Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective Rajesh Arora
INDEX
A
Acid phosphatases activity 418
Activation enzymes 269
Adhatoda vasica 57
Adipokines in cancer 133
Adoptogenic and antistress properties 612
Adrenal cortical cancer 261
Aegle marmelos 57, 389, 396
AKT expression 317
Alkylglycerols 460
Allium sativum 57
Allyl isothiocyanate (AITC) 270
Aloe vera 58
Amaranthus 409, 413, 418
AMEL 396
radiation-induced DNA clastogenesis 400
radiation-induced gastrointestinal damage 396
radiation-induced hematological damage 397
Amifostine 391
Andrographis paniculata 58
Angiogenesis and metastasis 502
skin tumors 502
tea 502
Animal studies 283
Annato 187
chemopreventive agent 187
mutation-related diseases 187
natural and healthy food colorant 187
prevention 187
Anticancer activity 559, 618
dietary polyphenol 559
quercetin 559
Anticancer alkaloids 292
Catharanthus roseus 292
transition from traditional to modern medicine 292
Anticancer properties of phytosterols 279
Anticarcinogenic activity 173
Antigenotoxic activity 173
Anti-inflammatory action 24
Anti-inflammatory activity 398, 610
Anti-inflammatory effects of tea 496
Antilipid peroxidative activity 609
Antimicrobial activities 401, 611, 619
Antimutagenic activity of catechins 169
Antioxidant action 9
free radical scavenging properties 495
resveratrol 212
tea catechins 165
Antioxidant enzymes 399, 610
Antioxidant system 351
Antiplatelet aggregation 213
Antitumor in vivo activity of lace 91
Apigenin 246
health and disease 246
human diseases 252
human health 251
human malignancies 255
natural sources 246
role in cancer chemoprevention 252
structure and properties 248
Apigenin 249
Ayurveda 513, 600
Ayurvedic rasayana drug triphala 599
Azadirachta indica 59
B
Bael 394
Basal cell carcinoma 487
Bcl-2 expression 316
Benzyl isothiocyanate 271
Beta-carotene 408, 412, 444
Beta-cryptoxanthin 147
Bioactive dietary components 110
Bioactive food components 589
Bioactive phytochemicals isolated from PC-SPES 544
Blocking and suppressing agents 7
Botanical classification 293
Brassica campestris 59
Breast cancer 114, 255, 284
Broccoli 482
C
Caffeic acid phenethyl ester (CAPE) 323
Caffeine 481
Calendula extract 79, 82, 89
Calendula officinalis 81
Cancer
medicinal plants 150
oranges 147
radiotherapy 364
therapy vs cancer chemoprevention 4
uterus 71
Cancer cells 577
Carcinogen metabolism 591
Carcinogenesis 214
Carotenoids 410, 444
Catharanthus alkaloids 294
anticancer arsenal 294
clinical use 297
Catharanthus roseus 293
cancer patients 293
multifarious activities 292
Cell cycle
analysis 85
apoptosis 217
effects 285
progression 498
quercetin 566
Cell killing 579
genistein 579
soy isoflavones 579
Cell signaling 590
Central nervous system 623
Cervical cancer 256
Chemical adulterants 545
Chemical analyzes 189
Chemical radioprotection 391
Chemicals 98, 365
Chemistry 494
Chemoprevention 47
Cholesterol metabolism 288
Citrus and crataegus extract 99
Citrus aurantium and Crataegus microphylla extracts 98
Citrus extract on GSH content in mice liver 101
Classical small molecules 521
Colon cancer 256, 283
Colon carcinogenesis prevention 147
Combining drugs with radiation therapy 334
Concurrent paclitaxel and radiotherapy lung cancer 333
COX-2 expression 316
Culture 294
Cuminum cyminum 60
Curcuma longa 143, 523
Curcumin 116, 135, 321323, 480
apoptosis in cancer cells 144
DNA damage 144
enzyme 144
free radicals 144
Cytokines 354
Cytopathology, isoflavones and BCa risk 236
Cytotoxic activity on tumor cells 83
Cytotoxic agents derived from plants 79
Cytotoxic T cells in skin tumors 501
Cytotoxicity and apoptosis 604
D
Data extraction 156
Delta-tocotrienol 429
chemoprevention 429
radioprotection 429
Dermal immune system 500
DES-free PC-SPES 549
Detoxification enzymes 270
Dietary agents 9
Dietary and nutritional profile 127
Dietary carotenoids-lycopene 117
Dietary compounds 578
Dietary flavonoids 478
Dietary intake of apigenin 248
Dietary modulation 588
Dietary phytosterols and cancer 282
Dietary regimens and chemoprevention efficacy 129
DNA damage 352, 611
damage 518
repair 401, 518
UV radiation 489
Drug bioavailability by polyphenols 324
Drug combinations 109
Drug-metabolizing enzymes 288
Drug-nutrient combinations 109
E
EGFR expression 317
Emblica officinalis 60
Emodin 321
Endometrial cancer 261
Enzymes 496
Extraction vis-à-vis demonstration of anti-CaP activities 543
F
Fat layers of skin 500
Flavanone content 99
Flavonoids 448
botanic sources 480
radiation 450
Flavopiridol 321, 323
Flaxseed (Linum usitatissimum) 380
Flaxseed oil 377
Food combinations 108
Free radical scavenging activity 99, 608, 627, 398
Free radicals 46
initiation 46
oxidative stress 46
promotion 47
Fruit and vegetable consumption 153
G
G1 phase arrest 566
Gamma tocotrienol 426
chemoprevention and AFRRI studies 426
lipid peroxidation and reactive nitrogen species 428
radioprotection 428
GAP junction intercellular communication 219
Gastric cancer 261
Gastrointestinal system 624
Genistein 319, 322
Ginger 324, 481
GINSAN 351
chemotherapy 355
immunomodulatory polysaccharide 350
radioprotector 351
Ginseng 458
Glioma 210, 217
chemoprevention 218
classification 217
epidemiology 217
Glutathione 383
Gonadal system protection 624
Green tea 322
catechin 115, 117
polyphenols 166, 318
radiotherapy 175
UV-induced immunosuppression 500
Growth conditions 294
GSH level 100
H
Hard and cancerous swellings of liver 70
Harnessing medicinal plants 56
Hematologic cancer 257
Hematopoiesis 353
Hemopoietic system protection 623
Hepatic system 625
Herbal drugs for oncology 3
Herbal formulation 536
functional hypothesis 536
PC-SPES 538
Herbal medicines 423
Herbs 423
Homologous repair 518
Hormonal effects 287
Hormonal regulation 589
Hot swellings 70
HPLC analysis 99
Human studies 503
Human trials 179
I
Ibn sina (Avicenna, 9801037
AD) 70
Immune function 287
Immunomodulatory activity 401, 612
Individual herbs of PC-SPES 544
Insulin resistance and carcinogenesis 132
Ionizing radiation and reactive oxygen species 424
Isoflavones 230
animal studies 232
BCa chemoprevention 230
breast cancer chemoprevention 229
breast density and BCa risk 237
epidemiological studies 231
human clinical trials 234
Isothiocyanates 268
K
Key transcription factors 498
L
LACE activity 85
Lactoferrin 151
Laser-activated calendula extract (LACE) 82
Lawsonia inermis 60
Light 294
Lignans 379
Lipid peroxidation 399
Lipid peroxides 383
Liver cancer 261
Lung cancer 258
Lutein and zeaxanthin 446
Lycopene or rhodopurpurin 445
M
Marker enzymes 610
MDR protein expression 316
Medicinal plants 57
Medicinally useful plant parts 618
Melanoma 488
Melatonin 452
Mentha piperita 61
Metal chelation activity 398, 626
Methoxyestradiol 135
Mice survival studies 395
Micronucleus assay 99
Mitochondria 27
Mitogen activated protein kinase 28
pathway 563
signaling cascades 28
Modern medicine 294
Moisture 294
Moringa oleifera 61
Mouse lymphocyte subpopulations 89
Multifactorial disease 4
Multiple signaling pathways 314
Multistep carcinogenesis 44
Mutagenesis 497
Mutant p53 protein synthesis 564
N
Natural polyphenols 313
Naturally-occurring chemopreventive compounds 474
Neuroblastoma 261
NF-kappaB pathway 564
NF-κB activation 28, 314
NMSC formation 482
Nobiletin 149
Nonhomologous endjoining 518
Nonmelanoma skin cancer 473
Nonmelanomatous skin cancers 474
Normal tissue protection 432
Nutrigenetics 594
Nutrigenomics 592
Nutritional epigenomics 593
Nutritional interactions for cancer prevention 107
Nutritional proteomics 593
Nutritional transcriptomics 592
O
O. sanctum 429
Obesity 129
Ocimum 62
cancer prevention 432
cancer therapy 433
sanctum 62, 422
OMICS 594
Onion and garlic 117
Ophthalmo carcinoma 71
Orientin and vicenin 431
OS extract 431
Ovarian cancer 258
Oxidative stress and cancer 215
Oxygen 515
P
P. hexandrum 626
p53 in apoptosis by triphala 605
Paclitaxel and radiation therapy 335
Panax ginseng 63
Panax ginseng as a new adjuvant of radio/chemotherapy 348
Panax ginseng: a legendary medicinal herb 349
Pharmacokinetics 176, 273
Phenethyl isothiocyanate 272
Phenol and flavonoid analysis 101
Photocarcinogenesis 495
Photoprotection 492
Phyllanthus urinaria 64
Phytochemical analysis 403
Phytochemical immunomodulators 80
Phytochemicals 545
Phytochemicals in cancer chemoprevention 42
Piperine 324
Plant products 363
Plant products and dietary antioxidants in cancer radiotherapy 366
Plants as radioprotective agents 392
Podophyllum 622
Prostate cancer 258, 284
genistein/soy isoflavones and tumor irradiation 580
herbal formulation 531
radiotherapy 578
soy isoflavones 579
Protective components 109
Protein 385
Putative role of antiobesity agents 29
Q
Quality assessment 155
Quercetin 560
R
Radiation-induced depletion 418
Radiation-induced drug resistance 520
Radiation-induced lipid peroxidation level 418
Radio- and chemotherapy with improved response rate 514
Radiochemoresistance 521
Radiomodulation and chemoprevention 29
Radioprotectors 392
RAS activation inhibitor 26
Reactive oxygen intermediates 314
Renal system 625
Restoration of glutathione 399, 609
Resveratrol 200
S
Safety of drug 402
Safety profile 179
Screening test system 148
Selective estrogen receptor modulators 25
Selenium 453
Serum biochemistry 385
Signal transduction 286
anticancer effects of quercetin 561
effects 286
molecules 497
Silymarin 322
Skin 487
Skin cancer 260, 487
Soy isoflavones 581
Soy protein/geinstein 116
Spirulina fusiformis 64
Squamous cell carcinoma 488
Standardization and quality issues 542
Stat3 expression 317
Statistical analysis 100
Stilbenes 133
Sulforaphane (SFN) 272
Survivin expression 316
T
Taxonomic classification 618
Tea 475, 494
Camellia sinensis 493
leaves 494
photoaging 502
UV carcinogenesis in experimental systems 495
Thyroid cancer 260
Tocopherols and tocotrienols 426
Topoisomerase II inhibitors 26
Toxicity studies 191
Traditional medicine 294
Traditional uses of Bael 394
Transcription factors 216
Treatment modalities 334
Triphala 602
Tumor metastasis 286
Tumor-environment interactions and tumor invasion 219
Tumor-inhibitory phytochemicals 371
Tyrosine kinase pathway 561
U
Ultraviolet and immune system 491
Ultraviolet and photoaging 491
Ultraviolet radiation-induced skin damage 486
Unani physicians 68
Unani system 68
Urtica dioica 65
UV-induced carcinogenesis 490
UV-induced diseases and harmful effects 488
V
Vegetables and fruits as modifiers of cancer risk 128
Vinblastine 297
Vincristine 298
Vindesine 299
Vinflunine 299
Vinorelbine 299
Vitamin C 455
Vitamin E 425, 457
W
Withania somnifera 524
X
Xenobiotic detoxifying enzymes 610
×
Chapter Notes

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1HERBAL MEDICINE: A Cancer Chemopreventive and Therapeutic Perspective2
3HERBAL MEDICINE: A Cancer Chemopreventive and Therapeutic Perspective
Rajesh Arora PhD Scientist Defence Research and Development Service Institute of Nuclear Medicine and Allied Sciences (INMAS) Defence Research and Development Organization (DRDO) New Delhi, India
4Published by
Jitendar P Vij
Jaypee Brothers Medical Publishers (P) Ltd
Corporate Office
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Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
© 2010, Jaypee Brothers Medical Publishers (P) Ltd.
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editor and the publisher.
First Edition: 2010
9788184488418
Typeset at JPBMP typesetting unit
Printed at
5
This book is dedicated with love to
My Dear Grandparents
Late Smt Krishnavati Arora and Shri Sant Ram Arora
6
Om
Swasti prajabhyhah paripaalayantaam nyyayaen maargaen mahim maheeshah
Gobhrahmanebhyah shubhamasthu nityam lokaah samstaah sukhino bhavantu.
May good befall all people. May the sovereign rule the earth, following righteous path.
May all beings ever attain what is good.
May the worlds be prosperous and happy.
Lokaah samastaah sukhino bhavantu
Sarveshaam svastir-bhavatu
Sarvesham shantir-bhavatu
Sarvesham purnam bhavatu
Sarvesham mangalam bhavatu
Om Shanti! Shanti! Shanti!
May all beings in this Universe be happy
May prosperity and welfare be unto all beings
May peace be unto all beings
May plenitude and fullness be unto all beings
May auspiciousness and blessedness be unto all beings
Om Peace! Peace! Peace!
This Ancient Universal Sanskrit Prayer comes as a blessing from a Guru for the prosperity and welfare of the whole of humanity.
May it continue to guide us!
7Contributors
17
FOREWORD
Every year a number of precious human lives are lost due to cancer worldwide. Rapid advances in medical technology have helped decrease the number of deaths for certain forms/stages of cancers, but overall the picture still remains grim. In view of this, it is imperative that new scientific developments in the area be documented so that researchers actively engaged in the field as well as others, including clinicians, students and patients, can stay abreast of the latest state-of-the-art and further advances in prophylaxis and therapy can be made.
Scientific developments have universal application and impact a wider section of society transgressing all global barriers. The availability of information in the form of knowledge is vital for devising and implementing futuristic treatment strategies. It is with this intention in mind that the editor has conceived the present book, bringing together the viewpoints of world-renowned experts.
The currently available therapeutic interventions for cancer treatment viz, surgery, chemotherapy and radiotherapy cause a great deal of discomfort to the cancer patient and, therefore, there is a need to develop alternative modalities so that the quality of life of the cancer patient is not adversely affected during the course of treatment.
The concept of prevention is not new. India has had a strong traditional medicine base in the form of Ayurveda, which dates back to over 5000 years, wherein prevention has been advocated for all time as a better option for healthy life as compared to therapy. In recent years, it has been realized that there are hardly any synthetic drugs available that can prevent the initiation, promotion and progression of cancer in the human body. Herbal drugs offer immense promise in this regard and several herbs have been shown in various laboratories world over to prevent cancer, and possibly even radiation-induced cancer. Consequently, there has been a revival of interest in herbals in recent years, and they are being viewed as potential chemopreventive, radioprotective and therapeutic agents.
It is heartening to learn that Dr Rajesh Arora, who has been working in the important area of development of herbal radioprotectors for both defense and civil applications at the Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi has compiled this state-of-the-art book on cancer chemoprevention and therapy.
I wish the book all success.
W Selvamurthy18
19
FOREWORD
Way back in 1956 a small working group was created in Delhi, India for planning and executing peaceful uses of nuclear energy for health purposes with the tenet Atom for Peace under the leadership of Late Brigadier SK Mazumdar, our founder Director and the Father of Indian Nuclear Medicine. This group evolved into a full-fledged institute–presently known as the Institute of Nuclear Medicine and Allied Sciences (INMAS). Ever since, the institute has been working towards this ideal goal and has made significant contributions in frontline research in the areas of biological radioprotection, cancer biology, molecular imaging, nuclear medicine, radiopharmaceuticals. The focus of the institute presently is on developing radiation countermeasure agents for protection during any contingency. Armed Forces personnel, as well as the civilian population, have benefited immensely from the fruits of R&D being carried out at INMAS and several more useful drugs are likely to emerge in the future.
Cancer today is a global problem and cancer patients undergoing treatment have to endure the pain and side effects that accompany the therapeutic procedures. It is, therefore, imperative that the currently available treatment modalities be improved upon and novel methods of treatment be developed. With a view to improving the current therapeutic modalities, INMAS has developed differential radiosensitizers that can selectively kill the tumor tissue, sparing normal tissues. A plethora of compounds have been developed that can help identify tumors utilizing state-of-the-art imaging modalities available at INMAS. On the other hand, work on radioprotection with herbal drugs, particularly Podophyllum hexandrum, Hippophae rhamnoides, Rhodiola imbricata and Tinospora cordifolia has yielded promising results that may help in protecting normal tissues during radiotherapy, besides rendering protection during nuclear/radiological emergencies (NREs). Evidently, herbals offer great hope in the area of cancer chemoprevention and therapy in future.
It gives me a great pleasure in writing the foreword to this comprehensive book that discusses the role of herbal medicine in cancer chemoprevention and therapy. The book will have universal appeal since it is intended primarily for the benefit of humanity. The commendable efforts made by the editor in bringing together the various eminent authorities in the field from around the globe and giving shape to this valuable treatise need to be applauded.
I congratulate Dr Rajesh Arora for his endeavors and wish the book success.
Rajendra P Tripathi20
21Preface
Cancer continues to be a major public health concern worldwide, silently snatching away our near and dear ones. It pains to see cancer patients suffering incessantly, battling and braving the disease. Cancer research has become a high priority area in recent years as there is an urgent need to tackle this scourge that universally afflicts humanity. So far it was presumed that the incidence of cancer in developed nations was much higher as compared to developing nations; but with better access to modern diagnostic modalities, it is increasingly becoming evident that unfortunately the problem is grave in developing nations and elsewhere too.
Over the years, there have been substantial advances in the treatment of cancer and surgery, chemo- and radiotherapy remain the treatments of choice. These treatment modalities have indeed improved survival rates in cancer patients to a great extent. However, despite the enormous benefits, at times, the problem of a cancer patient is exacerbated during treatment due to the associated, often cumulative, side effects of chemo/radiotherapy and development of resistance to these therapeutic modalities. In addition, the cost of therapy is exorbitant, which patients in most countries cannot afford. Disease-free survival, coupled with a good quality of life is what cancer patients yearn for and naturally in its pursuit, they begin to look for reliable less toxic and cheaper alternatives.
The dramatic shift in trend from therapy to cancer prevention is apparently evident today. The old adage ‘Prevention is better than cure’ has once again become the new age mantra. Approximately one-third of the total cancer-related deaths in affluent nations are related to nutrition, obesity and lack of physical activity and consequently are avertable by straightforward lifestyle interventions, if adhered to at an opportune time.
Cancer is a complicated multifactorial disease involving cellular, genetic and epigenetic alterations that often occur over a period of several years. Carcinogenesis comprises of three distinct, yet closely-linked stages viz, tumor initiation, promotion and progression that can be advantageously intervened by administration of chemopreventive agents to inhibit, retard or reverse the process per se. Identification and delineation of the key pathways involved in carcinogenesis and targeting them aptly will help further improve cancer prevention interventions. Synthetic drugs, most being therapeutic in nature and in view of their symptomatic action, are usually not very effective as chemopreventive agents and consequently attention in recent years has shifted towards natural products.
Herbals have been utilized since ages, both in the form of diet as well as drug in different traditional systems of medicine, for the prevention and treatment of cancer. Recent scientifically-validated preclinical and clinical data clearly point towards the efficacy of herbals as effective agents for diverse oncological applications. This has resulted in a paradigm shift towards herbals, which in view of their holistic mode of action are increasingly being utilized for generating novel cancer chemopreventive and therapeutic drugs. Adoption of an interdisciplinary approach in oncology, striking an appropriate balance between modern and traditional medicine, is likely to reap benefits in coming years.
This book has been envisaged keeping in mind the necessity to document the state-of-the-art and has been designed in such a manner that basic, clinical and applied researchers as well as physicians can derive benefit from the substantial advances in the area. The book is organized into seven sections that cover some of the most important areas of contemporary interest.
The introductory chapters in provide an overview of the role of herbal medicine in oncology. The importance of medicinal plants used in Ayurveda, Unani system of medicine has been highlighted. The therapeutic role of some other medicinal plants vis-à-vis antitumor, cytotoxic and immunomodulatory activities is also discussed.22
A disease-free life is a blessing and recent studies have established a crucial link between diet and cancer. Dietary modulation will most likely play a major role in cancer chemoprevention in coming years. , comprising eight chapters, discusses the nutritional interactions in cancer prevention and specifically the role of select phytodietary ingredients in oral, colon and breast cancer prevention, besides focusing on therapeutics.
The seven chapters of clearly demonstrate the vital role of various chemopreventive compounds like isoflavones, polyphenols, apigenin, phytosterols, isothiocyanates and aryltetralin lignans, etc. Plant-derived bioactive compounds like taxol, vincristine, vinblastine and camptothecin have found a place of reverence in chemotherapy. Such compounds do hold enormous potential in cancer chemoprevention as well and have been discussed.
The chemoradiotherapy interface is gaining prominent attention in view of its widespread application in the clinic. presents some of the fundamental issues involved and how it could be made more useful for bedside applications utilizing natural compounds, e.g. paclitaxel, polyphenols, novel adjuvants and the like. During radiotherapy of cancer, it is crucial to protect the adjacent normal tissues from the deleterious effects of radiation. Recent advances in the area of radioprotection have shown that it is possible to modulate the radioresponse in normal/tumor tissues by making use of natural plant products. Five chapters of are entirely dedicated to this important issue in radiotherapy.
Both natural and manmade sources of radiation pose a risk for cancer development. The widespread use of ionizing radiation for a variety of purposes has substantially increased the risks of developing radiation-induced cancers. On the other hand, UV-radiation-induced cancer is a major problem and with the rapid depletion of the ozone hole, it is likely to get aggravated. specifically highlights the role of herbal drugs in prevention against both non-ionizing and ionizing radiation-induced cancers.
The last section, , comprising seven chapters, discusses the attempts being made to unravel the multifaceted mechanism of action of herbals and dietary ingredients useful in cancer prevention and therapy, highlighting in particular the intricate molecular pathways that are modulated.
The utility of herbal medicine as radiation countermeasure (RCM) agents is also a highlight of this book. Such agents are likely to be of immense use in the management of nuclear/radiological emergencies (NREs). Several chapters of the last four sections subtly discuss this crucial issue.
It is my earnest hope that the book will certainly touch and improve the lives of cancer patients in a befitting manner.
Rajesh Arora
The views expressed over here and elsewhere in the book are entirely my own and not those of the Government.
23Acknowledgments
I sincerely thank from the core of my heart one and all who supported this endeavor.
My special thanks to
Honorable Dr APJ Abdul Kalam
Former President, Republic of India
Mr M Natarajan
Former Scientific Adviser to Defence Minister, Secretary and Director General Research and Development (DRDO), Ministry of Defence, Government of India
Dr W Selvamurthy
Distinguished Scientist and Chief Controller Research and Development (Life Sciences and Human Resource), Ministry of Defence, Government of India
Dr RP Tripathi
Director, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
for guidance, inspiration and constant support
The Eminent Contributors
for their wholehearted cooperation
My Family
for their inexhaustible patience and support
My Teachers
who helped me in learning new concepts
My Students
present and former
The Publisher
and
Lord Sri Krishna
My Eternal Friend, Philosopher and Guide…