Berries and Cancer Prevention (eBook)

Preface 4
Contents 5
Contributors 7
Part I Berry Composition, Bioavailability, Metabolism and Biological Effects 10
1 Contribution of Berry Anthocyanins to Their Chemopreventive Properties 11
1 Introduction 11
2 Incidence of Anthocyanins in Berries 12
2.1 Types of Anthocyanins Found in Berries 12
2.2 Anthocyanin Concentration in Berries 18
3 Anthocyanin Chemoprotective Effects: In Vitro Studies 18
3.1 Antioxidative Activity 29
3.2 Detoxification Activity 29
3.3 Antiproliferation 30
3.4 Apoptosis Induction 31
3.5 Anti-inflammatory Effects 32
3.6 Anti-angiogenic Activity 32
3.7 Anti-invasiveness 33
4 In Vivo Chemoprotective Studies 33
4.1 Animal Studies 33
4.1.1 Colon Cancer 33
4.1.2 Esophageal Cancer 34
4.1.3 Other Cancers 34
4.2 Human Studies 35
5 Impact of Anthocyanin Chemical Structure on Their Chemoprotective Properties 36
6 Interaction Effects of Anthocyanins with Other Phytochemicals in Berries 38
7 Bioavailability 38
References 41
2 Ursolic Acid and Other Pentacyclic Triterpenoids: Anticancer Activities and Occurrence in Berries 49
1 Introduction 49
2 Occurrence of Ursolic Acid and Other Triterpenoids in Vaccinium Berries 50
3 Triterpenoids in Other Berries 52
4 Anti-cancer and Anti-inflammatory Activities of Ursolic Acid and Its Esters 53
5 Mechanisms of Action 54
6 Future Research Directions 55
References 55
3 The Effects of Berry Extracts on Cell Signaling Pathways: Leading to Cellular Transformation 58
1 Introduction 60
2 Receptor Tyrosine Kinases (RTKs) 60
2.1 RTK Signaling Pathways and Cancers 60
2.2 The Effects of Berry Extracts on RTK Pathways and Their Chemoprevention 62
3 PI3K/Akt Signaling Pathway 63
3.1 PI3K/Akt Signaling Pathway and Cancer 63
3.2 The Effects of Berry Extracts on PI3K/Akt Pathway and Their Chemoprevention 65
4 Mitogen-Activated Protein Kinases (MAPKs) 66
4.1 MAPK Signaling Pathways and Cancers 66
4.2 The Effects of Berry Extracts on MAPK Pathways and Their Role in Chemoprevention 69
5 Transcription Factors and Their Downstream Target Genes 69
5.1 The Role of NF B, AP-1, COX-2, and VEGF in Cancers 69
5.2 The Effects of Berry Extracts on Activation of NF B and AP-1, and Expression of COX-2 and VEGF 71
6 Conclusion 73
References 74
Part II Antioxidant Capacity of Berry Components 83
4 Correlation of Antioxidants and Antioxidant Enzymes to Oxygen Radical Scavenging Activities in Berries 84
1 Introduction 84
2 Correlation Related to Species and Genotype Variation 85
3 Correlation Related to Specific Tissues 88
4 Correlation Affected by Maturation 89
5 Correlation Affected by Preharvest Conditions 91
5.1 Environmental Conditions 91
5.2 Cultural Practices 91
6 Correlation Affected by Postharvest Handling 92
6.1 Storage Conditions 92
6.2 Controlled Atmospheres 93
6.3 Heat Treatment 94
6.4 Illumination 95
6.5 Ozone 96
6.6 Treatment with Naturally Occurring Compounds 96
6.6.1 Methyl Jasmonate 97
6.6.2 Essential Oils and Other Natural Volatile Compounds 97
7 Conclusion 98
References 98
Part III Chemopreventive Effects of Berries and Berry Components in Animal Model Systems 103
5 Berries in the Prevention of Esophageal Adenocarcinoma 104
1 Esophageal Adenocarcinoma and Related Precursor Lesions 105
1.1 Epidemiology of Barrett's Esophagus and Esophageal Adenocarcinoma 105
1.1.1 Obesity as a Risk Factor 105
1.1.2 Tobacco and Alcohol as EAC Risk Factors 106
1.1.3 Dietary Factors and Supplementation Relative to EAC Risk 106
1.1.4 Additional Risk Factors for EAC 107
1.1.5 Summary of Molecular Alterations 108
2 Methodological Challenges 109
2.1 Preclinical Assessments Utilizing Animal Models and In Vitro Systems 109
3 Berries as Chemopreventive Agents Targeting BE or EAC 113
References 114
6 Endothelial Cell Tumor Prevention with Berry Extracts: Clinical Problems, Molecular Mechanisms and Therapeutic Opportunities 119
1 Endothelial Cell Tumors: The Clinical Problem 119
1.1 Incidence 119
1.2 Indications for Treatment 120
1.3 Current Treatment Options 121
1.4 Experimental Models of Endothelial Cell Tumors 121
2 Molecular Mechanisms Oxidant Production Promotes Endothelial Cell Tumor Growth 122
2.1 Contribution of Nox-4 Derived Oxidants 122
2.2 The Role of AP-1 and NF-kB 123
2.3 MCP-1 Is Required for Endothelial Cell Tumor Formation 124
3 Therapeutic Opportunities Using Blueberry Extract 125
3.1 Oxidant Derived Biomarkers to Monitor Response to Treatment 125
3.2 Effects of BBE on Pro-tumorigenic Responses In Vitro 126
3.3 Effects of BBE Treatment on Endothelial Cell Tumor Growth In Vivo 126
4 Summary 127
References 128
7 Effects of Black Raspberries on UV-Induced Cutaneous Inflammation and Tumor Development 133
1 The Skin 134
1.1 Structure/Function 134
1.2 Malignancies 134
1.2.1 Susceptible Populations 135
2 Ultraviolet Light 135
2.1 Wavelengths 135
2.2 Role in Cutaneous Inflammation and Carcinogenesis 136
2.3 Murine Models of UV Induced Inflammation and Skin Cancer 137
3 Black Raspberries 137
3.1 Background 137
3.2 Role as Chemopreventive/Chemotherapeutic Agents in Skin 138
4 Conclusion 139
References 140
8 Chemopreventive Effects of Berries and Berry Components in the Rodent Esophagus 145
1 Introduction 146
1.1 Esophageal Cancer 146
1.2 Rat Model of Esophageal Squamous Cell Carcinoma 146
1.2.1 Metabolism of NMBA 146
2 Chemoprevention of Esophageal Cancer in Rats 147
2.1 Chemoprevention Protocols 147
2.2 Black Raspberries 150
2.3 Berries Inhibit Initiating Events in NMBA-Treated Rat Esophagus 151
2.3.1 Effects on DNA Adduct Formation 151
2.3.2 Effects on Cytochrome P450 Enzymes 151
2.3.3 Potential Effects on H-ras Oncogene Activation 152
2.3.4 Effects on Gene Expression as Determined by DNA Microarray 152
2.4 Effects of BRBs on Preneoplastic Lesions and Papilloma Formation 153
2.5 Berries Inhibit Post-initiation Events in Rat Esophageal Carcinogenesis 155
2.5.1 Effects on Genes Associated with Inflammation 155
2.5.2 Effects on Genes Associated with Cell Proliferation and Cell Cycle Progression 155
2.5.3 Effects on Genes Associated with Apoptosis and Cell Differentiation 156
2.5.4 Effects on Genes Associated with Angiogenesis 156
3 Identification of Bioactive Agents in Berries for Prevention of Esophageal Cancer in Rats 157
4 Other Berry Types Also Prevent Esophageal Tumorigenesis in Rats 159
References 162
9 Chemopreventive Effects of Berries and Berry Components in Animal Models: Prevention of Estrogen-Mediated Mammary Tumors in ACI Rats by Berries 164
1 Introduction 165
1.1 Breast Cancer Risk Factors and Prevention 165
1.2 Estrogen-Induced Mammary Tumors in ACI Rats 167
1.3 Berries in the Prevention of Estrogen-Mediated Mammary Tumorigenesis 171
1.4 Prevention of Mammary Tumorigenesis by Dietary Berries 175
1.5 Correlation Between Chemopreventive Potential and Anthocyanin Profiles of Blueberry and Black Raspberry 178
1.6 Translation to Community and Clinical Nutrition 179
References 182
10 Inhibition of Oral Cancer in Animal Models by Black Raspberries and Berry Components 189
1 Oral Cancer as a Site for Chemoprevention 190
1.1 Oral Cancer 190
1.2 Oral Cancer and Chemoprevention 191
1.3 Berry--Based Chemoprevention 191
2 Animal Models of Chemically-Induced Oral Cancer 192
2.1 Hamster Oral Carcinogenesis Model 192
2.2 Rat and Mouse Oral Carcinogenesis Models 193
3 Prevention of Oral Cancer by Black Raspberries 195
3.1 Complete Chemoprevention Bioassay with Dietary Administration of Black Raspberries 196
4 Prevention of Oral Cancer by Berry Components 197
4.1 Quercetin 198
4.2 Ferulic Acid 198
4.3 -carotene 199
4.4 Protocatechuic Acid 200
5 Summary and Discussion 201
References 201
11 Prevention of Cancer with Pomegranate and Pomegranate Anthocyanins 208
1 Pomegranates: An overview 208
2 Pomegranate Chemistry 209
3 Pomegranates and Cancer 210
3.1 Pomegranates and Skin Cancer 211
3.2 Pomegranate and Prostate Cancer 213
3.3 Pomegranate and Breast Cancer 217
3.4 Pomegranate and Colon Cancer 219
3.5 Pomegranate and Lung Cancer 220
4 Future Perspective and Conclusions 221
References 222
12 Chemoprevention of Chronic Inflammatory Bowel Disease-Induced Carcinogenesis in Rodent Models by Berries 226
1 Introduction 226
2 Molecular Pathogenesis and Modeling of Inflammatory Bowel Disease-Induced Carcinogenesis 228
3 The Protective Effects of Berries Against Colitis and Colitis-Induced Cancer: Epidemiologic and Experimental Evidence 230
3.1 Epidemiologic Studies 230
3.2 Experimental Studies 231
4 Key Active Components of Berries in Prevention of Colitis and Colitis-Induced Cancer in Rodent Models 233
4.1 Berry-Derived Fiber, Especially Fructooligosaccharides, as a Crucial Probiotic Against Colitis 233
4.2 Berry-Derived Anthocyanins as an Active Phytonutrient Against Inflammation and Carcinogenesis 234
5 Molecular Target or Mechanism of Berry and Its Extract on Inhibiting Inflammation and Carcinogenesis 235
5.1 Anti-Inflammation-Induced Nitro-Oxidative Stress 235
5.2 Inhibition of Aberrant Oxylipin Metabolic Profile 236
5.3 Modulation of Inflammation or Carcinogen-Activated Gene Expression Profile, Particularly Focusing on Inflammation and Cancer Signaling Including Apoptosis, Proliferation and Angiogenesis 237
6 Summary and Conclusion 238
References 239
Part IV Berry Chemoprevention in High-Risk Populations 243
13 Cancer Prevention in Humans at High-Risk for Development of Cancer: Prevention of Oral Dysplasia in Humans by Berry Formulations 244
References 253
14 Cancer Prevention in Populations High At-RiskINTnl for the Development of Oral Cancer: Clinical TrialsINTnl
1 Oral Cancer 257
1.1 Oral Cancer Background 257
1.2 Molecular Biology of Oral Cancer 259
1.3 Prevention of Oral Cancer by Whole Foods 260
1.4 Food-Based Phytochemicals and Cancer Prevention 262
1.5 Black Raspberries as a Cancer Prevention Agent 262
1.6 Pre-clinical Studies with Black Raspberries in Human Oral Cancer Cells 263
1.6.1 Black Raspberry Extract and Human Oral Cancer Cell Proliferation 263
1.6.2 Modulation of In Vitro Gene Expression Profiles Associated with Oral Carcinogenesis 264
1.7 Clinical Studies with Black Raspberries in Oral Cancer Patients 266
1.7.1 Phase I Clinical Trial: Pre-surgical Model 266
1.7.2 Phase I/II Clinical Trial: Post-surgical Model 270
1.8 Black Raspberries, Cancer Prevention, and Future Directions 273
References 274
15 Effects of Black Raspberries on Cellular and Epigenetic Biomarkers of Colon Cancer Development in Humans 278
1 Introduction 279
1.1 Colon Cancer 279
2 Molecular Basis of Colon Cancer 280
2.1 Chromosomal Instability 280
2.2 DNA-Repair Defects 280
2.3 Aberrant DNA Methylation 281
2.4 Mutational Activation of Oncogenes 281
2.5 Mutational Inactivation of Tumor Suppressor Genes 281
2.6 Other Molecular Events 283
3 Epidemiological Evidence for the Prevention of Colon Cancer with Berries 284
4 Preclinical Studies with BRBs and Colon Cancer 284
4.1 Cell Culture Studies 284
4.2 Animal Bioassays 285
5 Human Clinical Trials 285
5.1 Phase Ia Clinical Trial 285
5.2 Phase Ib Clinical Trial in Patients with Colorectal Cancer 286
5.2.1 Black Raspberry Powder 287
5.2.2 Patient Population and Clinical Trial Procedures 287
5.3 Laboratory Analyses 290
5.3.1 Measurement of Berry Anthocyanins in Colorectal Tissues and Urine 290
5.3.2 Analysis of DNA Methylation 290
5.3.3 Statistics 291
5.4 Results 291
5.4.1 Patient Characteristics 291
5.4.2 Berry Treatment and Compliance Data 293
5.4.3 Anthocyanins in Urine and Colorectal Tissue 293
5.4.4 BRBs Cause Promoter Demethylation of Tumor Suppressor Genes in Wnt Pathway 293
5.4.5 Wnt Signaling, Cell Proliferation, Apoptosis and Angiogenesis 295
6 Summary and Conclusions 298
References 298
Index 301