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Molecular Mechanisms of Cannabinoids As Anti MOLECULAR MECHANISMS OF CANNABINOIDS AS ANTI- CANCER AGENTS A Dissertation by SANDEEP SREEVALSAN Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Stephen H. Safe Committee Members, Robert C. Burghardt Yanan Tian Weston Porter Intercollegiate Faculty Chair, Weston Porter August 2013 Major Subject: Toxicology Copyright 2013 Sandeep Sreevalsan ABSTRACT Cancer is a growing health concern world-wide and is the second most common cause of death after heart diseases. Current treatment strategies such as surgery, chemotherapy and radiation provide some relief to cancer patients but the toxic side effects associated with chemotherapy and radiation often lead to further adverse health effects. Hence there is a need for drugs with better safety profile and improved efficacy. Cannabinoids are a group of compounds with several therapeutic properties and besides their appetite stimulant, anti-emetic and analgesic effects, cannabinoids can inhibit tumor growth, survival and metastasis. The mechanisms of action of cannabinoids as anticancer agents are highly complex and not completely understood. Studies from our laboratory indicate that the specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 that belong to the Sp/KLF family of transcription factors are overexpressed in many tumors and regulate critical factors responsible for cancer cell proliferation, growth, angiogenesis and survival. Hence, we hypothesized that cannabinoids elicit their responses on cancer cells by downregulating the expression of Sp proteins and Sp- regulated gene products. Treatment of colon and prostate cancer cells with the cannabinoids WIN and cannabidiol (CBD) inhibited cancer cell proliferation, induced apoptosis and downregulated Sp proteins and Sp-dependent genes. Furthermore, we demonstrated that WIN and CBD-mediated induction of apoptosis and repression of Sp proteins were mediated by phosphatases and that the phosphatase involved in WIN- ii dependent downregulation of Sp proteins was protein phosphatase 2A (PP2a). In addition WIN induced expression of ZBTB-10, an Sp repressor and downregulated microRNA-27a (miR27a) and these effects were PP2a-dependent indicating that WIN transcriptionally represses Sp protein expression by activating the phosphatase, PP2a. We also investigated the effects of 1,1-bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM- C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr), on survivin expression in colon and pancreatic cancer cells. Survivin is an anti-apoptotic protein associated with cancer cell survival and confers radiation-resistance in patients receiving radiotherapy. In addition radiation induces survivin, leading to radioresistance in tumors. In this study we demonstrated that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr inhibit cell proliferation and induce apoptosis in colon and pancreatic cancer cells and in combination with radiotherapy, these drugs suppress radioresistance by inhibiting radiation induced survivin. iii To my grandparents, Chandrika Sreenivasan and Sreenivasan C. iv ACKNOWLEDGEMENTS I would like to express my gratitude to my mentor and committee chair, Dr. Safe for all the guidance and encouragement that he provided over the course of my study. I also thank my committee members, Dr. Burghardt, Dr. Tian and Dr. Porter for their support and input. I thank my colleagues and the Toxicology department faculty and staff for making my stay at Texas A&M University memorable. Special thanks to Kim Daniel, Kathy Mooney, Lorna Safe and Safe laboratory members Indira Jutooru, Gayathri Chadalapakka, Vijayalekshmi Vasanthakumari and Xi Li for all their assistance. Last but not the least, I thank my mother, father, mother and father-in-law, my sisters, friends and my wife for all their patience and support. v TABLE OF CONTENTS Page ABSTRACT .................................................................................................. ii DEDICATION .............................................................................................. iv ACKNOWLEDGEMENTS .......................................................................... v TABLE OF CONTENTS .............................................................................. vi LIST OF FIGURES ...................................................................................... viii LIST OF TABLES ........................................................................................ xii CHAPTER I INTRODUCTION ................................................................... 1 Cancer a historical perspective ................................................. 1 Cancer statistics and global health ............................................ 7 Colon cancer ............................................................................. 9 Prostate cancer .......................................................................... 22 Cancer classification ................................................................. 32 Carcinogenesis .......................................................................... 40 Cancer therapy .......................................................................... 95 Novel group of therapeutic targets ............................................ 107 Cannabinoids ............................................................................. 126 CHAPTER II INDUCTION OF APOPTOSIS BY CANNABINOIDS IN PROSTATE AND COLON CANCER CELLS IS PHOSPHATASE- DEPENDENT ............................................................................................... 151 Introduction ............................................................................... 151 Materials and methods .............................................................. 152 Results ....................................................................................... 156 Discussion ................................................................................. 166 CHAPTER III THE CANNABINOID WIN 55,212-2 DECREASES SPECIFICITY PROTEIN TRANSCRIPTION FACTORS AND ONCOGENIC CAP PROTEIN EIF4E IN COLON CANCER CELLS ...... 171 Introduction ............................................................................... 171 vi Page Materials and methods .............................................................. 173 Results ....................................................................................... 179 Discussion ................................................................................. 192 CHAPTER IV CANNABIDIOL (CBD) INHIBITS GROWTH OF COLON CANCER CELLS THROUGH PHOSPHATASE DEPENDENT DOWNREGULATION OF SPECIFICITY PROTEINS ............................. 199 Introduction ............................................................................... 199 Materials and methods............................................................... 202 Results ....................................................................................... 206 Discussion ................................................................................. 216 CHAPTER V 1,1-BIS (3'-INDOLYL)-1-(P- BROMOPHENYL)METHANE AND RELATED COMPOUNDS REPRESSION SURVIVIN AND DECREASE RADIATION-INDUCED SURVIVIN IN COLON AND PANCREATIC CANCER CELLS ............. 219 Introduction ............................................................................... 219 Materials and methods .............................................................. 221 Results ....................................................................................... 225 Discussion ................................................................................. 236 CHAPTER VI SUMMARY ......................................................................... 239 REFERENCES ............................................................................................. 243 vii LIST OF FIGURES Page Figure 1 The Egyptian medical texts Edwin and Ebers papyri ..................... 3 Figure 2 Total number of cancer cases and cancer mortality in men worldwide ....................................................................................... 9 Figure 3 Total number of cancer cases and cancer mortality in women worldwide ....................................................................................... 10 Figure 4 Colorectal cancer cases and cancer mortality worldwide in 2008 ............................................................................................... 12 Figure 5 Prostate cancer cases and mortality worldwide in 2008 ................. 23 Figure 6 Histopathological representation of benign and malignant neoplasia ......................................................................................... 36 Figure 7 Histopathological representation of hyperplasia, dysplasia, metaplasia and anaplasia ................................................................. 38 Figure 8 Schematic representation of processes involved in tumor development .................................................................................... 59 Figure 9 Genetic model of colorectal cancer ................................................ 66 Figure 10 Genetic model of prostate cancer ................................................... 73 Figure 11 Hallmarks of cancer ........................................................................ 80 Figure 12 Emerging hallmarks and enabling characteristics of cancer ........... 91 Figure 13 Structural features of Sp proteins ..................................................
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