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Effects of Bromelain and N-Acetylcysteine on Mucin

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Effects of Bromelain and N-Acetylcysteine on Mucin i Effects of bromelain and N-acetylcysteine on mucin- expressing human gastrointestinal carcinoma cells and their peritoneal spread: towards development of novel locoregional approaches to peritoneal surface malignancies and pathological mucin synthesis Afshin Amini MD A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy St George & Sutherland Clinical School Faculty of Medicine University of New South Wales Sydney, NSW, Australia May 2015 THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: AMINI First name: Afshin Other name/s: N/A Abbreviation for degree as given in the University calendar: PhD School: St George & Sutherland Clinical School Faculty: Medicine Title: Effects of bromelain and N-acetylcysteine on mucin expressing human gastrointestinal carcinoma cells and their peritoneal spread: towards development of novel locoregional approaches to peritoneal surface malignancies and pathological mucin synthesis Abstract 350 words maximum: (PLEASE TYPE) Gastrointestinal cancers account for more than one third of all deaths from cancer. Peritoneal dissemination is considered as an advanced stage in the natural history of these malignancies and a frequent finding in the recurrent condition. As a curative approach to peritoneal surface malignancies confined to the peritoneal cavity, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has brought about long-term benefits in selected patients with peritoneal carcinomatosis (PC) of gastrointestinal origin and pseudomyxoma peritonei (PMP) syndrome. However, HIPEC fails to maintain the surgical complete response in a proportion of patients. Furthermore, tumor- secreted mucin makes a major contribution to tumor cell growth and survival, resistance to chemotherapy, evasion of immune surveillance, and formation of mucinous ascites, and is a key player in the pathogenesis of PMP and mucinous carcinomatosis. In order to discover novel locoregional approaches to gastrointestinal PC and PMP, the present project aimed to develop a novel formulation capable of enhancing microscopic cytoreduction and eliminating mucin. To this end, I investigated growth-inhibitory and mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), two natural agents with good safety profile, in experimental models of gastrointestinal cancers. Using a panel of human cancer cell lines, I observed that BR and NAC, on their own and more potently in combination, significantly inhibited proliferation and survival of cancer cells and reduced the expression of the characteristic mucins, in vitro. Mechanistically, apoptosis was found to mediate inhibitory effects of BR/NAC, with likely contribution of cell cycle arrest and autophagy. BR/NAC was also shown to sensitize cancer cells to cytotoxic agents. In vivo, I developed and treated nude mice models of PC and PMP-like syndromes with intraperitoneal administration of BR and NAC, individually and in combination. My results indicated that BR/NAC significantly inhibited peritoneal tumor growth in both models. Specific immunohistochemical staining of tumor sections revealed a significant decrease in the expression of the tumor-secreted MUC2 and MUC5AC. Taken together, this novel formulation with dual effects on gastrointestinal cancer cells and their mucin product holds promise for locoregional therapies targeting residual disease and mucin barrier in peritoneal malignancies. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). 2/12/2015 …………………………………………………………… ……………………………………..……………… ……….……………………...…….… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date ……………………………………………..............2/12/2015 COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………..........2/12/2015 ................. AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………..........2/12/2015 ................. ii Abstract Gastrointestinal cancers account for more than one third of all deaths from cancer. Peritoneal dissemination is considered as an advanced stage in the natural history of these malignancies and a frequent finding in the recurrent condition. As a curative approach to peritoneal surface malignancies confined to the peritoneal cavity, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has brought about long-term benefits in selected patients with peritoneal carcinomatosis (PC) of gastrointestinal origin and pseudomyxoma peritonei (PMP) syndrome. However, HIPEC fails to maintain the surgical complete response in a proportion of patients. Furthermore, tumor-secreted mucin makes a major contribution to tumor cell growth and survival, resistance to chemotherapy, evasion of immune surveillance, and formation of mucinous ascites, and is a key player in the pathogenesis of PMP and mucinous carcinomatosis. In order to discover novel locoregional approaches to gastrointestinal PC and PMP, the present project aimed to develop a novel formulation capable of enhancing microscopic cytoreduction and eliminating mucin. To this end, I investigated growth-inhibitory and mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), two natural agents with good safety profile, in experimental models of gastrointestinal cancers. Using a panel of human cancer cell lines, I observed that BR and NAC, on their own and more potently in combination, significantly inhibited proliferation and survival of cancer cells and reduced the expression of the characteristic mucins, in vitro. Mechanistically, apoptosis was found to mediate inhibitory effects of BR/NAC, with likely contribution of cell cycle arrest and autophagy. BR/NAC was also shown to sensitize cancer cells to cytotoxic agents. In vivo, I developed and treated nude mice models of PC and PMP- like syndromes with intraperitoneal administration of BR and NAC, individually and in combination. My results indicated that BR/NAC significantly inhibited peritoneal tumor growth in both models. Specific immunohistochemical staining of tumor sections revealed a significant decrease in the expression of the tumor-secreted MUC2 and MUC5AC. Taken together, this novel formulation with dual effects on gastrointestinal cancer cells and their mucin product holds promise for locoregional therapies targeting residual disease and mucin barrier in peritoneal malignancies. iii Acknowledgments This thesis
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