Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2014 Copyright © 2014 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-802215-3 ISSN: 1874-6047 For information on all Academic Press publications visit our website at store.elsevier.com CONTRIBUTORS Javad Alizadeh Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Sumit Arora Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA Courey Averett Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA S Zahra Bathaie Department of Clinical Biochemistry, Tarbiat Modares University, Tehran, Iran, and Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, California, USA Arun Bhardwaj Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA Azam Bolhassani Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran Chu Chen Institute of Pharmaceutical Research, Sichuan Academy of Chinese Medicine Sciences, Chengdu, P.R China Jayson X Chen Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA Jun-Rong Du Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, P.R China Saeid Ghavami Department of Human Anatomy and Cell Science, College of Medicine; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada, and Health Policy Research Centre, Shiraz University of Medical Science, Shiraz, Iran Chin-Lin Hsu School of Nutrition, Chung Shan Medical University, and Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan Amir Kiumarsi Chang School of Continuing Education, Ryerson University, Toronto, Ontario, Canada ix x Contributors Young Sup Lee School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea Fang-Yi Long Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, P.R China Hassan Marzban Department of Human Anatomy and Cell Science, College of Medicine, and Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada Yoichi Matsuo Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Adel Rezaei Moghadam Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran Siddavaram Nagini Faculty of Science, Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India Raheem Shahzad School of Applied Biosciences, College of Agriculture and Life Sciences, Kyungpook National University, Daegu, Republic of Korea Adeeb Shehzad School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea Shahla Shojaei Department of Biochemistry, Recombinant Protein Laboratory, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran Ajay P Singh Department of Oncologic Sciences, Mitchell Cancer Institute, and Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA Seema Singh Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA Hiromitsu Takeyama Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Fuyuhiko Tamanoi Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, California, USA Contributors xi Hong Wang Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA Chung S Yang Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA, and International Joint Research Laboratory of Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, PR China Gow-Chin Yen Department of Food Science and Biotechnology, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan Jinsong Zhang International Joint Research Laboratory of Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, PR China Haseeb Zubair Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA PREFACE Anticancer activities of compounds from natural resources have been documented extensively in recent decades However, molecular mechanisms of the action of these compounds need to be further elucidated In particular, it will be important to understand the signaling pathways targeted by these natural compounds We have realized that various recent activities have started to shed new lights into this problem To capture these developments, we decided to put together a volume describing recent studies concerning the role of natural compounds in cancer therapy and cancer prevention We believe that compiling the knowledge on elucidating targets of natural compounds is important, as it may provide hints about future developments such as possible combination therapies In this volume, we described studies on isoprenoids, polyphenols, and flavonoids In future volumes, we plan to cover other classes of natural products We are very grateful to the authors for their effort in providing excellent and informative chapters in a timely fashion We also thank Mary Ann Zimmerman and Helene Kabes of Elsevier for their guidance and encouragement during the preparation of this volume S ZAHRA BATHAIE FUYUHIKO TAMANOI UCLA, Los Angeles September 2014 xiii CHAPTER ONE Introduction S Zahra Bathaie*,†, Fuyuhiko Tamanoi†,1 *Department of Clinical Biochemistry, Tarbiat Modares University, Tehran, Iran † Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, California, USA Corresponding author: e-mail address: fuyut@microbio.ucla.edu Contents References Abstract Natural products and phytochemicals have extensively attracted for their various biological effects, especially for both treatment and prevention of cancer In this book, we try to introduce various phytochemicals as cancer therapy targets with emphasize on their effect on signal transduction pathways and their molecular targets Natural products are chemical substances produced by living organisms and have distinctive biological and pharmacological effects, even if they can be prepared by total synthesis These are foreign to humans (i.e., xenobiotics) and are subject to the same pharmacological issues encountered by synthetic therapeutic agents [1] Plants and microbes are two important sources of natural products Antibiotics are the oldest biologically active compounds separated from microbes and used as drug to cure various human diseases, especially cancer Among the wide range of biologically active compounds obtained from different sources in nature, medicinal uses of plants possibly are the oldest one and came back to the ancient time, as they used by various nations Historically, various parts of the plants, such as fruit, flower, leaves, stalks, root, seed, and even the whole plant, have been used as the home remedy Different methods have also been used for preparation of the herbal remedy; they include preparation of the pills, capsules, or sachets from the powder; decoctions (boiled); infusion; extraction with water or oil; and so on [2] All of these preparations have been used orally However, some preparations may have the topical application Thus, they can be used for inhalation therapy or in a mixture as the skin cream In all of the above-mentioned The Enzymes, Volume 36 ISSN 1874-6047 http://dx.doi.org/10.1016/B978-0-12-802215-3.00001-X # 2014 Elsevier Inc All rights reserved S Zahra Bathaie and Fuyuhiko Tamanoi methods, the main goal is the efficient absorption of the effective ingredient(s) in the body Nowadays, targeted therapy or molecularly targeted therapy, especially in cancer treatment, has been considered to accomplish more effective treatment with less harmful effect to normal cells In this regard, scientists try to use the more effective ingredient of the herbals, instead of the crude extract to achieve the more powerful therapy with no or minimum side effect Therefore, fractionation, purification, and characterization of the active components have been extensively considered Phytochemicals (from the Greek word phyto, meaning plant) are compounds found in plants They are biologically active and provide health benefits for humans These chemicals have metabolic or protective role in their own plants, but may exert the same or other effects in other organisms like animal or human bodies Table 1.1 shows the overall classification of phytochemicals according to their chemical structure, biological activity, and plant sources Different chapters of this book reviewed the mechanism(s) of the anticancer effect of some of these phytochemicals Various biological or pharmacological activities have been reported for phytochemicals Some of them include antimicrobial, antivirus, or antifungal effects; antioxidant activity or activation of the antioxidant defense system; modulation of the detoxifying enzymes; stimulation or suppression of the immune system; decrease of platelet aggregation; modulation of hormone metabolism; and regulation of the metabolism of the building blocks in the body Chemoprevention and anticancer property are two novel approaches emphasizing the prevention or delay of carcinogenesis, or treatment of cancer by means of natural products through pharmacologic, biologic, and even nutritional intervention This involves the discovery and characterization of the phytochemicals as a new drug with specific effect on cell cycle proteins, growth factors, or hormone receptors, and/or specific inhibitory or activatory effect on specific enzymes Chemotherapeutic and chemoprevention by targeting key components of the apoptosis pathways, cell cycle checkpoints, autophagy regulation, ER stress response, and protein folding targets are the main goal of the new drug design approaches (Fig 1.1) Targeting of the tumor microenvironment, more particularly inflammatory mediators and reactive oxygen/nitrogen species; upregulation of intercellular communication through gap junction or tight junction; regulation of upstream kinases of intracellular signaling cascades or downstream transcription factors; elimination of endogenous and environmental Introduction Table 1.1 Family and Chemical Structure of Phytochemicals Found in Plants Row Family Chemical Structure Component Plant Name Isoprenoids or terpenoids Monoterpenoids Zingerone or vanillylacetone Ginger Terpineol Picrocrocin Saffron Diterpenoids Taxol (or paclitaxel) Taxus brevifolia Triterpenoids Saponins Many plants Ganoderic acid Ganoderma mushrooms Ganoderma mushrooms Apple, basil, bilberries Lucidenic acid Ursolic acid Tetraterpenoids or carotenoids Beta-carotene Carrot Lycopene Tomato Lutein Spinach, kale, and yellow carrot Saffron Crocin and crocetin Tetranortriterpenoids Limonoids Citrus fruits Steroids (phytosterols) Withanolide Tomatillo Curcuminoid Curcumin Turmeric Stilbenoid Resveratrol Skin of red grapes 12 Lignan Honokiol Magnolia 13 Chalconoids Chalcones Geranyl chalcone Geranylgeraniol 14 Tannins 10 11 Phenolics and polyphenols Pomegranates, persimmon, berries, nuts Continued Table 1.1 Family and Chemical Structure of Phytochemicals Found in Plants—cont'd Row Family Chemical Structure Component Plant Name 15 Quercetin Radish leaves, dill, red anion 16 Kaempferol Tea, broccoli, grapefruit 17 Flavan-3-ols Catechins Flavones Apigenin, chrysin, Parsley, celery, luteolin and citrus peels Eriodictiol, Citrus fruits hesperitin 18 Flavonoidpolyphenolics Flavonoids Flavanones 19 Isoflavonoids 20 Licoflavanone Genistein Anthocyanidins Cyanidin 22 Polycyclic compounds Quinoline alkaloid 23 Aromatic compounds Aromatic acids Cinnamic acid (hydroxycinnamates) Caffeic acid 25 26 Fava beans, soybeans Glycyrrhiza glabra 21 24 Green tea Grapes, bilberry, blackberry, blueberry, cherry Camptothecin Camptotheca, happy tree Cinnamon Basil, apple Coumarin Citrus fruits Aromatic aldehyde Safranal Saffron Mustard, radish, horseradish 27 Glucosinolates Isothiocyanates Allyl isothiocyanate 28 Vanilloids Phenolic aldehyde Vanilla bean Vanillin and derivatives (vanillic acid, vanillyl alcohol, etc.) Capsaicin Chili peppers 29 30 Organosulfurs Allylic sulfurs Allicin Diallyl disulfide 31 Thiosulfates 32 Aromatic heterocyclic Garlic Leek Indole alkaloids Ergot alkaloids Monoterpenoid alkaloids Calabar bean seed, rye and related cereals Introduction Procarcinogen Potential carcinogen ROS production or direct interaction DNA damage/ mutagenesis Protein conformation/function changes Pro-apoptotic factors ER stress response Signal transduction pathway Oxidant/antioxidant balance Autophagy regulators Inflammatory response Cell cycle check points Carcinogenesis Figure 1.1 The process of carcinogenesis from beginning Various phytochemicals and drugs can inhibit any step(s), which is extensively discussed in the chapters of this book carcinogens; and/or reduction of angiogenesis are some proposed chemopreventive strategies by means of pharmacological or nutritional factors Among the mechanisms mentioned in Fig 1.1, reactive oxygen species (ROS) production (the cellular distortion in the balance of oxidant/antioxidant) is the most important in both carcinogenesis and killing of cancer cells A set of 13 p53-induced genes (PIG genes) have a key role in the reactions 244 Rodel, W., 59, 79 Rodina, A., 136, 145 Rodriguez, L., 164, 165, 173 Rodriguez, S K., 209, 219 Rodrı´guez-Casado, A., 151, 167 Rodriguez-Lopez, J N., 207, 218 Roe, S M., 182, 192 Rohmer, M., 41, 55 Romano, D., 140, 147 Rombola, L., 21, 24, 32 Rosche, M., 178, 182, 183, 190 Rosetti, M., 21, 32 Ross, K N., 136, 145 Roth, M., 199, 215 Roussos, C., 9, 13, 17, 26, 28 Rovira, D D., 9, 27 Rowlands, M G., 16, 19, 20, 24, 30, 31 Roy, M K., 134, 136, 144 Roy, S., 139, 140, 146 Roya, M., 158, 170 Roychoudhury, J., 137, 138, 146 Rozati, R., 64, 81 Ruffin, M T., 150, 167 Ruiz, A L., 22, 23, 32 Ruiz, B., 9, 27 Russo, G L., 177, 189 Russo, R., 21, 24, 32 Rust, W L., 14, 18, 29 Rychahou, P G., 163, 172 Ryu, J H., 154, 167 S Saboda, K L., 16, 30 Sabouni, F., 67, 82 Sadano, H., 207, 218 Sadeghizadeh, M., 64, 65, 69, 71, 81 Sadeghnia, H R., 67, 73, 82 Saha, T., 72, 84 Sahoo, B K., 160, 171 Saito, H., 79, 86 Sakaguchi, K., 159, 170 Sakai, H., 200, 209, 214, 215, 219 Sakai, N., 19, 22, 23, 31 Sakinah, S A., 89, 94 Sakthisekaran, D., 62, 72, 77, 81, 84 Sakthivel, R., 135, 138, 141, 145 Salam, M A., 132, 144 Salasche, S J., 16, 30 Sale, S., 161, 171 Author Index Salleh, M Z., 88, 92 Salo, K., 10, 27 Salomi, M J., 66, 72, 77, 82, 84 Salvato, B., 206, 218 Sam, S., 64, 81 Samarghandian, S., 61, 80 Sang, S., 154, 167, 196, 198, 199, 203, 204, 209, 214, 215, 216 Santel, T., 160, 171 Santhiya, S T., 67, 72, 82, 84 Santhosh, M S., 75, 85 Santos-Beneit, A., 14, 29 Santuccio, C., 203, 214, 216 Sareth, S., 204, 217 Sarkar, D., 25, 32 Sarkar, F H., 140, 146, 155, 156, 168, 169 Sarkar, K., 139, 140, 146 Sarkar, S., 25, 32, 139, 146 Sarkara, R., 158, 170 Sarker, S D., 133, 136, 146 Sarma, G C., 88, 93 Sarria, A L., 136, 145 Sartor, L., 206, 218 Sastry, B S., 136, 146 Satomi, Y., 12, 14, 17, 28 Sattler, C A., 12, 14, 17, 28 Saw, C L., 98, 102, 118, 126 Sawada, H., 14, 28 Sawai, H., 14, 28 Saxena, A., 163, 172 Saxena, A K., 136, 146 Saxena, N K., 180, 191 Schade, R., 156, 169 Schaăfer, A., 160, 171 Schatzkin, A., 88, 92 Schink, J C., 15, 30 Schmezer, P., 25, 32 Schneider, A., 138, 146 Schneider-Stock, R., 71, 84 Schuhly, W., 187, 193 Schulz, C O., 178, 182, 183, 190 Schulze-Luehrmann, J., 71, 84 Schuster, T F., 205, 217 Schwartsmann, G., 16, 30 Schwartz, J L., 203, 216 Schwender, J., 41, 55 Scorilas, A., 45, 56 Scudder, G G E., 132, 144 Sebastian, T., 18, 31 Author Index Seeger, M., 156, 169 Sei, Y., 213, 221 Seifert, W E., 164, 173 Selman, S H., 154, 167, 168 Selvam, C., 155, 168 Selvanayagam, Z E., 209, 219 Selvendiran, K., 72, 77, 84 Semenov, M., 161, 172 Senthilkumar, K., 135, 138, 141, 145, 147 Senthilkumaran, V., 203, 216 Senthilnathan, P., 72, 84 Senzaki, H., 14, 17, 29 Seo, H W., 34, 36, 52 Seo, K S., 178, 190 Sessa, A K., 182, 191 Sethi, G., 182, 184, 186, 191 Sethi, J K., 141, 147 Severino, V G., 136, 145 Seyedhosseini Tamijani, S M., 78, 86 Seyedian, R., 71, 84 Shahbazfar, A A., 64, 81 Shahsavand, S., 63, 66, 80 Shaik Mossadeq, W M., 88, 93 Shamoto, T., 91, 94 Shanafelt, T D., 201, 216 Shanmugam, M K., 180, 191 Shao, X M., 185, 192 Shapiro, G R., 15, 16, 30 Shariaty, V M., 73, 85 Sharma, C., 132, 144 Sharma, D., 180, 191 Sharma, I., 88, 93 Sharma, J N., 88, 93 Sharma, P., 20, 31 Sharma, R A., 164, 173 Sharmila, G., 134–136, 138, 141, 144, 145, 147 Sharp, P A., 159, 170 Shayesteh, L., 178, 190 Shehzad, A., 150, 161, 164, 166, 171, 173 Shen, C C., 186, 192 Shen, D F., 75, 85 Shen, D Y., 98, 99, 125 Shen, G., 204, 216 Shen, H M., 181, 191 Shen, L., 155, 169, 178, 182, 183, 185, 186, 190 Shen, T S., 165, 173 Shen, X., 25, 32 245 Shen, X C., 75, 85 Shen, Y., 156, 169 Sheng, L., 75, 85 Sheng, Q., 89, 94, 178, 182, 183, 185, 186, 190 Sheng, S., 199, 215 Sheu, M L., 185, 186, 192 Shi, C B., 164, 173 Shi, F., 64, 70, 81 Shi, J., 176, 177, 189 Shi, J M., 98, 100, 118, 125 Shi, L., 37, 55, 89, 94 Shi, L S., 43, 44, 46, 55 Shi, W., 12, 14, 17, 18, 28 Shiah, H S., 72, 84 Shiao, M S., 34, 41, 52, 55 Shibata, T., 91, 94 Shih, C A., 155, 168 Shih, P H., 183, 192 Shih, Y S., 185, 192 Shikata, N., 14, 17, 29 Shilpi, J A., 133, 136, 146 Shim, J H., 178, 190, 205, 217 Shimada, T., 11, 25, 27, 32 Shimazaki, N., 159, 170 Shimazawa, M., 76, 85, 86 Shimizu, M., 200, 208, 209, 213, 214, 215, 218, 219 Shimizu, Y., 176, 188 Shin, D I., 163, 164, 172 Shin, D M., 184, 192 Shin, D W., 207, 218 Shin, E S., 207, 218 Shin, H J., 184, 192, 209, 219 Shin, J C., 178, 190 Shin, J M., 207, 218 Shin, S W., 163, 164, 172 Shindo, M., 11, 25, 27, 32 Shinmoto, H., 134, 136, 144, 146 Shinozaki, T., 132, 137, 145, 146 Shiow, S J., 67, 69, 77, 82, 83, 86 Shirakami, Y., 200, 209, 214, 215, 219 Shishodia, S., 91, 94, 151, 165, 167, 173, 182, 184, 186, 191 Shoeb, M., 133, 136, 146 Shojaei, S., 20, 31 Shoji, K., 205, 217 Shoji, M., 164, 173 Shoyama, Y., 79, 86 246 Shringarpure, R., 209, 219 Shu, Y., 156, 169 Shukla, S., 207, 211, 218 Shukriyah, M H., 88, 93 Shulka, O P., 10, 27 Siddappa, N B., 158, 170 Siddiqui, I A., 201, 214, 216 Siegel, R., 151, 167 Siemann, L., 15, 29 Sigman, C C., 9, 26 Silva, H., 14, 18, 29 Silva, M F., 136, 145 Silva, M M., 25, 32 Silverman, S., 165, 174 Silvestrini, R., 21, 32 Sim, N L., 88, 92 Simi, B., 154, 155, 167, 168, 200, 215 Simmonds, M S J., 34, 52 Simon, K., 15, 29 Simonsen, J L., 9, 27 Simonyi, M., 67, 82 Sinakos, Z., 77, 86 Singh, A K., 135, 138, 141, 145 Singh, A P., 176, 178, 182, 188, 189 Singh, D V., 163, 172 Singh, J., 165, 174 Singh, J P V., 72, 77, 84 Singh, R., 164, 173 Singh, S., 176, 178, 182, 188, 189 Singh, S V., 98, 104, 108, 109, 128, 178, 190, 191 Singh, T., 178, 183, 186, 190, 211, 220 Singhal, S S., 164, 173 Sirat, H M., 88, 93 Sironi, M., 14, 28 Sistla, R., 133, 138, 145 Sivakamasundari, V., 135, 141, 145 Skouridou, V., 9, 13, 17, 26, 28 Skrzypczak-Jankun, E., 154, 167, 168 Sliva, D., 34, 48, 53 Smirnova, N A., 140, 147 Smith, A., 15, 29 Smith, D M., 206, 218 Snader, K M., 176, 188 Snyder, J P., 164, 173 Soares, M S., 136, 145 Soda, M., 163, 172 Soff, G., 176, 179, 185, 189 Soh, J W., 209, 219 Author Index Solinas, M., 59, 79 Somchit, M N., 88, 93 Somparn, P., 153, 167 Son, M K., 98, 106, 129 Song, R., 156, 169 Song, Y., 160, 171 Song, Y S., 45, 56 Souza, R F., 180, 191 Sparg, S G., 97, 101, 124 Spechler, S J., 180, 191 Speer, R E., 140, 147 Sperling, J., 156, 169 Spohn, W H., 162, 172 Spooner, G., 158, 170 Spriggs, D R., 15, 16, 29 Squires, M S., 161, 171 Srinivas, P., 134, 136, 144 Srinivas, P V., 136, 146 Srinivasan, N., 140, 147 Sripriya, D., 134, 136, 138, 144 Sripriya, P., 134, 136, 138, 144 Srivastava, K D., 34, 50, 53 Srivastava, P., 138, 146 Srivastava, S K., 176, 178, 182, 188 Srividhya, R., 203, 216 Staab, M J., 15, 16, 30 Stafford, L J., 151, 167 Stanley, G., 34, 53 Stavinoha, W B., 176, 189 Stayrook, K R., 12, 17, 28 Steele, V E., 9, 26 Steffan, J J., 210, 212, 220, 221 Stegmaier, K., 136, 145 Steinmetz, K A., 88, 92 Stenzel, R A., 14, 17, 28 Stetler-Stevenson, W G., 45, 56 Steward, W P., 164, 173 Stewart, J., 153, 167 Stewart, J A., 15, 16, 29, 30 Stocker, R., 155, 168 Stone, B A., 165, 173 Stratton, S P., 16, 30 Su, C Y., 34, 52 Su, Q., 178, 186, 189 Su, S L., 161, 171 Su, W J., 187, 193 Su, Z Y., 205, 217 Subapriya, R., 132, 144 Subar, A., 88, 92 247 Author Index Subar, A F., 88, 92 Subbaramaiah, K., 154, 168, 186, 192 Subhadhirasakul, S., 88, 93 Subramaniam, D., 178, 190 Subramanian, A., 136, 145 Suenaga, K., 132, 144 Suganthapriya, E., 135, 141, 145 Suganuma, M., 213, 221 Sugawara, F., 159, 170 Sugihara, K., 210, 211, 214, 220 Sugiura, M., 79, 86 Sulaiman, M R., 88, 92, 93 Sultan, P., 64, 81 Sultana, G N N., 88, 93 Sultana, S., 9, 26 Sun, A., 164, 173 Sun, H., 64, 70, 81 Sun, H G., 142, 147 Sun, J., 10, 18, 22, 25, 27, 67, 82 Sun, X Z., 21, 22, 24, 32 Sun, Y., 89, 94, 136, 146, 156, 169, 204, 207, 209, 211, 214, 217, 219 Sundar, I K., 158, 170 Sundaram, C., 165, 173 Sundin, T., 15, 18, 29 Sung, B., 90, 91, 94, 141, 147, 182, 184, 186, 191 Supko, J., 15, 29 Supko, J G., 15, 29 Suresh Babu, K., 136, 146 Surh, Y J., 155, 168 Suryanarayana, P., 163, 172 Suzui, M., 209, 219 Suzuki, T., 136, 138, 145, 210, 211, 214, 220 Swaminathan, V., 158, 170 Swamy, K V., 155, 168 Swamy, M V., 155, 168 Swee, K Y., 88, 93 Syam, M M., 88, 93 Syam, S., 89, 93 Szarka, C E., 15, 16, 29 Szkudlarek, M., 154, 168 T Tabata, K., 136, 138, 145 Tachi, Y., 132, 137, 145, 146 Tachibana, H., 205, 210, 212, 217, 220, 221 Taferner, B., 187, 193 Taghikhani, M., 67, 83 Taha, M M., 89, 93 Taha, M O., 162, 172 Tajima, K., 163, 172 Tajima, T., 165, 173 Tajmir-Riahi, H A., 67, 82 Takada, Y., 90, 94 Takagi, M., 132, 137, 139, 145, 146 Takahashi, A., 136, 138, 139, 145, 146 Takahashi, D., 88, 92 Takahashi, H., 91, 94 Takahashi, M., 66, 82 Takahashi, S., 19, 31 Takasaki, M., 62, 81 Takeda, Y., 14, 28, 153, 167 Takenaka, M., 134, 136, 144, 146 Takeuchi, T., 159, 170 Takeyama, H., 91, 94 Tamir, S., 49, 56 Tammali, R., 163, 172 Tamura, T., 34, 52 Tan, S M., 98, 99, 117, 119, 125 Tan, T H., 157, 169 Tan, Y., 161, 172 Tanaka, H., 62, 81 Tanaka, J., 76, 85 Tanaka, T., 207, 218 Tang, B., 142, 147 Tang, F., 204, 205, 209, 217 Tang, L., 204, 214, 217 Tang, M., 204, 214, 217 Tang, M H., 185, 192 Tang, W., 47, 55 Tang, Y J., 35, 41, 42, 53, 55 Taniguchi, M., 34, 43, 53 Taniguchi, S., 207, 218 Tannenbaum, S R., 49, 56 Tanner, M A., 19, 31 Tao, Y., 206, 218 Tarantilis, P A., 60, 62, 63, 65, 67, 79, 80–82, 86 Tasaka, K., 34, 53 Tashima, M., 14, 28 Tatebe, H., 209, 219 Tatsuta, M., 19, 21–23, 31 Tavakkol-Afshari, J., 61, 69, 80 Tayarani, N Z., 75, 85 Teekachunhatean, S., 50, 56 Teh, L K., 88, 92 248 Teleczky, J., 59, 79 Teng, L., 178, 182, 183, 185, 186, 190 Tengku Mohamad, T A S., 88, 93 Teow, S S., 45, 56 Tergaonkar, V., 181, 191 Tesei, A., 21, 32 Teti, D., 154, 168 Tewtrakul, S., 88, 93 Thakur, V S., 207, 211, 212, 218, 221 Thalhammer, T., 187, 193 Thiele, C J., 142, 147 Thilagavathi, R., 155, 168 Thirunavukkarasu, C., 62, 67, 72, 81, 82 Thiviyanathan, V., 164, 173 Thoh, M., 139, 146 Thomas, A., 76, 85 Thomas, J P., 15, 16, 30 Thomas, P., 155, 168 Thomas, S M., 184, 192 Thompson, P A., 18, 21, 25, 26, 30, 32 Thompson, V., 182, 192 Thomson, C A., 18, 25, 26, 30 Thorneley, R N., 207, 218 Thota, N., 133, 138, 145 Thulasiram, H V., 139, 146 Thushara, R M., 75, 85 Thyagarajan, A., 43, 55 Tighiouart, M., 209, 219 Tilg, H., 49, 56 Timcheh Hariri, A., 72, 84 Timmermann, B N., 199, 215 Timo, H J., 34, 52 Tinwell, H., 25, 32 Tipoe, G L., 155, 168 Tiraihi, T., 74, 85 To, S., 209, 219 Tokuda, H., 62, 81, 137, 139, 146 Tollefsbol, T O., 211, 220 Tomaszewski, J., 15, 29 Tome, M E., 204, 214, 217 Tong, W P., 15, 16, 29 Torres-Lozano, C., 22, 32 Tostado-Pelayo, K., 22, 32 Toth, J O., 34, 53 Trachootham, D., 6, Trepel, J., 157, 170 Trichopoulos, D., 88, 92 Trichopoulou, A., 88, 92 Trompouki, E., 182, 191 Author Index Tsai, J J., 186, 192 Tsai, S J., 212, 221 Tsai, S K., 176, 189 Tsai, T H., 186, 192 Tsang, W P., 212, 220 Tseng, T H., 77, 86 Tsuboi, K., 91, 94 Tsubura, A., 14, 17, 29 Tsujita-Kyutoku, M., 14, 17, 29 Tsukamoto, S., 210, 211, 214, 220 Tsurudome, Y., 210, 211, 214, 220 Tsuruma, K., 76, 85, 86 Tsushida, T., 134, 136, 144, 146 Tu, P., 153, 167 Turgeon, D K., 164, 173 Turkson, J., 180, 191 Turner, S D., 25, 32 Tushar, 88, 93 Tutsch, K., 15, 16, 30 Tutsch, K D., 15, 29 Tyler, V., 9, 26 Tzeng, S C., 176, 189 Tzeng, T -F., 88, 93 U Uddin, S J., 133, 136, 146 Uedo, N., 19, 22, 23, 31 Uhle, S., 156, 169 Ukiya, M., 137, 146 Ulivi, P., 21, 32 Uma, N U., 34, 52 Umar, S., 178, 190 Umeda, D., 210, 220 Umehara, H., 14, 28 Umigai, N., 76, 85, 86 Ummersen, L V., 15, 16, 30 Unchern, S., 153, 167 Urusova, D V., 205, 217 Ushio-Fukai, M., 176, 179, 185, 189 V Vacirca, J., 157, 169 Vadlapatla, R K., 185, 192 Vafaei, A A., 73, 84 Vaiana, N., 205, 217 Vaid, M., 211, 220 Vainio, H., 176, 188 Vali, S., 180, 191 Valins, W., 9, 26 Author Index van Beilen, J B., 9, 11, 27 van der Werf, M., 11, 28 van Staden, J., 97, 101, 124 Van Veldhuizen, P., 62, 70, 71, 81 Van Way, C W III., 76, 85 Vande Woude, G F., 209, 219 Vandevelde, M., 155, 168 Vandresen, F., 22, 23, 32 Vannini, I., 21, 32 Vareed, S., 164, 165, 173 Varghese, C D., 60, 62, 66, 77, 80, 82 Varier, R A., 158, 170 Vas, A J., 132, 144 Vasaturo, M., 133, 145 Vasconcelos, M H., 136, 145 Vassallo, A., 133, 145 Vavilala, D T., 185, 192 Vedejs, E., 12, 16, 20, 28, 30 Veena, M S., 165, 173 Venza, I., 154, 168 Vereczkey, L., 199, 215 Vernon, K., 76, 85 Vidal-Puig, A., 141, 147 Vidjaya Letchoumy, P., 141, 147 Vidya Priyadarsini, R., 135, 138, 141, 145, 147 Vieira, P C., 136, 145 Vigushin, D., 16, 19, 30 Vigushin, D M., 16, 18, 19, 24, 26, 30 Vining, D R., 204, 214, 217 Vinothini, G., 141, 147 Vittal, R., 209, 219 Vlamis-Gardikas, A., 162, 172 Vo, D D., 177, 189 Vogelstein, B., 178, 190 Volinsky, N., 140, 147 von Schweinitz, D., 211, 220 W Wadler, S., 15, 30 Waer, A., 21, 32 Wagner, J E., 14, 18, 29 Wahab, S I A., 88, 93 Wahamaki, A., 15, 29 Wahid, F., 150, 166 Wakimoto, N., 176, 178, 188 Waldman, T., 178, 190 Waldron, R., 156, 169 Wallis, D A., 59, 79 249 Wan, H S., 156, 169 Wan, S B., 156, 169 Wang, B., 176, 178, 182, 188 Wang, B H., 71, 84 Wang, B L., 164, 173 Wang, C C., 88, 92, 186, 192 Wang, C J., 59, 67, 69, 71, 72, 77, 78, 79, 80, 82–84, 86 Wang, C T., 34, 52 Wang, C Z., 63, 81, 97, 122, 124 Wang, D H., 180, 191 Wang, F., 36, 54, 70, 83 Wang, H., 184, 192, 196–198, 200, 201, 212, 215, 220 Wang, H M., 185, 192 Wang, J., 6, 6, 89, 94, 164, 173 Wang, J N., 74, 85 Wang, L., 156, 169 Wang, L S., 142, 147 Wang, L X., 98, 103, 115, 127 Wang, Q., 64, 70, 81, 178, 186, 189 Wang, Q L., 70, 83 Wang, R C., 14, 29 Wang, S F., 34, 50, 53 Wang, T., 176–178, 187, 189, 191, 193 Wang, W., 98, 105, 108, 110, 128, 153, 167 Wang, X., 98, 103, 111, 127, 160, 171, 176, 177, 184, 189, 192, 196–198, 201, 215 Wang, X H., 187, 193 Wang, X M., 50, 56 Wang, Y., 71, 84, 98, 100, 112, 125, 204, 207, 211, 217 Wang, Y J., 212, 221 Wang, Y S., 185, 192 Wang, Y Y., 176, 189 Wang, Z., 209, 219 Waqas, M., 176, 179, 185, 189 Warneke, J A., 16, 30 Warner, N., 140, 147 Warren, D., 15, 16, 30 Watabe, M., 14, 29 Watanabe, K., 139, 146 Watson, J., 6, 6, 203, 216 Wattenberg, L W., 19, 31 Way, T D., 212, 221 Webb, L J., 151, 167 Wei, C., 203, 216 Wei, G., 136, 145 Wei, L H., 184, 192 250 Wei, R., 136, 145 Wei, Y., 176, 177, 179, 185, 189 Wei, Y Q., 178, 185, 187, 190, 192, 193 Wei, Z H., 35, 42, 54 Weiderpass, E., 176, 188 Weinberg, R A., 136, 139, 146, 177, 184, 189 Weiner, L M., 15, 16, 29 Weinstein, I B., 209, 213, 219 Wen, H., 164, 173 Wen, J., 185, 192 Wen, J L., 187, 193 Wen, N., 70, 77, 83 Weng, C J., 34–36, 45, 48, 52–54, 56 Weng, X Y., 98, 100, 112, 125 Wenham, R., 134, 136, 144 Werb, Z., 139, 147, 157, 169 Whang-Peng, J., 183, 192 White, M K., 161, 171 Wiechec, E., 20, 31 Wilding, G., 15, 16, 29, 30 Willett, S L., 67, 82 Williams, J., 178, 190 Williamson, G., 196, 197, 215 Wilson, C L., 157, 169 Wing, G., 9, 26 Wink, M., 63, 69, 71, 80, 81 Winnik, B., 199, 215 Winterstein, E., 59, 79 Wisutsitthiwong, C., 142, 147 Witholt, B., 9, 11, 27 Wolf, I., 176, 178, 188 Wong, J., 154, 168 Wong, V K., 98, 101, 113, 126 Wong, Y Y., 88, 92 Woo, M S., 157, 169 Wrobel, M J., 136, 145 Wu, D C., 182, 191 Wu, G S., 34, 45, 53 Wu, L C., 159, 170 Wu, N., 98, 104, 121, 127 Wu, T S., 43, 44, 46, 55 Wu, X., 159, 170, 187, 193 Wu, X H., 68, 83 Wu, Y F., 178, 187, 191, 193 Wu, Y Y., 21, 22, 24, 32 X Xi, G P., 21, 23, 32 Xi, L., 66, 70, 71, 77, 82–84 Author Index Xia, C., 151, 167 Xia, X X., 35, 42, 54 Xian, M., 90, 94 Xiang, M., 70, 83 Xiao, H., 200, 203, 213, 215, 216 Xie, D., 176, 177, 189 Xie, J H., 19, 20, 22, 23, 31 Xie, J T., 63, 81 Xie, X J., 185, 192 Xie, Z., 159, 170 Xiong, Y., 134, 136, 144 Xu, C., 204, 216 Xu, F F., 142, 147 Xu, G., 73, 85, 151, 167, 177, 189 Xu, J W., 35, 37, 41–43, 54, 55 Xu, K., 121, 129 Xu, L., 74, 85, 204, 214, 217 Xu, M Y., 98, 101, 107, 113, 114, 126, 129 Xu, Q., 156, 160, 169, 171 Xu, W., 162, 172 Xu, X., 98, 100, 112, 125 Xu, X L., 178, 187, 191, 193 Xu, X M., 67, 82 Xu, Y., 89, 94, 176, 177, 189, 203, 216 Xu, Y N., 35, 41, 42, 54, 55 Xu, Z X., 98, 99, 110, 113, 124 Xue, G., 98, 100, 114, 125 Xue, Y., 159, 170 Y Yadav, N., 132, 133, 138, 144, 146 Yadav, V R., 135, 141, 145, 147 Yamada, K., 205, 210, 212, 217, 220, 221 Yamaguchi, H., 153, 167 Yamaguchi, K., 213, 221 Yamaji, R., 207, 218 Yamamoto, H., 14, 28 Yamauchi, M., 76, 86 Yan, L., 75, 85 Yan, R., 163, 172 Yan, S., 142, 147 Yan, Y., 136, 146 Yang, B., 156, 169 Yang, C S., 154, 167, 196–201, 203, 204, 206, 212, 214, 215–218, 220 Yang, F., 142, 147, 178, 190 Yang, F C., 45, 56 Yang, G., 200, 201, 206, 214, 216 Yang, G L., 178, 185, 187, 191–193 251 Author Index Yang, G Y., 203, 209, 214, 216, 219 Yang, H., 156, 169 Yang, H L., 43, 45, 55 Yang, H S., 178, 190 Yang, J., 151, 167 Yang, J C., 6, Yang, L., 64, 70, 71, 75, 81, 84, 85, 206, 218 Yang, L N., 75, 85 Yang, L Q., 98, 103, 119, 127 Yang, R., 71, 76, 84, 85 Yang, R H., 75, 85 Yang, S., 176, 177, 189 Yang, S F., 184, 192 Yang, W., 153, 167 Yang, X., 13, 17, 28, 207, 218 Yang, Y., 75, 85 Yang, Y M., 21, 23, 32 Yang, Z., 196–198, 200, 201, 215 Yano, H., 19, 22, 23, 31 Yano, S., 210, 220 Yao, C J., 183, 192 Yasuda, Y., 209, 219 Yasukawa, K., 139, 146 Ye, H., 176, 177, 189 Ye, K., 176, 179, 185, 189 Ye, M., 153, 167 Ye, Y., 98, 106, 114, 128 Yeap, S K., 88, 90, 93, 94 Yeasmin, T., 88, 93 Yeel, H C , 88, 93 Yeganeh, B., 20, 31 Yeh, C T., 183, 192 Yelekc,i, K., 158, 170 Yen, G C., 34, 35, 43, 44, 52 Yen, S H., 185, 192 Yeo, H S., 161, 163, 164, 171, 172 Yeo, M., 182, 192 Yeslow, G., 15, 16, 29 Yi, F F., 75, 85 Yi, J., 6, Yi, J S., 98, 104, 112, 128 Yi, T., 91, 94 Yi, Y C., 186, 192 Yin, R., 176, 179, 185, 189 Yin, X H., 178, 191 Yin, Y., 98, 100, 112, 125 Yob, N J., 88, 92 Yodkeeree, S., 90, 94 Yoon, J C., 211, 220 Yoon, J H., 98, 102, 104, 114, 126, 127 Yoon, K., 9, 11, 18, 25, 27 Yoon, W J., 19, 31 Yoshida, H., 159, 170 Yoshioka, K., 176, 178, 189 You, B J., 35, 41, 42, 54, 55 You, H., 198, 203, 209, 214, 215 You, Y O., 157, 169, 170 Youn, U J., 178, 180, 183, 184, 190 Young, A., 178, 190 Young, C Y., 14, 29 Young, R A., 182, 191 Yu, C., 180, 191, 212, 221 Yu, C C., 205, 217 Yu, J., 159, 170, 178, 190, 204, 214, 217 Yu, J S., 98, 106, 111, 128 Yu, L H., 19, 20, 22, 23, 31 Yu, L J., 98, 100, 112, 125 Yu, W., 73, 85 Yu, W C., 154, 168 Yu, Y S., 34, 35, 43, 44, 52 Yuan, C S., 97, 122, 124 Yuan, M., 160, 171 Yue, Q X., 34, 45, 46, 52, 56 Yun, T K., 123, 130 Yuri, T., 14, 17, 29 Yurkow, E J., 203, 216 Z Zafar, R., 88, 93 Zahra, B S., 71, 84 Zain, Z N., 90, 94 Zakaria, Z A., 88, 92 Zang, C., 178, 182, 183, 190 Zarei Jaliani, H., 68, 83 Zavodszky, M I., 154, 168 Zeenathul, N A., 90, 94 Zeki, A A., 20, 31 Zent, C S., 201, 216 Zetter, B R., 90, 94 Zhai, D., 204, 217 Zhai, H., 176, 188 Zhan, L B., 19, 20, 22, 23, 31 Zhan, W H., 209, 219 Zhang, C., 98, 103, 111, 127 Zhang, C L., 67, 82 Zhang, F., 154, 159, 168, 170 252 Zhang, H., 67, 82, 209, 219 Zhang, H Y., 180, 191 Zhang, J., 98, 105, 119, 128, 132, 137, 145, 146 Zhang, L., 21, 22, 24, 32, 120, 129 Zhang, L H., 98, 105, 128 Zhang, M., 21, 23, 32 Zhang, M Z., 98, 103, 115, 127 Zhang, Q., 180, 191 Zhang, T., 98, 107, 114, 129 Zhang, W., 35, 42, 53 Zhang, W X., 41, 55 Zhang, X., 180, 191, 209, 219 Zhang, X X., 176, 189 Zhang, X Y., 187, 193 Zhang, Y., 98, 100, 112, 125, 142, 147, 178, 190 Zhang, Z., 122, 129 Zhao, B H., 75, 85 Zhao, C., 176, 189 Zhao, H., 89, 94 Zhao, H T., 163, 172 Zhao, P., 68, 83 Zhao, Q., 98, 105, 117, 118, 128, 204, 217 Zhao, W., 35, 37, 41, 42, 54, 55 Zhao, X., 176, 178, 179, 185, 187, 189, 190, 192, 193 Zheng, D., 204, 205, 209, 217 Zheng, H., 187, 193 Zheng, R X., 142, 147 Zheng, S., 70, 77, 83, 178, 187, 191, 193 Zheng, X., 75, 76, 85 Author Index Zheng, X L., 64, 70, 81 Zheng, Y Q., 74, 85 Zhong, J J., 34–37, 41, 42, 45–47, 53–56 Zhong, L., 13, 17, 28 Zhong, Q., 178, 190 Zhong, Y J., 64, 70, 81 Zhong, Z H., 178, 191 Zhou, C H., 70, 75, 83, 85 Zhou, J F., 158, 170 Zhou, J N., 200, 211, 214, 215 Zhou, K., 154, 167 Zhou, M., 178, 190 Zhou, Z., 156, 169 Zhu, B H., 209, 219 Zhu, F., 205, 217 Zhu, H., 142, 147 Zhu, H S., 45, 55 Zhu, L X., 154, 168 Zhu, M., 34, 52 Zhu, W., 176, 177, 189 Zhu, X., 98, 106, 129 Zhu, X Y., 21, 22, 24, 32 Zick, S., 88, 93 Zoli, W., 21, 32 Zon, L I., 182, 191 Zou, C., 69, 83 Zou, Z., 151, 167 Zsila, F., 67, 82 Zu, X., 163, 172 Zucker, S., 157, 169 Zuraini, A., 88, 93 Zykova, T A., 205, 217 SUBJECT INDEX Note: Page numbers followed by “f ” indicate figures and “t ” indicate tables A Absorption, distribution, metabolism, and excretion (ADME), 187 Aesculus pavia, 121–122 Aldose reductase (AR), 163 Angiogenesis Astragalus saponins, 115 definition, 115 Pulsatilla saponin D (SB365), 115, 116 Rg3, 115–116 senegasaponins, 116 Anticancer effects antiangiogenic effect, 179 apoptosis induction, 178–179 cell-cycle arrest, 178 tumor cell migration and invasion, 179–180 Anti-inflammatory effects β-escin, 117 Ds-echinoside A, 118 ginsenoside Rg3, 117 NF-κB and STAT3 pathways, 117 Apoptosis avicin D, 110–111 extrinsic death receptor-mediated pathway, 110 ginsenosides Rh2, 112 intrinsic mitochondria-mediated pathway, 110 platycodin D, 110–111 programmed cell death, 110 Rg3, 111–112 tubeimoside-1, 112–113 Autophagy Akebia saponin PA, 113 avicin D, 113 caspase-independent autophagic cell death, 113 cell survival promotion, 113 cucurbitacin-B/I, 114 cytoprotective mechanism, 113 definition, 113 Jujuboside B, 113–114 Saikosaponin-D, 113 Azadirachta indica A Juss See Neem limonoids Azadirachtin anticancer effects, 134t anti-inflammatory effects, 137f, 139 antioxidant activity, 137f, 140 apoptosis induction, 137f, 138 cell proliferation inhibition, 136–138, 137f cytotoxic effects, 133–136 seed kernels, 132–133 structure of, 132–133, 133f B Beta-catenin (β-catenin), 182–183 Black tea, 196 C CDK inhibitor See Cyclin-dependent kinase (CDK) inhibitor Cellular sarcoma (c-Src), 161 COX See Cyclooxygenases (COX) Curcumin aldose reductase, 163 Ca2+-ATPase sarcoplasmic reticulum, 156 chemical structure, 152–153, 152f clinical trials, 150, 164–165 cost and effectiveness, 151 COX enzymes, 154–155 cytochrome P450 isozymes, 151–152 dietary supplement, 150 DNA methyltransferases 1, 158–159 DNA polymerase λ, 159 glyoxalase I, 160 HAT and HDAC, 157–158 lipoxygenase, 154 MMP, 157 NADPH, 163–164 253 254 Curcumin (Continued ) phase I and II carcinogen-detoxifying enzymes, 151–152 PK (see Protein kinases (PK)) proteasome, 155–156 ribonucleases, 159–160 treatment, 150 TrxR1, 162–163 xanthine oxidase, 155 Cyclin-dependent kinase (CDK) inhibitor, 108–109 Cyclooxygenases (COX) curcumin, 154–155 Honokiol, 186–187 D Deacetylgedunin, 132–133, 133f Deacetylnimbin, 132–133, 133f D-Limonene See Limonene E EGCG See (–)-Epigallocatechin-3-gallate (EGCG) Enzymes modulation, curcumin, 153f Ca2+-ATPase sarcoplasmic reticulum, 156 COX enzymes, 154–155 cytochrome P450 isozymes, 151–152 DNA methyltransferases 1, 158–159 DNA polymerase λ, 159 glyoxalase I, 160 HAT and HDAC, 157–158 lipoxygenase, 154 MMP, 157 phase I and II carcinogen-detoxifying enzymes, 151–152 proteasome, 155–156 ribonucleases, 159–160 xanthine oxidase, 155 (–)-Epicatechin (EC) bioavailability, 198–199 structures, 197f (–)-Epicatechin-3-gallate (ECG) structures, 196, 197f systemic bioavailability, 200 Epidermal growth factor receptor (EGFR), 184–185 (–)-Epigallocatechin (EGC) Subject Index plasma concentrations, 198–199 structures, 197f (–)-Epigallocatechin-3-gallate (EGCG) biotransformations, 199 enzyme activity, inhibition of, 206–207 high-affinity binding proteins, 204–206 human studies, 201 lipids binding, 212–213 67LR, 210–211 lung tumorigenesis, 200–201 microRNAs, 211–212 nucleic acids binding, 213 p53-dependent events, 212 plasma levels, 198–199 PubMed search, 196–197 small intestinal tumorigenesis, 200 SOD, 198 structures, 197f in vivo vs in vitro effective concentrations, 213–214 Wnt signaling, 211 Epithelial-to-mesenchymal (EMT) phenotype, 179–180 Epoxyazadiradione anti-inflammatory effects, 137f, 139 structure of, 132–133 G Ganoderic acid antiasthma, 49–50 antihepatitis B activity, 50 anti-inflammatory effect, 49 anti-invasive effect, 45–48 antiosteoclastogenesis, 49 autophagy, 48–49 biosynthesis of, 35–36 cell cycle arrest, 45 chemical structures, 36, 38f cytotoxic and apoptotic effects, 43–45, 46t fermentation process, 41–43, 42t mushroom fruiting cap, 35–36 pharmacokinetics of, 50–51 Gedunin anticancer effects, 134t antioxidant activity, 137f, 140 antiproliferative effects, 133–136 apoptosis induction, 137f, 138 cell proliferation inhibition, 136–138, 137f 255 Subject Index immunomodulatory effects, 137f, 139–140 neem seeds, 132–133 structure of, 132–133, 133f Glycogen synthase kinase-3β (GSK-3β), 141, 151, 161–162, 182–183 Glyoxalases (Glo1 and Glo2), 151, 160 Green tea, 196, 197–199, 200, 201, 204, 209 H Histone acetyltransferases (HAT), 157–158 Histone deacetylases (HDAC), 157–158 Honokiol ADME, 187 anticancer effects antiangiogenic effect, 179 apoptosis induction, 178–179 cell-cycle arrest, 178 tumor cell migration and invasion, 179–180 beagle dogs’, 187 biological properties, 176 30 ,5-diallyl-2,40 -dihydroxy-[1,10 -biphenyl]-3,5-dicarbaldehyde, 177 30 ,5-diformylhonokiol, 177, 177f 30 -formylhonokiol, 177, 177f 5-formylhonokiol, 177, 177f Magnolia, 176 molecular targets β-catenin, 182–183 cancer development and progression, 180, 181f COX enzymes, 186–187 EGFR, 184–185 HIFs, 185–186 NFAB, 182 PI3K/Akt/mTOR signaling pathway, 183–184 STAT, 180–182 VEGFR, 185 para-allyl-phenol and ortho-allyl-phenol groups, 177, 177f PEGylated liposomal honokiol, 187–188 Sprague-Dawley rats, 187 Wistar rats, 187 Human umbilical vein endothelial cells (HUVEC), 75, 76, 116 Hypoxia-inducible factors (HIFs), 185–186 K 67 kDa laminin receptor (67LR), 210–211 L Limonene aerobic degradation tests, 10 anticancer activity and clinical trials, 18–19 biosafety and adverse effects, 24–25 biotransformation pathway, 10–11, 11f gastric cancer, 22 hepato-carcinogenesis, 21–22 industrial use of, 10 isoprenylation, 20–21 metabolites of, 10–11 nitric oxide (NO) production, 22 pharmacokinetics, 16–18 preclinical studies, 22, 23t Ras-ERK signaling pathway, 22 structural formula, 9–10, 10f VEGF inhibition, 22 Limonoids See Neem limonoids Lipoxygenase (LOX), 151, 154 Lucidenic acid antiasthma, 49–50 antihepatitis B activity, 50 anti-inflammatory effect, 49 anti-invasive effect, 45–48 antiosteoclastogenesis, 49 autophagy, 48–49 biosynthesis of, 35–36 cell cycle arrest, 45 chemical structures, 36, 37f cytotoxic and apoptotic effects, 43–45, 46t sources of, 35–36 Lung tumorigenesis, 200–201 M Mahmoodin limonoids, 132–133, 133f Mammalian target of rapamycin (mTOR), 183–184 Matrix metalloproteinases (MMP) cancer cell invasion and metastasis, 157, 206–207 cell proliferation, 157 degrading extracellular matrix proteins, 157 256 Subject Index Matrix metalloproteinases (MMP) (Continued ) differentiation and angiogenesis, 157 extracellular matrix processing, 139 MMP-2 and MMP-9, 179–180 proangiogenic factors, 139 zinc-dependent endopeptidases, 157 MicroRNAs location, 120–121 noncoding small RNA molecules, 120–121 target genes, 120–121 tea catechins, 211–212 upregulation and downregulation, 120–121 myriad cancer cell lines, 136 structure of, 132–133, 133f tumor invasion and angiogenesis, 137f, 139 Nuclear factor kappa B (NFκB), 91, 182 N Perillyl alcohol (POH) antitumor effects, 12–13, 13f biosafety and adverse effects, 15–16, 17t chemical structure, 8–9, 9f cholesterol biosynthesis, 12–13 c-Jun and c-fos, 14–15 cyclin D1 gene expression, 14–15 farnesylation, 12–13 HMG-CoA conversion, 12–13 Mek-extracellular signal-regulated kinase, 12–13 preclinical studies, summary of, 15–16, 17t RAPTOR protein complex, 14–15 Ras-independent pathway, 12–13 TGF-β signal transduction pathway, 12 Pharmacological effects angiogenesis, 115–116 anti-inflammatory effects, 117–118 antioxidative effects, 118 apoptosis (see Apoptosis) astragaloside IV, 108–109 autophagy, 113–114 β-escin, 108–109 CSC inhibition, 119–120 echinoside A, 108–109 ginsenosides Rh2 and Rg3, 109–110 inhibiting cellular proliferation, 98–108 invasion and metastasis attenuation, 114–115 miRNA modulation, 120–121 multidrug resistance, 118–119 Natural products phytochemicals, plants and microbes, Neem limonoids anticancer effects, 132–133, 134t anti-inflammatory effects, 137f, 139 antioxidant activity, 137f, 140 apoptosis induction, 137f, 138 cell proliferation inhibition, 136–138, 137f cytotoxic effects, 133–136 definition, 132 drugs discovery and development, 132 features, 132 immunomodulatory effects, 137f, 139–140 JAK/STAT signaling pathways, 142 MAPK/ERK signaling pathways, 142 NF-κB signaling pathways, 140–141 PI3/Akt signaling pathways, 141–142 structure of, 132–133, 133f tumor invasion and angiogenesis, 137f, 139 Wnt/β-catenin signaling pathways, 141 Nimbin, 132–133, 133f Nimbolide anticancer effects, 134t antioxidant activity, 137f, 140 apoptosis induction, 137f, 138 cell proliferation inhibition, 136–138, 137f O Oncogenic signaling pathways JAK/STAT signaling, 142 MAPK/ERK signaling, 142 NF-κB signaling, 140–141 PI3/Akt signaling, 141–142 Wnt/β-catenin signaling, 141 Oxidative stress, 140 P 257 Subject Index protopanaxadiol and 20(S)-25methoxyldammarane-3β,12, 20-triol, 110 in vitro and in vivo studies, 98, 99t Phosphoinositide 3-kinases (PI3Ks), 141–142, 183–184 Phytochemicals carcinogenesis process, 2, 5f chemoprevention and anticancer property, family and chemical structure, 2, 3t ROS production, 5–6 Placental growth factor (PlGF), 139 Polyethylene glycol-coated (PEGylated) liposomal honokiol, 187–188 Prostate carcinogenesis, 201 Protein kinases (PK), 153f cellular sarcoma (c-Src), 161 ErbB2, 162 GSK-3β, 161–162 PKA, PKB, and PKC, 160–161 Protein reductases, 153f aldose reductase, 163 TrxR1, 162–163 Pulsatilla chinensis, 121 Pulsatilla koreana, 121 R Radix astragli, 97 Radix et Rhizoma Ginseng, 97 Radix et rhizoma glycyrrhizae, 97 Reactive oxygen species (ROS), 197–198, 202–203, 204 Receptor tyrosine kinases (RTKs), 207–210 ROS See Reactive oxygen species (ROS) RTKs See Receptor tyrosine kinases (RTKs) S Saffron carotenoids AMP-activated protein kinase (AMPK), 71 anticancer effect crocetin, 59, 66f α-crocin, 59–60 mechanisms, 59, 66f provitamin A activity, 60 SEE, 59–60 Bax expression, 70–71 bladder carcinoma T24 cell, 68 caspases activity, 69 chemoprevention, 71–72 crocetin vs crocin gastrointestinal (GI) tract, 64 HeLa cells inhibition, 62 NMU-induced breast cancer, 60–62 DNA, RNA, and protein synthesis, 66–67 HCT-116 colorectal cancer cells, 71 κB-kinaseβ activation, 71 liposome formulation, 64–65 metalloproteinases (MMPs) overexpression, 70 prostate cancer cell, 68–69 protein binding, 67–68 telomerase, HepG2, 69 TPA supression, 69 Saffron ethanolic extract (SEE), 59–60 Salannin, 132–133, 133f Signal transducers and activators of transcription (STATs), 140, 142, 180–182 Small intestinal tumorigenesis, 200 STATs See Signal transducers and activators of transcription (STATs) Superoxide dismutase (SOD), 198 T Tea catechins animal vs human studies, 202 bioavailability, 198–199 biotransformations, 199 chemistry, 197–198 digestive tract tumorigenesis, 200 enzyme activity, inhibition of, 206–207 epigenetic DNA methylation, 211 histone modification, 211 human studies, 201–202 lipids binding, 212–213 67LR, 210–211 lung tumorigenesis, 200–201 microRNAs, 211–212 nucleic acids binding, 213 p53-dependent events, 212 prostate carcinogenesis, 201 ROS production, 202–203, 204 RTKs, 207–210 258 Tea catechins (Continued ) in vivo vs in vitro effective concentrations, 213–214 Wnt signaling, 211 Thioredoxin reductase (TrxR1), 162–163 TNF-related apoptosis-inducing ligand (TRAIL), 111–112, 119, 138 4,4,8-trimethyl-17 furanyl steroid, 132 Triterpenoids fermentation, 34–35 ganoderic acid (see Ganoderic acid) lucidenic acid (see Lucidenic acid) pharmacological properties, 34–35 saponins biosynthesis, 96 clinical study, 122–123 cytotoxicity, 98, 99t Dammarane-type saponins, 122 distribution, 96–97 oleanane-type saponins and lupanetype saponins, 121 pharmacological effects (see Pharmacological effects) platycodon saponins and prosapogenins, 121–122 sources, 97–98 types, 96–97, 97f in vitro and in vivo studies, 98, 99t Subject Index U Ubiquitin proteasome system (UPS), 155–156 V Vascular endothelial growth factor receptor (VEGFR), 185 W Wnt/β-catenin signaling pathway, 109–110, 211 X Xanthine oxidase (XO), 155 Z Zerumbone angiogenesis, 90–91 Bcl-2 protein, downregulation of, 89 caspase-3, cellular level of, 89 c-FLIP, downregulation of, 90 characteristic feature, 89 cyclin B1/CDK1, 90 G2/M cell cycle, 90 invasion, 90 nuclear factor-Kappa B, 91 tumor necrosis factor, 90 ... Neuro-2A cells [36] Incubation of these cells with POH showed that it suppressed DNA synthesis [36] The histologic evaluation of the sites that induced regression of tumor growth by the application... and Fuyuhiko Tamanoi methods, the main goal is the efficient absorption of the effective ingredient(s) in the body Nowadays, targeted therapy or molecularly targeted therapy, especially in cancer... regard, scientists try to use the more effective ingredient of the herbals, instead of the crude extract to achieve the more powerful therapy with no or minimum side effect Therefore, fractionation,