Natural Compounds in Cancer Therapy: Promising Nontoxic Antitumor Agents From Plants & Other Natural Sources

541 Pages·2001·4.95 MB·English

by  John Boik

Natural Compounds
in Cancer Therapy

John Boik

This book is being made available in electronic form
on the honor system. Readers are expected to mail
compensation, in the form of a check or money or-
der, to the address given in the front pages. The
price of the electronic version is $25.
Copyright © 2001 by John Boik. All rights reserved. Printed in the United States of America. Except as permitted under the
United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any manner whatsoever, or
stored in a data base, without the prior permission in writing from the publisher.

Editor: Silvine Farnell
Cover design: Michelle Lundquist

Publisher's Cataloging-in-Publication (Provided by Quality Books, Inc.)

Boik, John.
Natural compounds in cancer therapy / [John Boik].--
1st ed.
p. cm.
Includes biographical references and index.
ISBN 0-9648280-1-4

1. Cancer--Alternative treatment. 2. Herbs--
Therapeutic use. 3. Alternative medicine. I. Title.

RC271.A62B65 2001 616.99'406
QBI00-971

Library of Congress Control Number: 2001117271

Disclaimer
Medical knowledge is constantly expanding. As new experimental and clinical experiences are gained, modifications to research
and treatment protocols are required. The author and publisher of this book have consulted sources believed to be reliable in
their effort to provide information that is complete and true to the body of knowledge available at the time of publication.
However, due to the possibility of human error or changes in medical knowledge, neither the author, publisher, nor any other
party involved with the publication or preparation of this book warrants that the information contained herein is fully accurate or
complete, and these parties are not responsible for any omissions or errors, or for the results obtained from using this
information. Readers are advised to confirm all such information with appropriate written sources and experts in the field.
Neither the publisher nor author advocate the use of any particular therapy but believe this information should be made available
to the public. There is always some risk involved in therapy, and the publisher and author are not responsible for any adverse
effects, lack of efficacy, or consequences that may result from using the material presented in this book.

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CONTENTS
CONTENTS iii 5 TRANSCRIPTION FACTORS AND
REDOX SIGNALING 51
FOREWORD vii Introduction to Redox Reactions 51
Transcription Factors 54
PREFACE ix
Mechanisms of Redox Modulation 60
1 BACKGROUND FOR PARTS I AND II 1 Conclusion 61

References 62
Development of Cancer and Characteristics of
Cancer Cells 1
6 CELL-TO-CELL COMMUNICATION 67
Seven Strategies for Cancer Inhibition 2
Cell Adhesion Molecules 67
Using Natural Compounds in Combination 4
Gap Junctions 71
Introduction to the Compounds 5
Conclusion 72
Practical Considerations on Effective Concentrations
and Scaling of Doses 8 References 72
References 10

PART II: CANCER AT THE LEVEL OF THE
ORGANISM
PART I: CANCER AT THE CELLULAR LEVEL
7 OVERVIEW OF ANGIOGENESIS 79
2 MUTATIONS, GENE EXPRESSION, AND

PROLIFERATION 13 Mechanics of Angiogenesis 79
DNA, RNA, and Gene Expression 13 Angiogenic Factors and Angiogenesis Inhibition 80
Cell Proliferation 15 Similarity of Angiogenesis in Wound Healing and
Cancer 81
Mutations During Carcinogenesis and Progression 17
Wound Healing and Angiogenic Factors 81
How Natural Compounds and Chemotherapy Drugs
Inhibit Proliferation 23 Conclusion 88
References 88
Cytosine Methylation and DNA: A Note on Cancer
Prevention 25
8 NATURAL INHIBITORS OF
Conclusion 26 ANGIOGENESIS 91
References 27
Inhibition of Angiogenic Factors 91
3 RESULTS OF THERAPY AT THE Additional Natural Compounds That may Inhibit
CELLULAR LEVEL 29 Angiogenesis 97
Cell Differentiation 29 Conclusion 98
Failure to Enter the Cell Cycle 31 References 98
Apoptosis and Necrosis 31 9 INVASION 105

Conclusion 33
Connective Tissue and the Extracellular Matrix 105
References 34
The ECM and Cancer 105
4 GROWTH FACTORS AND SIGNAL Glycosidases, Proteases, and Cancer 107
TRANSDUCTION 37 Enzyme Inhibitors 107
Proliferation and Apoptosis in Normal Cells Versus Adhesion Proteins and Cancer Cell Migration 110
Cancer Cells 37 Conclusion 111
Growth Factors 38 References 111
Signal Transduction 39
10 METASTASIS 113
Conclusion 47
References 47 Steps of Metastasis 113
Cell Detachment and Movement into a Vessel 113
iv Natural Compounds in Cancer Therapy

Migration Through the Circulation 114 16 POLYSACCHARIDES 203
Cell Arrest at a New Location 114 Introduction to Polysaccharides 203
Movement Out of the Vessel 116 Individual Compounds 203
Induction of Angiogenesis 116 Estimated Therapeutic and LOAEL Doses of
Conclusion 116 Polysaccharides 208
References 116 Using Combinations of Polysaccharides 209
Conclusion 209
11 THE IMMUNE SYSTEM 119
References 210
Innate and Adaptive Immunity 119
Antigens and Antibodies 121 17 LIPIDS 215
MHC Molecule 122 Types of Dietary Fat and Their Sources 215
Role of Cytokines in Immunity 123 Stimulation of Cancer Progression by Saturated
Role of Immune Cells in Cancer 123 and Omega-6 Fatty Acids 215
Role of the Immune System in Cancer Prevention 124 Inhibition of Cancer by Omega-3 Fatty Acids 218
Immune System in Cancer Treatment 125 Conclusion 224
Conclusion 128 References 224
References 128
18 AMINO ACIDS AND RELATED
COMPOUNDS 231
12 NATURAL COMPOUNDS THAT AFFECT
THE IMMUNE SYSTEM 131 Amino Acids 231
Natural Compounds That Stimulate and/or Support Garlic 236
the Immune System 131 Bromelain and Other Proteolytic Enzymes 239
Clinical Studies with Chinese Herbal Formulas 135 Conclusion 243
Natural Compounds That Suppress the Immune References 243
System 137
Conclusion 139 19 FLAVONOIDS 251
References 140 Introduction 251
Isoflavones, Flavones, and Flavonols 252
Flavanols—EGCG and Related Green Tea
PART III: CLINICAL CONSIDERATIONS Catechins 260
Anthocyanidins and Proanthocyanidins 263
13 BACKGROUND FOR PART III 147
Conclusion 266
Synergism 147 References 267
Estimating Effective and Safe Doses 153
Available Formulations 156 20 NONFLAVONOID PHENOLIC
Combination Design 157 COMPOUNDS 275
Conclusion 159 CAPE and Propolis 275
References 160 Curcumin 278
Lignans 280
14 TRACE METALS 163 Stilbenes—Resveratrol 284
Selenium 163 Quinones 286
Iron 168 Conclusion 290
Copper 171 References 291
Conclusion 172
References 173 21 TERPENES 297
Monoterpenes 297
15 VITAMIN C AND ANTIOXIDANTS 179 Triterpenoids 300
Vitamin C 180 Saponins 304
Antioxidants 188 Sesquiterpenes 309
Conclusion 196 Conclusion 311
References 196 References 311
Contents v
22 LIPID-SOLUBLE VITAMINS 317 APPENDIX J: DOSE CALCULATIONS 445
Vitamin A 317 Estimating Doses Based on Pharmacokinetic and
Vitamin D 322 In-vitro Data 445
3
Vitamin E 326 Modifications to the Estimated Required Dose 447
Melatonin 330 LOAEL Dose Calculation Methods 447
Conclusion 333 Dose-Dependent Bioavailability 448
References 334 Therapeutic and LOAEL Dose Estimates for
Natural Compounds 449
23 NATURAL COMPOUNDS, CHEMO- References 484
THERAPY, AND RADIOTHERAPY 343
Introduction 343 APPENDIX K: SUPPLEMENTAL
MATERIAL FOR CHAPTER 19 493
Effects of Natural Compounds on Chemotherapy 347
Effects of Natural Compounds on Radiotherapy 356 APPENDIX L: SOFTWARE AND SERVICES 497
Drug Metabolism 358
Conclusion 359 APPENDIX M: NATURAL COMPOUNDS
References 359 RESEARCH FUND 499
APPENDIX A: CHEMICAL DATA ON ACRONYMS 501
NATURAL COMPOUNDS 369
INDEX 503
APPENDIX B: PHARMACOKINETICS,
PHARMACODYNAMICS, AND DOSE
SCALING 377
Pharmacokinetic Models 377
Linking Pharmacodynamic and Pharmacokinetic
Models 379
Scaling Between Species 381
References 383
APPENDIX C: SUPPLEMENTAL
MATERIAL FOR CHAPTER 2 385
APPENDIX D: SUPPLEMENTAL
MATERIAL FOR CHAPTER 3 391
APPENDIX E: SUPPLEMENTAL
MATERIAL FOR CHAPTER 4 401
APPENDIX F: SUPPLEMENTAL
MATERIAL FOR CHAPTER 8 409
APPENDIX G: SUPPLEMENTAL
MATERIAL FOR CHAPTER 9 417
APPENDIX H: SUPPLEMENTAL
MATERIAL FOR CHAPTER 12 425
APPENDIX I: PREDICTIVE MODELS 431
Free Oral Clearance (FOC) Model 431
Total Oral Clearance (TOC) Model 433
TOPKAT Model 435
Oral-Intraperitoneal (ORIN) Model 437
References 442

FOREWORD
As a practicing cancer physician, I find my patients of- In addition to the scientific information it provides, the
ten come to their appointments with a sheaf of papers book makes a crucial contribution by drawing a clear,
downloaded from the Internet, seeking guidance. John organized picture of what we know so far about natural
Boik’s previous book, Cancer and Natural Medicine, is compounds. Today, doctors and patients alike have to
dog-eared because it has been a constant source of in- sort through an overwhelming bombardment of informa-
formation in my own practice. I am delighted to add his tion on both natural and traditional cancer therapies.
new book, Natural Compounds in Cancer Therapy, to Boik gives us an extremely valuable overview of what is
my shelf; it deserves to be included in the personal ref- known and what remains to be learned. The use of natu-
erence library of every researcher and cancer doctor. ral compounds in cancer therapy is a field still in its in-
But most of all, it is my hope this book will be read by fancy, as he states, but publication of this book is a huge
every cancer patient interested in including natural com- step forward.
pounds in his or her treatment.
For the patient, this book addresses the hype in the lay
Cancer patients and cancer physicians are two sides of media about the merits of natural compounds and count-
a single coin: we share similar hopes and dilemmas. ers it with solid, scientific information. It emphasizes
Patients hope to be cured of cancer without paying an the scientific rationale for a multipronged approach and
unbearable price; doctors hope to cure the cancer with- provides an organized starting point for a team effort by
out harming the patient. Understandably, cancer pa- patients and their doctors.
tients want to survive not only the disease but also the
For the physician, Boik delivers a better scientific un-
treatment, without loss of function or quality of life.
derstanding of the activities of natural compounds and
The dilemma, of course, is that when you blast cancer
the scientific basis for using them in applied cancer ther-
with the big guns of modern Western medicine, little
apy. Physicians desperately need this information for
may be left standing after the smoke clears.
two reasons. First, traditional Western medicine in the
Faced with dismaying treatment options, it is no won- past has discounted the role of natural compounds in
der that horrified patients turn to alternative therapies. cancer therapy because the scientific approach was lack-
Unfortunately, in seeking to educate themselves, they ing. Second, the modern physician needs to serve pa-
find information that is unscientific, disorganized, or tients who are sorting through more information than
biased by media or commercial hype. That is why ev- ever before. With this book, the value of using natural
eryone should welcome this book; it is honest, scientific, compounds in cancer therapy will gain new respect be-
it organizes the available information, and it fills a huge cause it makes the scientific framework accessible to the
need—for patients, doctors, researchers, and everyone physician for the first time.
concerned with better treatments for cancer.
For the researcher, this book organizes the details of
As its starting point, this groundbreaking book adopts the work done so far, which for the most part is at the
the scientific approach. Scientists and physicians de- level of in-vitro (test tube) and animal studies. But it
mand proof that alternative treatments work, and the also provides the big picture, indicating how the results
book adheres to the scientific accountability necessary to of these studies can guide human investigations—the
satisfy these demands. This approach is also important next logical and necessary step toward developing effec-
for patients because it helps them see cancer as a multi- tive natural compounds for cancer treatment. It will
faceted process, not a sole event. Boik shows us why help researchers set the direction for this undertaking.
each part of the process is a potential target for treat-
Natural Compounds in Cancer Therapy fills the gap
ment, and why all parts will be inhibited most effec-
between patient expectations and the reality of scientific
tively when combinations of compounds are used. In
information available in the field. It is a bridge between
other words, instead of looking for a single magic bullet
the skepticism of physicians and the hope of patients.
to cure cancer, we would do well to consider that a hol-
John Boik provides physicians, patients, and researchers
ster full of carefully chosen ones might produce the
with a map of where we are, where we need to go, and
greatest good. Overall, this book is unique in integrat-
how we will get there.
ing basic information on molecular biology with clinical
targets for cancer therapy, and will be of use to anyone I hope that one day we will not need to label medicine
wanting to understand either. as alternative or traditional, complementary or integra-
tive, Eastern or Western, but simply “Good Medicine.”
viii Natural Compounds in Cancer Therapy

Good medicine will be defined as medicine that prevents
illness, cures disease, avoids injury to the body, and
brings comfort to the soul of the patient. We will help
cancer patients by curing them sometimes, treating them
meanwhile, comforting them ever, hoping with them
always.

Israel Barken, M.D.
Urologic Oncologist
Chairman and Medical Director
Prostate Cancer Research and Education Foundation
San Diego, California
PREFACE
This book discusses numerous natural compounds that cancer progression. In fact, some of the natural com-
show promise in the treatment of cancer. It examines pounds discussed here have been used as probes in stud-
fully what research has told us about them, and it pro- ies that unraveled the mechanisms of cancer
poses ways of using them that could significantly in- progression.
crease their value in cancer treatment beyond what has
This is not to imply that these natural compounds have
previously been demonstrated. To understand the mean-
been clinically proven to inhibit cancer. Multiple human
ing of this new approach, one needs to see it in the con-
trials will be needed for that. What matters is that the
text of the big picture of cancer research.
preclinical information presented here, as well as data
We stand at a turning point in the field of cancer che- from the human trials, is promising. And the most cru-
motherapy. The last 50 years have been dominated by cial point, central to this book, is that the beneficial ef-
drugs that are not highly specific to cancer cells. Being fects of these compounds are likely to be much more
nonspecific, these drugs also destroy normal cells, and apparent when they are used in large combinations,
in the process can cause significant and sometimes permitting additive and synergistic interactions to occur.
deadly adverse effects. Before long, a new generation of
Second, although the future does look bright for even-
more powerful but less toxic drugs promises to be avail-
tual success in the fight against cancer, we are not there
able. These new drugs will target events and processes
yet. Much more work remains to be done. As a science,
that are more specific to cancer cells, and thus they will
the field of natural compound research can contribute to
not be as harmful to normal cells. This revolution in
a greater understanding of cancer and a faster develop-
therapy is already evident in the laboratory, and within
ment of successful therapies.
the next 10 years or so it will become evident in the
clinic. The ability to design and test this new generation Third, we must study natural compounds because they
of drugs comes from the many scientific discoveries are already being used in cancer treatment (and in the
made over the last 20 years that allow us to peer into the treatment of other diseases). For better or for worse,
workings of a cancer cell at the molecular level. By hundreds of thousands if not millions of patients around
seeing more clearly how cancer cells work, we are now the world are experimenting with natural compounds in
better able to design drugs to halt their proliferation and their efforts to heal themselves of cancer. Researchers
spread. This new approach of targeting the mechanisms estimate that anywhere from 10 to 80 percent of U.S.,
by which cancer cells prosper has been called, appropri- European, Australian, and Mexican cancer patients use
ately, a mechanism-based approach. some form of complementary medicine as part of their
overall therapy.1–12,_a For many of these patients, the use
These developments paint a very encouraging picture
of natural compounds is an essential part of the com-
for the eventual success of modern medicine in its battle
plementary approach. For example, two studies in the
to defeat cancer. But with such promising drugs on the
United States have reported that roughly 40 to 60 per-
horizon, the reader may ask, “Why does it make sense to
cent of cancer patients who use some form of comple-
turn to the study of natural compounds?”
mentary medicine include the use of herbs, vitamins,
antioxidant, or all three.12,_13 Most of these patients are
WHY NATURAL COMPOUNDS? using natural compounds without the guidance of their
oncologist or any real guidance from scientific studies.
There are three main reasons why natural compounds Because the popularity of using natural compounds in
are worth studying. First, natural compounds that show cancer treatment appears to be growing rather than de-
anticancer potential fit into the mechanism-based ap- clining, we are compelled to study natural compounds
proach as perfectly as a hand fits into a glove. All the so that we can properly guide the public.
natural compounds discussed in this book have been
reported to inhibit cancer. Although most of the infor-
mation available comes from preclinical (test tube and
animal) studies, as is the case with most new mecha-
nism-based drugs, some human studies have also been
conducted. There is solid evidence that these com- a Superscript numbers throughout the book refer to the numbered
pounds inhibit cancer by interfering with one or more of references at the end of each chapter. Hence, some numbers will
the mechanisms that researchers now feel are central to occasionally be repeated or appear out of sequence.