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Thai traditional medicine as a source for cancer prevention: from local concepts to the discovery of potential chemopreventive extracts Natchagorn Lumlerdkij Supervisors Professor Michael Heinrich Dr. Jose Prieto-Garcia A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy School of Pharmacy, University College London, UK 2017 Declaration This PhD thesis describes research conducted in the School of Pharmacy, University College London between October 2013 and June 2017 under the supervision of Professor Michael Heinrich and Dr. Jose Prieto-Garcia. I, Natchagorn Lumlerdkij confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature …………………………………………………………. Date ……………………....... (Natchagorn Lumlerdkij) 2 This thesis is dedicated to My mom, dad, and grandmothers And the memory of HM King Bhumibol Adulyadej (1927 – 2016) and his tireless efforts to maintain the benefits and happiness of Thai people 3 Abstract Cancer chemoprevention aims to prevent, delay, or reverse carcinogenesis. Thai Traditional Medicine (TTM) could be a source for cancer chemopreventive agents and – more broadly – could play a role in cancer prevention. Using an ethnopharmacology approach this thesis aims to understand the pharmacological basis of some of these botanical drugs and to discover new extracts which could be useful in cancer prevention. Interviews with 33 TTM practitioners revealed the five characteristics of cancer in TTM (mareng), which is described as an accumulation of waste, chronic inflammation, chronic illnesses (krasai), bad condition of body fluids (‘luead’ and ‘namlueang’), and imbalance of dhātu si. Further analysis of preventive methods led to the five strategies for preventing mareng. To link TTM actions to pharmacology, we proposed that three strategies, removal of waste, liver protection, and prevention from krasai, can be linked to the antioxidant system. After screening of fifty-two extracts, fifteen exhibited protective effect in a liver cancer cell line. Among them, ethanol extracts of Thunbergia laurifolia leaves (TLe) and Senegalia rugata leaves (SR1e) exhibited the most potent activities in the induction of NQO1 enzyme and glutathione. Upregulation of antioxidant genes and radical scavenging were among their protective mechanisms. While TLe induced NQO1 expression, SR1e upregulated the expression of Nrf2. Both extracts did not induce CYP1A1 expression nor reduce cell viability of primary rat hepatocytes which provided preliminary safety profile. Using HPLC-HRMS-SPE- ttNMR, we could identify some active constituents in the extracts. This is the first report analysing how cancer is perceived in TTM, what prevention strategies are used, linking this to pharmacological models, and on chemopreventive properties of TLe and SR1e and some of their constituents. The evidence supports the potential use of these medicinal plants in cancer prevention. Future work should be performed with more TTM practitioners and use in vivo models. 4 Impact Statement This thesis presents an analysis of knowledge in Thai traditional medicine (TTM) and links it to biomedical concepts and practical lab-based experiment, as well as provides in vitro pharmacological properties and phytochemical profiles of selected medicinal plants. This is the first time that characteristics of cancer in TTM (or mareng) were systematically analysed and grouped. The findings have direct impacts on providing scientific evidence for medicinal plants used in TTM and characteristics of cancer in TTM through a combination of ethnopharmacological and biomedical research. The proposed concept is also beneficial for future research on cancer in TTM or TTM drugs for cancer treatment and prevention. Moreover, it is fruitful for TTM education, most importantly at university level. Our results can be used as preliminary data for future research grants on TTM or cancer drug discovery, as well as another PhD project. For non-academia impacts, our data supports TTM practice and the integration of TTM to the main health care system. It could help local business, such as farmers and herbal medicine manufacturers, which are usually small and medium-sized enterprises (SMEs). In addition, it is also helpful in the promotion and conservation of TTM. 5 Acknowledgement I would like to thank Professor Michael Heinrich for giving me the opportunity to work under his supervision, his support, and helps. Throughout the years, he taught me many things and always support, encourage, and be patient. Also, I wish to thank Dr. Jose Prieto-Garcia for being my second supervisor. I am grateful to the Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand for offering me the scholarship and giving me the opportunity to study PhD, especially Associate Prof. Tawee Laohapand and Associate Prof. Pravit Akarasereenont, Head and Consultant of Center of Applied Thai Traditional Medicine (CATTM), respectively, for their supports, helps and suggestions. I appreciate my colleagues at CATTM, especially Ranida Boonrak, Jaturapat Tantiwongse, Poohmnapath Sangsumart, Watchaporn Khlainok, Natanan Sriruk, Sukritta Pongsitthichok, Hatthapan Wipanso, Suksalin Booranasubkajorn, Onusa Thamsermsang, and Khuannara Narajeenrone for their helps during the fieldwork in Thailand, providing the plants and plant extracts used in this study, and for the help in herbarium specimens preparation. I also thank Dr. Tony Booker for some materials. For the fieldwork, I would like to thank the Faculty of Medicine Siriraj Hospital for the funding (Grant number R015732024). I am very grateful for the list and locations of the informants from CATTM, Tharongchang Hospital (Suratthani), Phrapokklao Hospital (Chantaburi), villagers, and local herbal dispensaries. I also thank Chanthaburi botanical garden (Chanthaburi), Siri Ruckkhachati Nature Park (Salaya Campus, Mahidol University), and Suan Chalerm Phrakiat (Faculty of Medicine Siriraj Hospital) for providing authentic specimens. For cell-based assay, I would like to thank Mukrish Hanafi, André Mazzari, Varaporn Rakkhitawatthana, Kannika Sukadeetad, Sahar Awwad, and Francesca Scotti for protocols and helpful suggestions. I also thank Isabel Goncalves for the use of the lab 301a, Dr. Paul Stapleton and Dr. Gary Parkinson for the access to PCR equipment, and Dr. Andy Wilderspin for the access to GeneGnome system. I also thank staff at SoP for taking good care of the cell culture lab 205. For phytochemical analysis part, I would like to thank Professor Dan Stærk (Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen) for the opportunity to work in his lab for HPLC-HRMS-SPE-ttNMR analysis. I am very grateful for the help in the analysis from Yong Zhao, Rita de Cassia Lemos Lima (PhD students under Prof. Dan Stærk from University of Copenhagen). I also would like to thank Dr. Johanna Michl for the help with MZmine 2 program and Dr. Francesca Scotti and Acom Sornsute for the help in using TopSpin software. I wouldn’t be able to live happily in London without my friends in the UK, especially these people from SoP; André Mazzari, Banaz Jalil, Francesca Scotti, Hannah Jennings, Johanna Michl, Jeanne Thrill, Mariagiovanna Scarpa, Pedro Ernesto de Resende, Sarah Soares, Tony Booker, Amaka Ezuruike, M.J. Datiles, Vivek Saravanan and all second floor people, Thai 6 society at SoP; Acom Sornsute, Nattika Nimmano, Warunya Arunotayanun, Varaporn Rakkhitawatthana, Kannika Sukadeetad, Ukrit Angkawinitwong, Wunlapa Mueannoom, and Varin Titapiwatanakun. Please know that I love you so much. I also thank Leong family and my housemates for making a lovely house. I would like to thank dad, mom, my sister, cousins, aunties, and uncles who always support and encourage me throughout these years. I love you all. I want to say thank you especially to my mom for the help in the translation from Northern dialect and my sister for sending more plant samples to London. It was such a complicated and time-consuming process. Finally, thank you An for the support and patience (and snacks!) during the last and probably the most difficult year. Thank you for walking into my life. Also thank to a lot of Line and Facebook messages that encouraged me throughout the writing period from friends, colleagues, and my teachers. You make me know that ‘I’ll never walk alone’. Thank you. 7 Table of Contents Abstract ................................................................................................................................... 4 Impact Statement ................................................................................................................... 5 Acknowledgement ................................................................................................................. 6 List of tables ......................................................................................................................... 12 List of figures ....................................................................................................................... 14 Chapter 1 General introduction .......................................................................................... 21 1.1. Cancer- a global health problem .............................................................................. 21 1.2. Carcinogenesis .........................................................................................................

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