N17 and N23, were selected from a series of 20 quinoxaline-derived chalcones, based on an initial screening using human and rat squamous cell carcinoma lineages, representing compounds with at least one methoxy radical at the A-ring. The selected chalcones, mainly N9 and N17, displayed marked antiproliferative effects, via apoptosis and autophagy induction, with an increase of sub-G1 population and Akt inhibition. The three chalcones displayed marked in vitro antitumor effects in different protocols with standard chemotherapy drugs, with acceptable toxicity on normal cells. There was no growth retrieval, after exposure to chalcone N9 alone, in a long-term assay to determine the cumulative population doubling (CPD) of human oral cancer cells. A PCR array evaluating 168 genes related to cancer and inflammation, demonstrated striking actions for N9, which altered the expression of 74 genes. Altogether, our results point out quinoxalinic chalcones, mainly N9, as potential strategies for oral cancer treatment.

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          Inflammation and cancer: advances and new agents.

          Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
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            DNA polymerases and cancer.

            There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol ζ, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies.
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              MAPK/JNK signalling: a potential autophagy regulation pathway

              Herein, MAPK/JNK signalling is proposed as a potential autophagy regulation pathway for the transcription-dependent or independent role.
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                Author and article information

                Contributors
                maria.campos@pucrs.br
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 November 2017
                20 November 2017
                2017
                : 7
                : 15850
                Affiliations
                [1 ]ISNI 0000 0001 2166 9094, GRID grid.412519.a, Postgraduate Program in Medicine and Health Sciences, PUCRS, ; Porto Alegre, RS Brazil
                [2 ]ISNI 0000 0001 2166 9094, GRID grid.412519.a, Institute of Toxicology and Pharmacology, PUCRS, ; Porto Alegre, RS Brazil
                [3 ]ISNI 0000 0001 2200 7498, GRID grid.8532.c, Postgraduate Program in Hepatology and Gastroenterology, UFRGS, ; Porto Alegre, RS Brazil
                [4 ]ISNI 0000 0001 2166 9094, GRID grid.412519.a, Postgraduate Program in Cellular and Molecular Biology, PUCRS, ; Porto Alegre, RS Brazil
                [5 ]ISNI 0000 0001 2166 9094, GRID grid.412519.a, Laboratory of Genomics and Molecular Biology, PUCRS, ; Porto Alegre, RS Brazil
                [6 ]ISNI 0000 0001 2188 7235, GRID grid.411237.2, Department of Chemistry, UFSC, ; Florianópolis, SC Brazil
                [7 ]ISNI 0000 0001 2166 9094, GRID grid.412519.a, School of Dentistry, PUCRS, ; Porto Alegre, RS Brazil
                Article
                16199
                10.1038/s41598-017-16199-3
                5696528
                29158524
                e5a54c39-83f5-41fe-a9c8-cda2f8316ada
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 January 2017
                : 9 November 2017
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