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Add spice to your life

Bharat B. Aggarwal, Ph.D.

Professor of Medicine & Biochemistry

Chief, Cytokine Research Section
University of Texas M.D. Anderson Cancer Center

This presentation is for information only. Arya samaj and Dr. Aggarwal are not liable for any damages that may result from use of this information.
Bharat B. Aggarwal
Ph.D. Biochemistry: 1973-77
University of California, Berkeley

Postdoctoral Fellow: 1977-80

University of California, San Francisco

Senior Scientist & Project Leader: 1980-89

Genentech Inc., S. San Francisco

Professor of Medicine and Biochemistry and

Chief, Cytokine Research Section: 1989-present
The University of Texas, MD Anderson Cancer Center

Professor of Biochemistry (Adjunct): 1992-present

Texas A&M University (IBT), Houston

Published `350 original papers, seven books and 35 patents

Ancient spice route
Golden Triangle
Traditional Knowledge
(Ayurvedic medicine)

Modern Knowledge Modern technology

(Allopathic medicine)
FDA Study Estimates Vioxx Linked to
27,000 Heart Attacks
October 6, 2004: 4:43 a.m. EST
WASHINGTON -- A study led by a Food and Drug Administration safety
official projects that the widespread use of Vioxx may have led to more than
27,000 heart attacks and sudden cardiac deaths before the drug's abrupt
withdrawal last week by Merck & Co. (MRK), Wednesday's Wall Street
Journal reported.
The number is in comparison to how many similar incidents would have occu
occurred had the same patients been taking Celebrex, the Pfizer
Inc. drug that competed with Merck's blockbuster arthritis
treatment. The analysis specifically found that from Vioxx's
approval in 1999, through 2003, an estimated 27,785 heart attacks
and sudden cardiac deaths "would have been avoided" had
Celebrex been used instead of Vioxx.
J&J warns on lymphoma drug risk
By Val Brickates Kennedy,
Last Update: 5:06 PM ET Oct. 8, 2004

BOSTON (CBS.MW) - Drugmaker Johnson & Johnson will send out a

letter on Oct. 12 warning physicians that users of Remicade face an
increased risk of developing the deadly cancer lymphoma.

According to a spokesman at Johnson & Johnson, the company received

clearance from the Food and Drug Administration on Thursday night on
the language of the letter.

The letter, which states that Remicade users are six times more likely to
develop lymphoma, will be sent out to health professionals on Tuesday.
Remicade, which is manufactured by Johnson & Johnson's biotechnology
unit Centocor, already carries a warning that it can cause serious blood
and neurological disorders.
The drug, which is based on a monoclonal antibody, is used to treat such
autoimmune disorders as Crohn's disease and rheumatoid arthritis.
Cell signaling network
When under control, fire
is good for us. However,
when out of control
(dysregulated) fire can
burn everything!
Inflammation plays a major in development
of most diseases

Pulmonary Cardiovascular
diseases diseases

Neurological Dysregulated Alzheimer

diseases Inflammation

diseases Diabetes II

The surprising link between Inflammation and Heart
Attacks, Cancer, Alzheimer’s and other diseases

TIME Feb. 23, 2004

TIME Feb. 23, 2004
NF-κB activation is a major
mediator of inflammation in
most diseases & inhibition of
NF-κB activation can
suppresses inflammation
Inflammation has been linked to several diseases
Heart failure Chronic obstructive
pulmonary diseases
Cardiac hypertrophy
Atherosclerosis Asthma
Multiple sclerosis Headache
Muscular dystrophy Diabetes
Alzheimer’s disease Inflammation type 1 and II

Bone resorption Aging

Renal disease Lupus

Incontinentia pigmenti Sepsis
Ectodermal dysplasia Gut disease
Crohn’s disease Skin disease

Neuropathological Viral infections

Sleep apnoea
Helicobacter pylori-
associated gastritis Systematic inflammatory
response syndrome
Cancers linked to constitutive activation of NF-κB
Esophageal Laryngeal Pharyngeal Pancreatic Renal
cancer cancer cancer cancer carcinoma

Colon cancer Head and neck SCC Lung cancer Bladder cancer

Tobacco-linked cancers
leukemia Thyroid
disease Liver
lymphoma Breast
B cell
NF-κB Carcinogens
Adult T cell
leukemia Prostate
T cell

Mantle cell
lymphoma Viral cancers UV light
Multiple Acute lymphoblastic Cervical Nasopharyngeal Melanoma
myeloma leukemia cancer carcinoma
Working Model for Cigarette Smoke-Induced Damage

Cigarette smoke

Cardiovascular Chronic obstructive

diseases: pulmonary diseases
Chronic bronchitis &
Myocardial infarction Emphysema

Lung, larynx, oral cavity,
pharynx, esophagus,
pancreas, kidney and bladder
* War on Cancer (1976)

Total Deaths Due to Cancer in the USA*

Cancer 1971 2001
Lung 53,000 90,000
Colorectal 22,000 28,000
Prostate 17,000 32,000
Pancreas 10,000 14,000
CML 4,500
Cancer 1971 2001
Lung 11,000 67,000
Colorectal 24,000 29,000
Breast 31,000 ---
Pancreas ---- ---
Comparison of cancers incidence
between USA and India
Cancer United States India
(Rates per 100,000)

Prostate (Men) 61.8 6.9

Breast (Women) 89.2 24.6
Colon/rectum (Men) 46.3 6.4
(Women) 33.2 5.1
Stomach (Men) 8.0 7.3
(Women) 3.5 4.3
Lung (Men) 64.3 14.0
(Women) 29.9 3.0
Oesophagus (Men) 4.0 11.4
(Women) 1.3 8.4

Source: Food, Nutrition and the Prevention of Cancer: a global perspectives by

American Institute for Cancer Research, 1997
Comparison of Cancer Incidence
USA India Japan
Cancer Cases Deaths Cases Deaths Cases Deaths
Oral cavity 50 11 102 60 29 12
Nasopharynx 4 2 4 3 3 2
Other Pharynx 19 9 57 42 10 7
Oesophagus 31 31 63 59 58 43
Stomach 56 34 43 39 489 225
Colon/Rectum 356 139 40 26 342 143
Liver 30 31 17 16 186 146
Pancreas 72 68 11 11 76 71
Larynx 33 11 35 22 17 5
Lung 463 402 55 51 262 214
Melanoma of skin 113 21 3 1 3 2
Breast 914 212 191 99 314 77
Cervix uteri 78 33 307 174 111 30
Corpus uteri 155 20 17 5 45 13
Ovary etc. 106 62 49 29 66 37
Prostate 1043 179 46 28 111 55
Testis 40 2 6 3 13 2
Bladder 144 28 20 16 56 17
Kidney etc. 86 31 8 6 42 19
Brain, nervous system 54 37 21 16 24 9
Thyroid 46 3 14 4 31 5
Non-Hodgkin lymphoma 135 59 24 19 58 30
Hodgkin's disease 22 4 8 4 3 1
Multiple myeloma 35 26 8 6 16 12
Leukemia 80 54 26 20 48 34
All sites but skin 3223 1391 1017 688 2230 1213
Showing cases were after standardized with world standard population, called World Standardized incidence
or mortality rate. It is also expressed per million. J. Ferlay, etal.GLOBOCAN 2000.URL:
Drug-discovery from natural sources
¾There are 121 prescription drugs in use today, which
come from 90 plant species.
About 74% came from following folklore claims.
(Benowitz S, The Scientist 10, 1996, 1-7).

¾Approximately 25% of the drug prescription in the USA

are compounds derived from plants and were discovered
through scientific investigation of folklore claims
(Reynold T, J. Natl. Cancer Inst. 183, 1991, 594-596).

Pacific yew Taxol
Rosy periwinkle Vinblastin and vincristine
Foxglove Digitalis
Meadowsweet Aspirin
Why natural products are good
Source of anticancer drugs?
Almost 74% (48/65) of all drugs
approved either were natural products,
were based thereon, or mimicked them
in one form or another (1981-2002)

Newman DJ, Cragg GM, and Snader KM.,

J. Nat. Prod., 2003, 66, 1022-1037.
Hippocrates proclaimed
~2500 years ago
“Let food be thy
and medicine be
thy food”
“You are what you eat”
More Americans using alternative therapies
June 1st, 2004
Development of therapeutics: opportunities
within complementary and alternative medicine.
Engel LW, Straus SE. , Nat Rev Drug Discov. 2002 Mar;1(3):229-37.

Whereas other components of the NIH support the discovery

and subsequent development of novel chemical entities into
drugs, the National Center for Complementary and
Alternative Medicine (NCCAM) studies complex natural
products that are marketed as dietary supplements.

Regulatory framework for dietary supplements and drugs,

outlines the challenges of evaluating dietary supplements for
safety and clinical effectiveness, and describes the evolving
drug model for botanicals.
Ayurveda (Sushruta Samhita)
™Ayurveda means “science of long life”.

™This is an ancient medical system primarily practiced in India for

over 6000 years.

™Ayurveda is a part of life style and philosophy of Indians.

™It emphasizes body, mind and spirit in disease prevention and


™It believes disease is caused by the imbalance of “tridoshas”

(biomaterials), called vatta, pitta and kapha

™Vatta controls all movements

Pitta controls biotransformation (metabolism)
Kapha controls cohesion and functions through body fluids

™Together they control and conduct all functions of the body.

Ayuvedic medicine

Among the first drugs for

the treatment of high
blood pressure was
resperine from the herb
Rauwolfa serpentina.
(How to treat cancer?)
™Sushruta recommends complete surgical removal of the
malignant growths.

™Incomplete removal is considered a conduit for recurrence.

™Other treatments for cancer constitute:

Therapeutic diet,
Breathing exercises

™Adjuvant treatments for cancer therapy involves the usage of

Rasayanas, a group of herbal drug preparations
™ These rasayanas are potent protective agents against
chemotherapeutic agents and radiation in pts with cancer
undergoing chemotherapy and/or radiation therapy.

™ Chyavanprash is one type of rasayana prescribed for

immune deficiency and helps body to fight the disease and
protect from chemo/radiation therapy.

™ Chyavanprash was first described for its healing properties

2000 B.C.

™ Chyavanprash has prophylactic, curative and restorative


™ Chyavanprash protects from age-associated degenerative

¾ The primary ingredient of this formula is Embelica officinalis.
Several formulations of Chyavanprash exists:

¾ Bhaishajya Ratnavali
¾ Sharangadhara-Samhita
¾ Charaka Samhita
¾ Ayurvedic formulary

¾ Chyavanprash has 45 ingredients which falls in five


1. Pradhana Dravya (primary ingredient)……EO (Amla)

2. Samsadhana Dravya (blend of herbs)
3. Yamaka dravya (lipids)
4. Prakshep Dravya (flavoring or seasoning agents)
5. Samvahaka dravya (perserving agent)
™ Modern studies have shown that Chyavanprash has a potent
free-radical scavening effects, prevents carcinogenesis and
mutagenesis, and boosts the immune system in pts undergoing

™ EO, also called Amla, has been shown to exhibit antoxidant,

hepatoprotective, antibacterial, antiinflammatory,
hypocholerolemic, adaptogenic, immunomodulatory,
cytoprotective and anti-tumor activities.

™ These activities are assigned to emlicanin A. emblicanin B,

punigluconin, pedunculagin.

™ Clinical trials with Breast cancer and H&N cancer patients, has
shown that Chyavanprash can protect patients from toxicity
induced by radiation treatment
Spices can block NF-κB activation
Spices can block NF-κB activation
Chemical Composition of Most Common Spices
Spice Botanical name* Part of Plant Major Constituents
Tumeric Curcuma longa rhizome Essentil oils 5%: tumerone (58%),
borneol (6.5%), cineole (1%),
a-phellandrene (1%), curcumin (0.6%),
zingerone, zingiberene (25%)
Pepper (red) Capsicum frutescens fruit Pigments: carotene, zeaxnthin,
cryptoxanthin; oleoresin (1.5%);
Cloves Syzgium aromaticum buds Essential oils 17%: eugenol (93%),
caryophyllin, vanillin, Eugenin,
(Caryophyllus aromaticus, methylamylketone

Eugenia caryophyllata)

Coriander Coriandrum sativum seeds Essential oils 1%: (+)-linalool (60-70%),

a-pinene, b-pinene, a-terpinene,
b-terpinene, geraniol, borneol,
decylaldehyde, dipentene, cymene

Cumin Cuminum cyminum seeds Essential oil 4.5%: cuminaldehyde

(40-65%),thymol, cymol, cymene
Chemical Composition of Most Common Spices
Spice Botanical name* Part of Plant Major Constituents
Cinnamon Cinnamomum zeylanicum bark Essential oils 1.5-2.5%: cinnamaldehyde (65-
75%), (-)-linalool, furfural, methylamylketone,
nonylaldehyde, benzaldehyde,
hydrocinnamaldehyde, cuminaldehyde,
eugenol, caryophyllene, (-)-phellandrene, p-
cymene, a-pinene
Allspice Pimenta dioica berry Volatile oil 4.5%; eugenol (80%), O-methyl
(P. officinalis) eugenol, cineole, phellandrene,

Fennel Foeniculum vulgare seeds Essential oils 6%: anethole (50-60%), (+)-
fenchone (15-20%), a-pinene, camphne,
(+)-a- phellandrene, dipentene, p- hydroxy-
phenylacetone, estragole, anisaldehyde, anisic
acid, 1,3-dimethylbutadiene

Anise Pimpinella anisum seeds Fixed oil 8-20%; essential oil 1.5%; anethole
(90-96%), estragole (2%), p- methoxy

Star anise Illicium verum seeds Essential oils 8-9%: anethole (88%), limonine
(5%), estragole, safrole, p-methoxy-
Chemical Composition of Most Common Spices
Spice Botanical name* Part of Plant Major Constituents
Ginger Zingiber officinale rhizome Essential oils 1-2.5%: zingerone, shogaol,
gingerol, cineole, borneol, geraniol, linalool,
farnesene, citral, zingiberene, zingiberol,
camphene, phellandrene, methyl heptanone

Basil Ocimum basilicum Essential oil: (+)-linalool (40%), estragole

(25%), eugenol, cineole, geraniol

Cardamon Elettaria cardomonum seeds Fixed oils 1-2%: fatty acid

glycerides;essential oils 2-10%: cineole (25-
40%), methylheptanone, terpenene, a-
terpinyl acetate (28-34%), b-terpineol,
borneol, nerylacetate, geraniol,
nerolidol, a-pinene, sabinene, mycrene,
limonene, p-cymene

Capers Capparis sppinosa seeds Fixed oil 15%: fatty acids; essential oil 7.5%:
Caraway Carum carvi (+)-carvone (60%), carvol, (+)-limonene,
carveol, diacetyl, furfural

Curry Leaves Murraya koenigii leaves Essential oils 4.0%: carvone (60%),

Dill Anethum graveolens dihydrocarvone, (+)-limonene,

aphellandrene, a-pinene, dipentene
Chemical Composition of Most Common Spices
Spice Botanical name* Part of Plant Major Constituents
Fenugreek Trigonella foenumgraecumseeds Fixed oils 7%: trigonelline, choline Essential

Garlic Allium sataivum bulb oils 0.2%: diallyldisulfide (60%),

diallyltrisulfide (20%), allylpropyldisulfide
(6%), alliin, allicin

Lemon Grass Andropogon nardus grass Essential oils 0.3-0.55%:citral(70-85%),

(A. citratus);Cymbopogon geraniol
citratus (C. flexuosus)

Licorice Glycyrrhiza glabra rhizome Water extract: glycyrrhizin 12-20% Essential

Mace Myristica fragrans aril 1115%:monoterpenes(88%),
monoterpenols (55%)

Mint (black) Mentha vulgaris (M. Piperita) Essential oils 1%: a-pinene, b-pinene,
Mint (white) M. officinalis cineole, ethylamylcarbinol, (-)-menthol,
menthone, menthylacetate, piperitone

Mustard (white)Brassica alba (B. hirta, seeds Fixed oils 30-35%; sinalbin
B. Juncea, Sinapsis alba)

Mustard (black)B. Nigra (S. nigra) seeds Sinigrin

Chemical Composition of Most Common Spices

Spice Botanical name* Part of Plant Major Constituents

Nutmeg Myristica fragens seeds Fixed oils 24-30%; essential oils 16%; elemicin
(2%), eugenol, isoeugenol, o-methyleugenol,
safrole (0-6%), myristic acid, a-pinene,
sabinene, (+)-camphene (60-80%), dipentene
(8%), geranioil,(+)-borneol,(-)-terpeneol,
Oregano Oreganum vulgare Essential oils: thymol 50%, a-pinene 7-8%,
cineole, linalyl acetate,linalool, dipentane, p-
cymene, b-cymene, b-cryophyllene

Pepper (black) Piper nigrum unripe fruit Essential oils 1.5%: monoterpenes (70-80%)
Pepper (white) ripe fruit Sesquiterpenes (20-30%), chavicine; oleoresin:
piperine, piperidine
Rosemary Rosmarinus officinalis twigs Essential oils 2%: borneol (16-20%), cineole (27-
30%), camphor (10%), bornyl acetate (2-7%), a-
pinene camphene, terpinol, verbenone

Saffron Crocus sativus stigmas Essential oils 1%: 2,2,6-trimethyl-4,6-

cyclohexadienal, crocin, picrocrocin, crocetin

Sesame Sesamum indicum seeds Fixed oils: 45-65%

Spearmint Mentha spicata Essential oils 0.6%: (-)-carvone (56%),

dihydrocuminyl esters, dihydrocarveyl acetate
Intake of 1, 3, or 6 g of cinnamon per day reduces serum
glucose, triglyceride, LDL cholesterol, and total
cholesterol in people with type 2 diabetes

The inclusion of cinnamon in the diet of people with

type 2 diabetes will reduce risk factors associated with
diabetes and cardiovascular diseases.

Cinnamon extract (traditional herb) potentiates in vivo

insulin-regulated glucose utilization via enhancing
insulin signaling

Accelerates wound healing

Cinnamon & diabetes
Cinnamon improves glucose and lipids of people with type 2 diabetes.
The results of this study demonstrate that intake of 1, 3, or 6 g of
cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol,
and total cholesterol in people with type 2 diabetes and suggest that the
inclusion of cinnamon in the diet of people with type 2 diabetes will
reduce risk factors associated with diabetes and cardiovascular diseases.
Khan A, ……Anderson RA. Diabetes Care. 2003 Dec;26(12):3215-8.

Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated

glucose utilization via enhancing insulin signaling in rats.
Qin B, …….Sato Y. Diabetes Res Clin Pract. 2003 Dec;62(3):139-48.

Regulation of PTP-1 and insulin receptor kinase by fractions from

cinnamon: implications for cinnamon regulation of insulin signalling.
Imparl-Radosevich J, ……….. Graves DJ. Horm Res. 1998;50:177-82.

Cinnamon extracts' inhibitory effect on Helicobacter pylori.

J Tabak M,….Neeman I. Ethnopharmacol. 1999;67(3):269-77.

Apogenin is a potent antioxidant

Exhibits insulin-releasing and

insulin-like activity

Exhibits hypolipidemic effect

Exhibits hypotensive effects

Coriander (Coriandrum sativum)
Insulin-releasing and insulin-like activity
of the traditional anti-diabetic plant
Gray AM, Flatt PR. Br J Nutr. 1999 Mar;81(3):203-9.

Hypolipidemic effect of coriander seeds

mechanism of action.
Chithra V, Leelamma S. Plant Foods Hum Nutr. 1997;51(2):167-72.
Curry leaves
Carbazole alkaloids

Potent antioxidant


Anethole suppresses NF-κB activation


[1-Methoxy-4-(1-propenyl benzene)

Anethole blocks both early and late cellular responses transduced by tumor
necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis.
Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB.
Oncogene. 2000;19(25):2943-50.

Potent antioxidant



4-hydroxyisoleucine, Diosgenin

Fenugreek has a long history of medical uses in Ayurvedic and Chinese medicine.

Tradionally used for labor induction, and for aiding digestion,

Preliminary animal and human trials suggest possible hypoglycemic and

antihyperlipidemic properties of oral fenugreek seed powder.

For diabetes, fenugreek reduces insulin resistance through activation of the early
steps of insulin signaling in peripheral tissues and in liver.

For hyperthyroidism, trigonella (200 mg/kg) was found to lower the serum
concentrations of T3 and T4

Supplementation of fenugreek seeds in the diet inhibits colon carcinogenesis, by

modulating the activities of beta-glucuronidase and mucinase.

Stimulates immune functions

Antiulcer potential

Nematicidal activity
Scientific evidence on the role of Ayurvedic
herbals on bioavailability of drugs.
Atal CK, Zutshi U, Rao PG. J Ethnopharmacol. 1981;4:229-32.

Experiments were conducted to evaluate the scientific basis of

the use of the trikatu group of acrids (long pepper, black
pepper and ginger) in the large number of prescriptions in

Impairment of UDP-glucose dehydrogenase and

glucuronidation activities in liver and small
intestine of rat and guinea pig in vitro by piperine
Reen RK, Jamwal DS, Taneja SC, Koul JL, Dubey RK, Wiebel FJ, Singh J..
Biochem Pharmacol. 1993;46:229-38.
Black pepper

Trikatu group (long pepper, black pepper and ginger) is

used in the large number of prescriptions in Ayurveda

Enhances drug bioavailability

Inhibits glucuronidation activity


Inhibits human P-glycoprotein and CYP3A4

Piperine inhibits gastric emptying.

Capsacin suppresses NF-κB activation
by inhibiting IκBα degradation

Vanillyl Acyl amide Alkyl



Red chilli
Singh et al, Journal of Immunology, 157, 1996, 4412-20
Eugenol suppresses NF-κB activation


[2-Methoxy-4 propenylphenol]




[2-Methoxy-4-(2-propenyl) phenol]
H 2C C CH 2

Anethole blocks both early and late cellular responses transduced by tumor
necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis.
Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB.
Oncogene. 2000;19(25):2943-50.

Antibacterial (inc. Helocobacter pylori)

Antiviral (Herpes, CMV,HSV)


Inhibits growth of oral pathogens

Inhibits platelet aggregation


Treatment of nausea and vomiting


Pregnancy-induced nausea

Reduces hyperglycemia

Reduces motion sickness





Time, 2004
Withania somnifera

Indian ginseng used to maintain positive

state of mental and physical health.
(Withania sominifera)
The roots of Withania somnifera (WS) are used extensively in
Ayurveda, and is categorized as a rasayana, which are used to
promote physical and mental health, to provide defense against
disease and adverse environmental factors and to arrest the aging

WS has been used to stabilize mood in patients with behavioral


WSG exhibited an antidepressant effect, comparable with that

induced by imipramine, in the forced swim-induced 'behavioural
despair' and 'learned helplessness' tests.

The investigations support the use of WS as a mood stabilizer in

clinical conditions of anxiety and depression in Ayurveda.
Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study.
Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S.
Phytomedicine. 2000;7:463-9.
Withania (Ashwagandha)
Withania somnifera root extract prevents DMBA-induced
squamous cell carcinoma of skin in Swiss albino mice.
Prakash J, Gupta SK, Dinda AK. Nutr Cancer. 2002;42:91-7.

Mechanisms of cardioprotective effect of Withania somnifera

in experimentally induced myocardial infarction.
Mohanty I, ….. Gupta SK. Basic Clin Pharmacol Toxicol. 2004;94:184-90.

Immunoprotection by botanical drugs in cancer

-Withania somnifera (Linn Dunal) (Solanaceae),
-Tinospora cordifolia (Miers) (Menispermaceae),
-Asparagus racemosus (Willd.) (Liliaceae),
Immunopharmacological activities in cyclophosphamide (CP)-treated mouse ascitic
sarcoma; resulted in protection towards CP-induced myelo- and immunoprotection as
evident by significant increase in white cell counts and hemagglutinating and hemolytic
antibody titers.
Diwanay S, Chitre D, Patwardhan B. J Ethnopharmacol. 2004 Jan;90(1):49-55.
Terminalia chebula, Emblica officinalis, Terminalia bellerica

Triphala is one of the rasayana that promotes, health, and


It is used to treat anemia, jaundice, constipation, asthma, fever and

chronic ulcers.

Triphala has radioprotective effects in mice (Jagetia GC, 2002).

Emblica officinalis has anticlastogenic activity (Talukder G etal,


Emblica officinalis has antitumor activity (Jose JK etal, 2001)

Terminalia chebula has antiproliferative activity (Saleem A etal,

Source: Ajanta Pharmaceuticals, Mumbai
Commiphora mukul (guugul)


Guggulsterone is used to treat obesity, diabetes, hyperlipidemia,

atherosclerosis, and osteoarthritis.

A natural product that lowers cholesterol as an antagonist ligand for FXR.

Urizar NL, et al Science. 2002;296:1703-6.
Guggulsterone inhibits NF-κB and
IκBα kinase activation, suppresses
expression of antiapoptotic gene
products and enhances apoptosis

Shishir Shishodia, and Bharat B. Aggarwal

Journal of Biological Chemistry 2004 Aug 17

[Epub ahead of print]
Boerhavia diffusa
(punarnava; Family Nyctaginaceae)

Creeping weed

Roots are used for the treatment of dyspepsia, jaundice,

enlargement of spleen, abdominal pain (Kirtikar & Basu, 1956)

Used as anti-stress agent (Chopra etal, 1996)

Liridendrin derived from it has calcium channel antagonist activity

(Lami etal, 1991)

Used for analgesic and antiinflammatory properties

(Hiruma-Lima etal, 2000)

Protects mice against E. Coli induced peritonitis

(Mungantiwar,1997, 1999)

Has antiproliferative and immunomodulatory activites

(Mehrotra etal, 2001, 2002)
Fruits & Vegetables
Our review of 206 human epidemiologic studies and 22 animal studies
suggests the existence of an inverse relationship between consumption of
vegetables and fruits and risk for cancers of the stomach, esophagus,
lung, oral cavity and pharynx, endometrium, pancreas, and colon .

The types of vegetables or fruits that most often appear to be protective

against cancer are raw vegetables, followed by allium vegetables, carrots,
green vegetables, cruciferous vegetables, and tomatoes.

Substances present in vegetables and fruit that may help protect against
cancer usually include dithiolthiones, isothiocyanates, indole-3-carbinol
(I3C), allium compounds, isoflavones, protease inhibitors, saponins,
phytosterols, inositol hexaphosphate, vitamin C, D-limonene, lutein, folic
acid, beta carotene, lycopene, selenium, vitamin E, flavonoids, and dietary

Noncancer-related effects of increased vegetable and fruit consumption

include benefits against cardiovascular disease, diabetes, stroke, obesity,
diverticulosis, and cataracts.
Potential sources of NF-κB blockers
Cancer Cancer Cancer Cancer Cancer
Urinary tract Vision Heart Heart, vision Heart, memory
Memory and Aging Bones Cholesterol Immune system Urinary tract

Anthocyanins Lutein Allicin Vitamin C, Caroteinids Lycopene

Phenolics Indoles Bioflavonoids Anthocyanins

Fruits Fruits Fruits Fruits Fruits

Blackberries Avacados Bananas Yellow apples Apples
Blueberries Green apples Dates Apricots Blood oranges
Black currants Green grapes White nectarines Cantaloupe Cherries
Dried plums Honeydew White peaches Gooseberries Cranberries
Elderberries Kiwifruit Brown pears Yellow figs Red grapes
Purple figs Limes Vegetables Grapefruit Red pears
Purple grapes Green pears Cauliflower Golden kiwifruit Pomegranates
Plums Vegetables Garlic Lemons Raspberries
Raisins Artichokes Ginger Mangoes Strawberries
Vegetables Asparagus Kohlrabi Nectarines Watermelon
Purple asparagus Broccoli Mushrooms Oranges Vegetables
Purple carrots Brussels sprouts Onions Papayas Beets
Egg plant Green beans Potatoes Peaches Red cabbage
Purple peppers Green cabbage Shallota Pineapple Red peppers
Purple potatoes Celery Turnips Tangarines Radishes
Black salsify Cucumbers White corn Vegetables Red onions
Lettuce Carrots and Beets Red potatoes
Okra and Peas Yellow peppers Rhubarb
Spinach Pumpkin Tomatoes
Watercress Sweet ccorn
Yellow tomatoes
Surh YJ, Nature Rev Cancer. 2003 Oct;3(10):768-80
Vegetables can block NF-κB activation
Spices, fruits and vegetables
can block NF-κB activation
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Watercress Arugula Kohlrabi Rutabaga/Turnips Daikon Radishes

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CH2OH QuickTime™ and a
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N Chinese cabbage

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Pok choy Collard greens Mustard greens Kale Brussels sprouts

Cruciferous vegetables

Suppress the tumorigenesis of the colon , lung , breast,

cervix and liver .

Effective clinically in treating precancerous lesions of

the cervix and laryngeal papillomas.

Alters the immune function, inhibit cigarette smoke-

induced DNA-adduct formation , and reverse multidrug
resistance in vivo.
Indole 3-carbinol
Indole-3-carbinol (I3C) is found in Brassica sp.
vegetables such as cabbage, cauliflower, and
brussels spouts.

It exhibits anticarcinogenic, antimetastatic, and

antiproliferative activities.

Indole-3-carbinol Abolishes Carcinogen-

Induced NF-κB and IκBα Kinase Activation
Causing Suppression of NF-κB-Regulated
Antiapoptotic and Metastatic Gene Expression
and Upregulation of Apoptosis

From Takada and Aggarwal, submitted)



Lupeol, a triterpene, is the principal constituent
of common fruit plants such as olive, mango,
fig and medicinal herbs that have been used to
treat skin aliments.

Lupeol has been reported to possess a wide

range of medicinal properties that include
strong antioxidant, antimutagenic, anti-
inflammatory and antiarthritic effects.
Sources of resveratrol

Arachis hypogea Morus rubra Vitis vinifera Veratrum grandiflorum Artocarpus sp. Vaccinum sp.
Peanut Mulberry Grapes White hellebore Jackfruit Blueberry

Cassia sp. Vaccinum sp.
Legumes HO Cranberry


Polygonum cuspidatum Rheum rhaponticum

Ko-jo-Kon (Japanese) Rheum

Eucalyptus Gnetum montanum Picea sp. Bauhinea sp. Veratrum sp.

Pinus sylvestris
Spruce Corn lily
Scots pine
An Ayurvedic remedy, also called Manakka




Resveratrol suppresses NF-κB activation
without inhibiting IκBα degradation

Stilbene trans-3, 4', 5-trihydroxystilbene Piceatannol


Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-

kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen
intermediates and lipid peroxidation
Manna SK, Mukhopadhyay A, Aggarwal BB.
Journal of Immunology, 164, 2000, 6509-6519

Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated

gene expression through suppression of IkappaBalpha kinase and p65
Ashikawa K, Majumdar S, Banerjee S, Bharti AC, Shishodia S, Aggarwal BB.
Journal of Immunology 2002;169:6490-7.
Sources of Caffeic Acid Phenethyl Ester

Poplar flower Beech tree Chestnut tree

Propolis of
honey bee



Caffeic Acid Phenethyl Ester

Sources of Sanguinarine

Sanguinaria canadensis Poppy

Root of Sanguinaria Fumaria sp.

Sanguinarin suppresses NF-κB activation
by inhibiting IκBα degradation

+ - - OCH3
CH3 CH3 + OCH3
+ N
N Cl- +N



Sanguinarine Chelerythrine chloride Berberine

Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-kappaB

activation, IkappaBalpha phosphorylation, and degradation.
Chaturvedi MM, Kumar A, Darnay BG, Chainy GB, Agarwal S, Aggarwal BB.
Journal of Biological Chemistry. 1997; 272:30129-34.
Emodin suppresses NF-κB activation
through suppression of IκBα degradation

CH 3


Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits TNF-induced NF-
kappaB activation, IkappaB degradation, and expression of cell surface
adhesion proteins in human vascular endothelial cells.
Kumar A, Dhawan S, Aggarwal BB. Oncogene. 1998;1:913-8.
Silymarin suppresses NF-κB activation
by inhibiting IκBα degradation




Manna et al Journal of Immunology, 163, 1999, 6800-6809 Artichok

Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-

terminal kinase, and apoptosis.
Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB.
J Immunol. 1999 Dec 15;163(12):6800-9.
Sources of Genistein

Soy plant Soy pod Soy beans


Protein tyrosine kinase inhibitors
block tumor necrosis factor-induced
activation of nuclear factor-kappaB,
degradation of IkappaBalpha,
nuclear translocation of p65, and
subsequent gene expression.
Natarajan K, Manna SK, Chaturvedi MM, Aggarwal BB.

Arch Biochem Biophys. 1998;352:59-70.

Nerium oleander


O CH 3
H 3C
H 3C


H 3 CO
Oleandrin suppresses activation
of nuclear transcription factor-
kappaB, activator protein-1, and
c-Jun NH2-terminal kinase.

Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB.

Cancer Research 2000;60:3838-47.

Sources of ursolic acid

H 3C


H 3C
Pears CH3
Holy basil

Cranberry Prunes Bearberry

Basil Tulsi
(Ocimum sanctum)
In several ancient systems of medicine including Ayurveda, Greek, Roman, Siddha
and Unani, Ocimum sanctum has vast number of therapeutic applications such as in
cardiopathy, haemopathy, leucoderma, asthma, bronchitis, catarrhal fever, otalgia,
hepatopathy, vomiting, lumbago, hiccups, ophthalmia, gastropathy, genitourinary
disorders, ringworm, verminosis and skin diseases etc.
The present review incorporates the description of O. sanctum plant, its chemical
constituents, and various pharmacological activities.
Gupta SK, Prakash J, Srivastava S. Indian J Exp Biol. 2002 ;40:765-73.

Chemopreventive activity of Ocimum sanctum seed oil.

The results of this study suggest that the potential chemopreventive activity of the
oil is partly attributable to its antioxidant properties. The chemopreventive efficacy
of 100 microl/kg seed oil was comparable to that of 80 mg/kg of vitamin E.4.
Prakash J, Gupta SK. J Ethnopharmacol. 2000;72:29-3

Lens aldose reductase inhibiting potential of some indigenous plants.

Cataract is the leading cause of blindness worldover. Diabetes is one of the major
risk factors for cataractogenesis and aldose reductase (AR) has been reported to
play an important role in sugar-induced cataract. OS possesses a significant
anticataract activity in vitro and its anticataract potential could be related with its AR
inhibitory effect
Halder N, Joshi S, Gupta SK. J Ethnopharmacol. 2003;86:113-6.
Ursolic Acid Inhibits NF-κB Activation
Induced by Carcinogenic Agents
Through Suppression of IκBα Kinase
and p65 Phosphorylation:
Correlation with Downregulation of COX2, MMP-9 and CyclinD1

Shishodia S., Majumdar S., Banerjee S. and Aggarwal B. B.

Cancer Research 2003, 63, 4375-83

Sources of betulinic acid

Platanus acerifolia Tryphyllum peltaum Syzygium formosanum

CH 3

H 2C
CH 3 CH 3 H

H CH 3
H 3C CH 3

Zizyphus mauritiana Zizyphus sp

Discovery of betulinic acid as a selective inhibitor of human melanoma

that functions by induction of apoptosis.
Pisha E,, et al. Nature Medicine 1995 Oct;1(10):1046-51
Betulinic acid Suppresses
Carcinogen-Induced NF-κB
Activation Though Inhibition of
IκBα Kinase and p65

Takada Y. and Aggarwal B. B.

Journal of Immunology,
2003, 171, 3278-86
CH 3




Flavopiridol is a semisynthetic flavonoid closely

related to a compound originally isolated from the
stem bark of Dysoxylum binectariferum (also called
rohitukine), a plant indigenous to India.

Flavopiridol has been found to inhibit cyclin-

dependent kinases, induce apoptosis, suppress
inflammation, and modulate the immune response.
Flavopiridol inhibits NF-κB
activation induced by various
carcinogens and inflammatory
agents through inhibition of IκBα
kinase and p65 phosphorylation

Takada Y, Aggarwal BB.

Journal of Biological Chemistry. 2004;279:4750-9.

Amoora rohituka
Amoora rohituka stem bark is one of the components of
a medicinal preparation used in the Indian Ayurvedic
system of medicine for the treatment of human

Amooranin (AMR) is a triterpene acid isolated from the

stem bark of a tropical tree grown wild in India.

Novel drug amooranin induces apoptosis through

caspase activity in human breast carcinoma cell lines.
Rabi T, …. Escalon E. Breast Cancer Res Treat. 2003;80:321-30.

Amooranin overcomes multidrug resistance in human

leukemia and colon carcinoma cell lines.
Ramachandran C, …. Escalon EA. Int J Cancer. 2003;105:784-9.
Alpina galanga

3 1' 3'
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AcO 4 6
1’- Acetoxychavicol Rhizomes

Suppression of NF-κB and IκBα
Kinase Activation by 1'-
Acetoxychavicol Acetate Inhibits
Invasion and Potentiates Apoptosis
Through Abrogation of NF-κB
Regulated Gene Products

Haruyo Ichikawa, Yasunari Takada,

Akira Murakami, Bharat B. Aggarwal

Evodia rutaecarpa

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Evodia Fruit N Dried Evodia Fruit
H 3C
Wu-Zhu-Yu, Go-syu-y/u
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Medicinal Evodia Fruit Plant

Evodiamine Abolishes
Carcinogen-Induced NF-κB and
IκBα Kinase Activation Causing
Suppression of NF-κB-Regulated
Antiapoptotic, and Metastatic Gene
Expression Leading to
Upregulation of Apoptosis
Takada Y, Kobayashi Y.,
& Aggarwal B. B.
(in preparation)
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The dried rhizome of a herbaceous plant, turmeric is

closely related to ginger. The spice is also sometimes
called 'Indian saffron' thanks to its brilliant yellow color.
Indian turmeric has been known to the world since
ancient times. Several unique properties of Indian
turmeric make it the ideal choice as a food flavor, an
effective ingredient in medicines and cosmetics, and
as a natural colorant.
Culinary U ses
In India it i s used to ti nt many sweet dishes. Apart from it s wide use in M oroccan cuisine
to spice meat, particularly lamb, and vegetables, its pri ncipal place is in curri es and curry
powders. It is used in many fi sh curries, possibly because it successfull y masks fishy
odours. When used in curry powders, it is usuall y one of the main ingredients, providing
the associated yell ow colour.

Attr ibuted M edicinal Proper ties

Turmeri c is a mild digestive, being aromati c, a stim ulant and a carmi nati ve. An ointment
base on the spice is used as an antisepti c in M alaysia. Turmeric water is an Asian
cosmeti c appli ed to im part a golden glow to the complexion. Curcumi n has been shown
to be acti ve against Staphlococcus aureus (pus-producing infecti ons) and cancer.

Curcuma longa root Turmeric (spice)

Diferuloylmethane (dye)
Traditional medicines &
herbal remedies
(Japanese Turmeric)

UKON-Tea UKON-Powder

UKON-Pill (portable)
UKON-Rice Topping

Ryukyu Bio-Resource Development Co., LTD. OKINAWA, Japan
Structure of Curcumin



Diferuloylmethane; MW 368
Therapeutic potential of curcumin

Multiple Cardiovasuclar diseases Alzheimer

sclerosis Cholestrol, platelet aggregation, disease
inhibition of smooth muscle cell


Antioxidant Skin, liver, colon, stomach

Gall-stones Curcumin Antiangiogenic



Cataract formation

Cardiotoxicity Wound healing HIV replication Lung fibrosis

Molecular targets of curcumin
Cyclin D1 ↓ 5-LOX ↓ COX2 ↓ iNOS ↓ MMP9 ↓ IL-8 ↓ IL-6 ↓ TNF ↓ IL-12 ↓

Gene expression NF-κB ↓
EGFR ↓ AP-1 ↓
HER2 ↓ Egr-1 ↓
Transcriptio STAT3 ↓
Src ↓
Protein Curcumin n factors STAT5 ↓
JAK2 ↓
kinases PPARγ ↑
TYK2 ↓
EpRE ↓
PKA ↓ β-catenin ↓
PKC ↓ Nrf2 ↑
Others Enzymes
VCAM-1 ↓ Bcl-2 ↓ Bcl-xl ↓ ICAM-1 ↓ FTPase ↓ GST ↑ GSH-px uPA ↓
TF ↓ AR/ARP ↓ P53 ↑ MDR ↓ ELAM-1 ↓ Hemeoxygenase ↑ Xanthine oxidase ↓
From Aggarwal B et al, Anticancer Research 23, 2003, 363-398
Curcumin confers radiosensitizing
effect in prostate cancer cell line PC-3

Radiation upregulated TNF leading to an increase in NF-κB

activity resulting in the induction of Bcl-2 protein.

Curcumin in combination with radiation inhibited TNF-

mediated NF-κB activity resulting in bcl-2 protein

Chendil D, et al Oncogene 2004, 26:1599-607.

Different stages of cancer progression and
its suppression by curcumin

Constitutive activation of Overexpression of Overexpression of

transcription factors ¾Oncogenes ¾Matrix metalloproteases
¾AP-1& NF-κB ¾HER2 ¾Cyclooxygenase-2
¾Growth factors ¾Adhesion molecules
(e.g; EGF, PDGF, FGF) ¾Chemokine
¾Tumor Suppressor genes ¾Growth factor receptors ¾TNF
¾Survival factors
(e.g; Survivin,Bcl-2 and Bcl-xl)
¾Cyclin D1
¾Decoy receptor

Transformation Proliferation Invasion

Normal Tumor Tumor Tumor
cells cells growth Metastasis


From Aggarwal B etal, Anticancer Research 23, 2003, 363-398

Dorai T, Gehani N, Katz A.
Therapeutic potential of curcumin in human prostate cancer-I.
curcumin induces apoptosis in both androgen-dependent and
androgen-independent prostate cancer cells.
Prostate Cancer Prostatic Dis. 2000;3:84-93.

Dorai T, Cao YC, Dorai B, Buttyan R, Katz AE.

Therapeutic potential of curcumin in human prostate cancer. III.
Curcumin inhibits proliferation, induces apoptosis, and inhibits
angiogenesis of LNCaP prostate cancer cells in vivo.
Prostate. 2001;47:293-303.

Dorai T, Gehani N, Katz A.

Therapeutic potential of curcumin in human prostate cancer. II.
Curcumin inhibits tyrosine kinase activity of epidermal growth factor
receptor and depletes the protein.
Molecular Urology. 2000;4:1-6.
Neuroprotective role of curcumin
from curcuma longa on ethanol-
induced brain damage

Oral administration of curcumin to rats caused a significant reversal in lipid peroxidation, brain lipids
and produced enhancement of glutathione in ethanol intoxicated rats

Rajakrishnan V, Viswanathan P, Rajasekharan KN, Menon VP

Phytother Res. 1999 Nov;13(7):571-4
The curry spice curcumin reduces
oxidative damage and amyloid
pathology in an Alzheimer
transgenic mouse.

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM.

J Neurosci. 2001;21:8370-7.
Phenolic anti-inflammatory antioxidant
reversal of A beta-induced cognitive
deficits and neuropathology

Frautschy SA, Hu W, Kim P, Miller SA, Chu T,

Harris-White ME, Cole GM.

Neurobiol Aging. 2001;22:993-1005

Protective effects of curcumin
against ischaemia/reperfusion
insult in rat forebrain.

Ghoneim AI, Abdel-Naim AB, Khalifa AE, El-Denshary ES.

Pharmacol Res. 2002;46:273-9.

Curcumin & Radiation
Radioprotective action of curcumin extracted from Curcuma longa
LINN: inhibitory effect on formation of urinary 8-hydroxy-2'-
deoxyguanosine, tumorigenesis, but not mortality, induced by γ-ray
Inano H, Onoda M. Int J Radiat Oncol Biol Phys. 2002;53:735-43.

Prevention of radiation-induced mammary tumors

Inano H, Onoda M. Int J Radiat Oncol Biol Phys. 2002;52:212-23

Potent preventive action of curcumin on radiation-induced initiation of

mammary tumorigenesis in rats
Inano H, Onoda M, Inafuku N, Kubota M, Kamada Y, Osawa T, Kobayashi H, Wakabayashi K..
Carcinogenesis. 2000;21:1835-41.

Chemoprevention by curcumin during the promotion stage of

tumorigenesis of mammary gland in rats irradiated with gamma-rays.
Inano H, Onoda M, Inafuku N, Kubota M, Kamada Y, Osawa T, Kobayashi H, Wakabayashi K.
Carcinogenesis. 1999;20:1011-8.

Protective effect of curcumin, ellagic acid and bixin on radiation

induced genotoxicity.
Thresiamma KC, George J, Kuttan R. J Exp Clin Cancer Res. 1998;17:431-4.
Phase I clinical trial of curcumin, a chemopreventive agent,
in patients with high-risk or pre-malignant lesions.
Cheng AL, et al Anticancer Res. 2001 Jul-Aug;21(4B):2895-900.

¾Tested on 25 pts (13 men & 12 women) with a median age of 60 yrs (36-77)

¾Curcumin was administered orally 8000 mg/day

¾Patients No. Histological response

Recently resected bladder cancer; 2 1/2
Oral leukoplakia, 7 2/7
Intestinal metaplasia of the stomach; 6 1/6
CIN 4 1/4
Bowen’s disease 6 2/6

¾All pts (except 2) completed 3 months treatment regimen

¾Peak serum conc. of curcumin at 1-2 h after oral intake was 0.4-1.6 uM

Curcumin is not toxic to humans even at the high dose (8000 mg/day).
Curcumin, a major constituent of
turmeric, corrects cystic fibrosis defects
¾Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis
transmembrane conductance regulator (CFTR).

¾The most common mutation, DeltaF508, results in the production of a misfolded CFTR
protein that is retained in the endoplasmic reticulum and targeted for degradation.

¾Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be

administered to humans safely.

¾Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses

comparable, on a weight-per-weight basis, to those well tolerated by humans corrected
these animals' characteristic nasal potential difference defect.

¾These effects were not observed in mice homozygous for a complete knockout of the
CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR
protein in the plasma membranes of transfected baby hamster kidney cells.

Egan ME, etal; Science. 2004;304:600-2.

Curcumin & Skin Diseases
Curcumin-induced suppression of phosphorylase
kinase activity correlates with resolution of
psoriasis as assessed by clinical, histological and
immunohistochemical parameters
MCY Heng, MK Song, J. Harker and MK Heng,
Br. J. Dermatology, 143, 2000, 937-949

Psoriasis, Actinic keratosis, Acne,

Warts, Dermatitis, Eczema
Wound healing, Sunburn
Skin cancer
Treatment of psoriasis
with Psoria-Gold


R Knee L Knee L Leg L Elbow

4 weeks

Courtesy of Dr. Madeline Heng from UCLA

MCY Heng, MK Song, J. Harker and MK Heng, Br. J. Dermatology, 143, 2000, 937-949
Curcumin and scleroderma

Curcumin induced apoptosis

in scleroderma lung
fibroblasts: role of PKCε
Tourkina E, Gooz P, Oates JC, Ludwicka-
Bradley A, Silver RM, Hoffman S

Am J Respir Cell Mol Biol.

Topical Application of Curcumin
How to prevent cancer?
¾Eliminate smoking

¾Exercise regularly

¾Eat a balanced diet and stay trim

¾Avoid sunburn

¾To detect early-stage cancer, undergo check ups:

mammography; colonoscopy; prostate exam and PSA

¾Practice caloric restriction

¾Limit alcohol consumption

¾Keep positive attitude and stress-less life

Self-control & discipline is better than pills

Thank you!
Gamsa hamnida!