Cancer as a Metabolic Disease

Transcription

1 Cancer as a Metabolic Disease

2 Cancer as a Metabolic Disease On the Origin, Management and Prevention of Cancer Thomas N. Seyfried A John Wiley & Sons, Inc., Publication

3 Copyright 2012 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) , fax (978) , or on the web at Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) , fax (201) , or online at Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) , outside the United States at (317) or fax (317) Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at Library of Congress Cataloging-in-Publication Data: Seyfried, Thomas N., 1946 Cancer as a metabolic disease : on the origin, management, and prevention of cancer / by Thomas N. Seyfried. p. ; cm. Includes bibliographical references and index. ISBN (cloth) I. Title. [DNLM: 1. Neoplasms diet therapy. 2. Neoplasms metabolism. 3. Energy Metabolism. 4. Ketogenic Diet. 5. Mitochondria metabolism. QZ 200] dc Printed in the United States of America

4 This book is dedicated to the millions of people who have suffered and died from toxic cancer therapies

5 Contents Forword Preface xiii xv 1. Images of Cancer 1 How Cancer is Viewed 2 References Confusion Surrounds the Origin of Cancer 15 The Oncogenic Paradox 18 Hallmarks of Cancer 18 Reassessment 26 References Cancer Models 31 Problems with Some Cancer Models 31 Animal Charges as a Major Impediment to Cancer Research 38 Problems with Tumor Histological Classification 39 Personal Perspective on Cancer 44 References Energetics of Normal Cells and Cancer Cells 47 Metabolic Homeostasis 47 The Constancy of the G ATP 54 ATP Production in Normal Cells and Tumor Cells 55 Energy Production Through Glucose Fermentation 57 Glutaminolysis with or without Lactate Production 61 Transamination Reactions 64 TCA Cycle, Substrate-Level Phosphorylation 66 Cholesterol Synthesis and Hypoxia 67 Summary 67 References 68 vii

6 viii Contents 5. Respiratory Dysfunction in Cancer Cells 73 Normal Mitochondria 74 Morphological Defects in Tumor Cell Mitochondria 77 Proteomic Abnormalities in Tumor Cell Mitochondria 79 Lipidomic Abnormalities in Tumor Cell Mitochondria 81 Cardiolipin: A Mitochondrial-Specific Lipid 83 Cardiolipin and Abnormal Energy Metabolism in Tumor Cells 85 Complicating Influence of the In Vitro Growth Environment on Cardiolipin Composition and Energy Metabolism 92 Mitochondrial Uncoupling and Cancer 97 Cancer Cell Heat Production and Uncoupled Mitochondria 98 Personal Perspective 99 Summary 100 References The Warburg Dispute 107 Sidney Weinhouse s Criticisms of the Warburg Theory 108 Alan Aisenberg s Criticisms of the Warburg Theory 110 Sidney Colowick s Assessment of the Aisenberg Monograph 113 Apples and Oranges 114 References Is Respiration Normal in Cancer Cells? 119 Pseudo-Respiration 119 How Strong is the Scientific Evidence Showing that Tumor Cells can Produce Energy Through OxPhos? 124 OxPhos Origin of ATP in Cancer Cells Reevaluated 124 What About OxPhos Expression in Other Tumors? 127 The Pedersen Review on Tumor Mitochondria and the Bioenergetics of Cancer Cells 128 References Is Mitochondrial Glutamine Fermentation a Missing Link in the Metabolic Theory of Cancer? 133 Amino Acid Fermentation can Maintain Cellular Energy Homeostasis During Anoxia 133 Evidence Suggesting that Metastatic Mouse Cells Derive Energy from Glutamine Fermentation 134 Fermentation Energy Pathways can Drive Cancer Cell Viability Under Hypoxia 138 Competing Explanations for the Metabolic Origin of Cancer 141 Chapter Summary 143 References 143

7 Contents ix 9. Genes, Respiration, Viruses, and Cancer 145 Does Cancer have a Genetic Origin? 145 Respiratory Insufficiency as the Origin of Cancer 150 Germline Mutations, Damaged Respiration, and Cancer 154 Somatic Mutations and Cancer 158 Revisiting the Oncogene Theory 160 Mitochondrial Mutations and the Absence or Presence of Cancer 163 Viral Infection, Damaged Respiration, and the Origin of Cancer 165 Summary 168 References Respiratory Insufficiency, the Retrograde Response, and the Origin of Cancer 177 The Retrograde (RTG) Response: An Epigenetic System Responsible for Nuclear Genomic Stability 177 Inflammation Injures Cellular Respiration 181 Hypoxia-Inducible Factor (HIF) Stability is Required for the Origin of Cancer 182 Mitochondria and the Mutator Phenotype 183 Calcium Homeostasis, Aneuploidy, and Mitochondrial Dysfunction 186 Mitochondrial Dysfunction and Loss of Heterozygosity (LOH) 187 Tissue Inflammation, Damaged Respiration, and Cancer 188 References Mitochondria: The Ultimate Tumor Suppressor 195 Mitochondrial Suppression of Tumorigenicity 195 Normal Mitochondria Suppress Tumorigenesis in Cybrids 196 Evidence from rho 0 Cells 198 Normal Mitochondria Suppress Tumorigenesis In Vivo 199 Normal Mouse Cytoplasm Suppresses Tumorigenic Phenotypes 200 Enhanced Differentiation and Suppressed Tumorigenicity in the Liver Microenvironment 202 Summary of Nuclear-Cytoplasmic Transfer Experiments 203 References Abnormalities in Growth Control, Telomerase Activity, Apoptosis, and Angiogenesis Linked to Mitochondrial Dysfunction 207 Growth Signaling Abnormalities and Limitless Replicative Potential 208 Linking Telomerase Activity to Cellular Energy and Cancer 209 Evasion of Programmed Cell Death (Apoptosis) 209 Sustained Vascularity (Angiogenesis) 210 References 211

8 x Contents 13. Metastasis 215 Metastasis Overview 215 Cellular Origin of Metastasis 217 Macrophages and Metastasis 221 Carcinoma of Unknown Primary Origin 232 Many Metastatic Cancers Express Multiple Macrophage Properties 233 Linking Metastasis to Mitochondrial Dysfunction 233 Revisiting the Seed and Soil Hypothesis of Metastasis 235 Revisiting the Mesenchymal Epithelial Transition (MET) 236 Genetic Heterogeneity in Cancer Metastases 237 Transmissible Metastatic Cancers 240 The Absence of Metastases in Crown-Gall Plant Tumors 240 Chapter Summary 241 References Mitochondrial Respiratory Dysfunction and the Extrachromosomal Origin of Cancer 253 Connecting the Links 254 Addressing the Oncogenic Paradox 255 Is Cancer Many Diseases or a Singular Disease of Energy Metabolism? 258 References Nothing in Cancer Biology Makes Sense Except in the Light of Evolution 261 Revisiting Growth Advantage of Tumor Cells, Mutations, and Evolution 262 Tumor Cell Fitness in Light of the Evolutionary Theory of Rick Potts 269 Cancer Development and Lamarckian Inheritance 271 Can Teleology Explain Cancer? 272 References Cancer Treatment Strategies 277 Current Status of Cancer Treatment 277 The Standard of Care for Glioblastoma Management 280 References Metabolic Management of Cancer 291 Is it Dietary Content or Dietary Composition that Primarily Reduces Tumor Growth? 292 Dietary Energy Reduction and Therapeutic Fasting in Rodents and Humans 294

9 Contents xi Ketogenic Diets 295 Glucagon and Insulin 297 Basal Metabolic Rate 298 Ketones and Glucose 298 Metabolic Management of Brain Cancer Using the KD 299 Glucose Accelerates Tumor Growth! 301 Glucose Regulates Blood Levels of Insulin and Insulin-Like Growth Factor Dietary Energy Reduction is Antiangiogenic 302 Dietary Energy Reduction Targets Abnormal Tumor Vessels 307 Dietary Energy Reduction is Proapoptotic 309 Dietary Energy Reduction is Anti-Inflammatory 310 Targeting Energy Metabolism in Advanced Cancer 314 Differential Response of Normal Cells and Tumor Cells to Energy Stress 316 Dietary Energy Reduction is Anti-Invasive in Experimental Glioblastoma 318 Influence of Growth Site and Host on Tumor Progression 322 Implications of Dietary Energy Reduction for Anticancer Therapeutics 324 Targeting Glucose 325 Metformin 326 Synergistic Interaction of the Restricted Ketogenic Diet (KD-R) and 2-Deoxyglucose (2-DG) 327 Can Synergy Occur with the KD-R and Hyperbaric Oxygen Therapy? 331 Targeting Glutamine 333 Glutamine Targeting Inhibits Systemic Metastasis 334 Targeting Phagocytosis 339 Targeting the Microenvironment 340 Dietary Energy Reduction as a Mitochondrial Enhancement Therapy (MET) 341 Summary 341 References Patient Implementation of Metabolic Therapies for Cancer Management 355 Introduction 355 Guidelines for Implementing the Restricted Ketogenic Diet as a Treatment Strategy for Cancer 356 Complicating Issues for Implementing the KD-R as a Treatment Strategy for Cancer 366 Radiation and Chemotherapy is a Standard Treatment for Many Malignant Cancers 366 Compliance 367

10 xii Contents Cancer as a Genetic Disease 367 Mechanism of Action? 368 Cachexia 368 Summary 369 References Cancer Prevention 375 Cell Phones and Cancer 376 Alzheimer s Disease and Cancer Risk 377 Ketone Metabolism Reduces Cancer Risk 378 Mitochondrial Enhancement Therapy 379 Therapeutic Fasting and Cancer Prevention 379 Autophagy and Autolytic Cannibalism: A Thermodynamic Approach to Cancer Prevention 381 Cancer Prevention by Following Restricted Ketogenic Diet 382 References Case Studies and Personal Experiences in Using the Ketogenic Diet for Cancer Management 387 Effects of a Ketogenic Diet on Tumor Metabolism and Nutritional Status in Pediatric Oncology Patients: Comments from Dr. Linda Nebeling 387 Raffi s Story: Comments from Miriam Kalamian 389 Biological Plausibility that Cancer is a Metabolic Disease Dependent for Growth on Glucose and Glutamine: Comments from Dr. Bomar Herrin 395 Using the Restricted Ketogenic Diet for Brain Cancer Management: Comments from Neuro-Oncologist, Dr. Kraig Moore 397 The Ketogenic Diet for Brain Cancer Management: Comments from Beth Zupec-Kania 400 Summary 402 References Conclusions 405 Major Conclusions 407 References 408 Index 409

11 Foreword Cancer persists as a major disease of mortality and is afflicting more people today than ever before. Few families remain untouched by this insidious and vicious disease. In fact, cancer is predicted to overtake heart disease as the prime cause of death in industrialized societies during this century. I have worked in the cancer metabolism field since the late 1960s and have extensively published works on the metabolic basis and properties of cancer. While I do not know Dr. Seyfried personally, I am very impressed with the excellent job he has done in highlighting abnormal energy metabolism as the central issue of the cancer problem. I recognized long ago the pivotal role of mitochondria and of aerobic glycolysis in sustaining and promoting cancer growth. The Nobel laureate, Otto Warburg, was the first to provide evidence during the early part of the last century for the involvement of disturbed respiration with compensatory fermentation (glycolysis) as a common property of cancer, thus perceived to be related to its uncontrolled growth and progression. Few subjects have been as controversial in the cancer field as Otto Warburg and his theory of cancer. It is nice to see how Seyfried shows that Warburg was largely correct in defining the nature of the disease as involving insufficient respiration with compensatory fermentation. I knew personally many of the key figures and their research mentioned in Seyfried s book, including Dean Burk, Peter Mitchell, Sidney Weinhouse, and my former Department Chair, Albert Lehninger, among others. Nevertheless, there were times in my early career when I felt almost alone in considering energy metabolism as important to the cancer problem. I even remember one of my colleagues, an expert in DNA technology, dumping Lehninger s Warburg Flasks in the trash as relics of a bygone era in cancer research. Fortunately for him, Lehninger was no longer the Department Chair, and fortunately for me, I salvaged many of these flasks and am now glad I did. After reading Seyfried s book, I think these flasks will become valuable as collector items. The cancer field went seriously off course during the mid-1970s when many investigators began considering cancer as primarily a genetic disease rather than as a metabolic disease. The metabolic defects in cancer cells were thought to arise as secondary consequences of genomic instability. Seyfried provides substantial evidence documenting the inconsistencies of the gene only theory. He critically reevaluates the evidence linking cancer progression to a Darwinian process and raises the intriguing possibility that cancer progression is an example of Lamarckian evolution. When viewed collectively, the documented inconsistencies of the gene xiii

12 xiv Foreword only theory make it clear why little progress has been made in the cancer war and in the development of effective nontoxic therapies. A key point made by Seyfried is that most of the genomic instability seen in cancer likely arises as a consequence rather than as the cause of the disease. When viewed more as a metabolic disease, many cost effective therapeutic strategies become recognized for cancer management. I know this first hand from our studies of 3-bromopyruvate (3BP), discovered in my laboratory by Dr. Young Ko, as a potent anticancer agent. This is a low cost drug with powerful and quick antitumor effects against multiple cancers in animal models and in cancer patients. 3BP works primarily by targeting tumor cell energy metabolism, thus depleting the energy-rich compound ATP essential for growth. At the effective doses used, it does this without toxicity to normal cells. Seyfried s book provides substantial evidence showing how cancer can be managed using various other drugs and diets that target energy metabolism. In addition, the restriction of glucose and glutamine, which drive cancer energy metabolism, cripples the ability of cancer cells to replicate and disseminate. The gene theory has deceived us into thinking that cancer is more than a single disease. Certainly, tumors do not all grow at the same rate. Nevertheless, cancer is a singular disease involving aberrant energy metabolism as Warburg originally showed and as I, and more recently many others, have documented in biochemical studies. Seyfried drives home this message throughout his book. Seyfried s treatise refocuses attention on the central issue of cancer as a metabolic disease according to Warburg s original theory. The book is unique in linking nearly all aspects of the disease to respiratory insufficiency with compensatory fermentation. Cancer has remained incurable for many due largely to a general misunderstanding of its origin, biology, and metabolism. Hopefully, Seyfried s thoughtful analysis of the cancer problem will change our understanding of the disease and move the field in the right direction toward solutions and therapies, such as 3BP, that act much faster and more effectively than those currently available. Dr. Peter Pedersen Professor of Biological Chemistry Johns Hopkins University School of Medicine Baltimore, MD

13 Preface Cancer persists as a plague in modern society. The lack of progress in either managing or preventing cancer motivated me to write this treatise. I am a biochemical geneticist and have worked on the lipid biochemistry of cancer since the early 1980s. I have developed numerous mouse models for brain tumors and for systemic metastatic cancer. Several major findings planted the seed for this treatise. First, it became clear to me that the therapeutic action of some anticancer drugs operated largely through reduced caloric intake. Second, that reduced caloric intake could target the majority of cancer hallmarks. Third, that ketone bodies can serve as an alternative fuel to glucose in most cells with normal respiratory function. Fourth, that metastatic cancer arises from cells along macrophage lineage. Fifth, that all cancer cells regardless of tissue origin express a general defect in mitochondrial energy metabolism. Finally, that cancer can be effectively managed and prevented once it becomes recognized as a metabolic disease. In recognizing cancer as a metabolic disease, it gradually became clear to me why so many people die from the disease. Many of the current cancer treatments exacerbate tumor cell energy metabolism, thus allowing the disease to progress and eventually become unmanageable. Most cancer patients do not battle their disease but are offered toxic concoctions that can eventually undermine their physiological strength and their will to resist. Cancer treatments are often feared as much as the disease itself. The view of cancer as a genetic disease has confounded the problem and is largely responsible for the failure to develop effective therapies. The view of cancer as a genetic disease is based on the flawed notion that somatic mutations cause cancer. Substantial evidence indicates that genomic instability is linked to protracted respiratory insufficiency. Once cancer becomes recognized as a metabolic disease with metabolic solutions, more humane and effective treatment strategies will emerge. My treatise highlights cancer as a metabolic disease and identifies the inconsistencies of the gene theory of cancer. Moreover, my treatise addresses most of the so-called provocative questions raised by the National Cancer Institute regarding outstanding issues in cancer research. This treatise lays the foundation for the eventual resolution of the disease. I would like to thank my many students and colleagues for helping me in producing the data and in developing the concepts for this treatise. I thank my former graduate students Mary Louise Roy (MS, 1987), Michelle Cottericho (MS, 1992), Mohga El-Abbadi (PhD, 1995), Hong Wei Bai (PhD, 1996), John Brigande (BS, 1989; MS, 1992; PhD, 1997), Jeffrey Ecsedy (PhD, 1998), Mark Manfredi xv

14 xvi Preface (PhD, 1999), Michaela Ranes (BS, 1998; MS, 2000), Dia Banerjee (MS, 2001), Michael Drage (MS, 2006), Christine Denny (BS, 2005; MS, 2006), Weihua Zhou (MS, 2006), Laura Abate (PhD, 2006), Michael Kiebish (PhD, 2008), Leanne Huysentruyt (PhD, 2008), John Mantis (PhD, 2010), and Laura Shelton (PhD, 2010). I would also like to acknowledge my current students Linh Ta and Zeynep Akgoc for their continued productivity. I would also like to thank the following undergraduate students for their input and help, including Katherine Holthause, Jeremy Marsh, Jeffery Ling, Will Markis, Tiernan Mulrooney, Todd Sanderson, Todd Theman, Lisa Mahoney, Michelle Levine, Emily Coggins, Erin Wolfe, Ivan Urits, Taryn LeRoy, and Emily Gaudiano. I would like to thank those students from my BI503 class on Current Topics in Cancer Research for their input. I would like to thank faculty colleagues in the Boston College Biology Department, including Drs. Thomas Chiles, Fr. Richard McGowan SJ, and Jeffery Chuang. I would like to thank Dr. Robert K. Yu, Dr. James Fox and my son Dr. Nicholas T. Seyfried for technical assistance. I would like to thank Avtar Roopa for provocative discussion. I would like to thank the late Drs. Sanford Palay, Harry Zimmerman, and Allan Yates for their encouragement and assistance. I would also like to give special acknowledgement to Dr. Purna Mukherjee and Roberto Flores. Purna was the first to make me aware of the powerful therapeutic action of calorie restriction. She is superbly trained in the areas of angiogenesis and inflammation and her work provided seminal information on the mechanisms by which dietary energy reduction can both treat and prevent cancer. Roberto Flores is exceptional in his dedication to finding the truth underlying the metabolic origin of cancer and in questioning the metabolic origin of cancer. Finally, I would like to thank my institution, Boston College, for providing animal care support over the first 23 years of my employment there ( ). The data collected supporting my treatise would not have been possible without this invaluable institutional support. This support was consistent with the Ignatian philosophy of service to others.