Targeting NF-kB Regulated Inflammatory Pathways by Small Molecules as Therapeutic Strategies:

Future Prespectives

Bharat B. Aggarwal, Ph.D.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Supercentenarian Research Foundation Continuing Medical Education (CME) Provider Antioxidants and Age-Management Medicine: First International Congress on Ergothioneine,
De Neve Auditorium; UCLA; July 15-17th, 2011 ; July 17th, 2011 (30 min)

(Host Drs. Okezie I. Aruoma, John Repine, and L. Stephen Coles)

WAR on CANCER
President Richard Nixon signing the

National Cancer Act on December 23, 1971

War on Cancer
I will ask for an appropriation of an extra $100 million to launch an extensive campaign to find a cure for cancer. Let us make a total national commitment to conquer this

dread disease. America has long been the wealthiest

nation in the world. Now it is time we became the healthiest nation in the world.

--President Richard Nixon, 1971 State of the Union address

Change in the US Death Rates* by Cause,

1950 & 2002

600 586.8

1950
500
400 300 200 100 0

2002

240.1 180.7 193.9 193.4

56.0

48.1 22.5

Heart Diseases

Cerebrovascular Diseases

Pneumonia/ Influenza

Cancer

* Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and Prevention, 2004

Global Cancer Incidence

From Parkin DM, EJC, 37, 2000, 4-66

Projection for Global Cancer Incidence and Cancer Deaths

25
New Cases Deaths 20

20
16

Millions

15
10 10

14

10 5 0

2002

2020

2030

Year

Cancer Is a Preventable Disease That Requires Major Changes in Life Style

40

30

20

10

0 Tobacco Diet Obesity Infections E. Pollution Genes & Radiations

HK 04-14-2008

Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009

Life style Carcinogens/Risk factors

Colorectal Cancer and Red Meat!

Colorectal cancer is the second most common cause of cancer deaths in affluent countries. Processed red meat (beef, mutton, lamb, veal, pork, and offal) intake is closely linked with the risk of CRC. Dietary modification can reduce this cancer burden by 70%. Heterocyclic amines, high saturated fat, carcinogenic Nnitroso compounds, high protein cholesterol and salt contents and heme iron are some of the components of meat linked with CRC.

Bastide NM, CAPR, 2011

Working Hypothesis:
Dysregulated chronic inflammation caused by life style factors mediate chronic diseases including cancer!

What is Inflammation?
Cornelius Celsus,
a physician in first century Rome:

Heat (calor) Pain (dolor) Redness (rubor)

Swelling (tumour)
21

Inflammation and cancer

Redness, swelling, heat and pain

Rudolf Virchow (1821-1902; in 1850)

His Pathology laboratory in Wurzburg, Germany

Linked Inflammation with atherosclerosis, rheumatoid arthritis, multiple sclerosis, cancer, asthma, Alzheimers From Heidland A et al, History of Nephrology, 2006
22

Inflammation is itis
Arthritis is inflammation of the joints Bronchitis. Bronchus Sinusitis Sinus Gastritis. Stomach Esophagitis.. Esophagus Pancreatitis.. Pancreas MeningitisBrain Rhinitis Rhina Gingivitis Gum

Inflammation as a risk factor for most cancers

Inducer Tobacco smoke Helicobacter pylori Human papilloma virus Hepatitis B & C virus Bacteria, GBS Gram- uropathogens Tobacco, genetics GA, alcohol, tobacco Asbestos fibers Epstein-Barr virus Gut pathogens Ultraviolet light Infections, STD Inflammation Cancers % predisposed progress to cancer Lung Cancer 11-24 Gastric Cancer 1-3 Cervical cancer <1 HCC 10 Gall bladder cancer 1 2% Bladder cancer <1 Pancreatic cancer 10% Esophageal cancer 15 Mesothelioma 1015 Burkitts lymphoma <1 1* 9% ?

Bronchitis Gastritis Cervicitis Hepatitis Cholecystitis Cystitis Pancreatitis Esophagitis Asbestosis Mononucleosis Hodgkins disease IBD Colorectal cancer Sunburn Melanoma PIA Prostate cancer

GA, gastric acid; GBS, gall bladder stones; HCC, hepatocellular carcinoma; STD, sexually transmitted diseases; PIA, prostate inflammatory atrophy.
From: Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology, 72, 2006, 1605-21

Hypothesis!
NF-kB activation is a major mediator of inflammation in most chronic diseases (including cancer) & inhibition of NF-kB can prevent/delay the onset of the chronic diseases!

NF-kappa B activation has been linked to most major diseases

Kumar A, Takada Y, Boriek AM, Aggarwal BB. Journal of Molecular Medicine 2004;82:434-48.

Potential Sources of Inflammation

Alcoholic beverages Environmental pollutants
Industrial pollutant, Diesel, Acid rain

Ultraviolet radiation Food Factors Grill, Fried, red meat

Stress
pH, hypoxia, heavy metals, chemotherapy

Bacteria
Helicobacter pylori Salmonella typhi Chlamydia pneumoniae Streptococcus bovis Escherichia coli

Cigarette smoke

Viruses
Herpes simplex virus 8, Hepatitis viruses, HPVs,HIV, EBV

Different faces of inflammation and its role in tumorigenesis

Stress
(Chemical, physical,and psychological)

Environmental pollutants
(Cigarette smoke, Diesel)

Viruses
(HTLV1, HPV,HCV, HBV, EBV )

Food Factors
(Grill, Fried, red meat)
Reactive oxygen species Tumor necrosis factor Interleukin-1 Interleukin-6 Iinterleukin-8 Interleukin-18 Nuclear Factor-kB Hypoxia-inducible factor Cyclooxygenase-2 5-Lipooxygenase Inducible nitric oxidesynthase Matrix metalloproteinase-9 Chemokines

Bacteria
(e.g; Helicobacter pylori )

Acute
inflammation
Innate Immunity Humoral immunity Immune surveillance

Chronic inflammation
Tumor cell survival Tumor cell proliferation Tumor cell invasion Tumor angiogenesis Tumor metastasis Tumor chemoresistance Tumor radioresistance

Therapeutic inflammation

Pathological inflammation

Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochem Pharmacol. 2006

Working Hypothesis
Stress NF-kappaB
Inflammation Cancer

Cigarette Smoke Activates Nuclear Factor-kB and Induces Cyclooxygenase-2

Anto R. J., Mukhopadhyay A., Gairola C. G. and Aggarwal B. B.,

Carcinogenesis, 23, 1511, 2002

Cigarette smoke-induced NF-kB activation is persistent

Cigarette smoke
0 0.5 1 2 4 8 12 24

t (h)

NF- kB

3.5

3.2

Fold

Shishodia S, and Aggarwal BB. Cancer Research. 2004;64:5004-12.

NF-kB expression in the pathogenesis of lung cancer

AAH Normal Epithelium Hyperplasia

Squamous Metaplasia

Moderate Dysplasia

Carcinoma In Situ

Tang et al, 2006

Obesity and Cancer

Esophageal cancer Multiple myeloma Renal cancer Gastric cancer Non-Hodgkins lymphoma Colon cancer

F5

Obesity
Cervical cancer

Gall bladder cancer

14% 20%

Pancreatic cancer

Ovarian cancer

Rectal cancer Uterine cancer Endometrial cancer

Breast cancer Liver cancer

Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009

Circulating mononuclear cells in the obese are in a proinflammatory state

Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P.

Circulation.
2004 Sep 21;110(12):1564-71.

Obese subjects express higher levels of activated NF-kB than lean subjects
Lean Obese

NF-kB

Modified from Ghanim H, 2004

Obese subjects express elevated levels of Inflammatory cytokines in plasma

4000 3000 2000 1000

CRP
4 3 2 1 0 600 450 300 150 0 4 3 2 1 0

TNF-

Obese

IL-6

MMP-9

MIF
Modified from Ghanim H, 2004

HK 03-28-08

Increase in intranuclear NF- kB and decrease in IkB in mononuclear cells after a mixed meal:
evidence for a proinflammatory effect.
Aljada A, Mohanty P, Ghanim H, Abdo T, Tripathy D, Chaudhuri A, Dandona P.

American Journal of Clinical Nutrition.

2004 Apr;79(4):682-90.

Protocol
Expt subjects:(N=9; BMI=25; non-diabetic; 29-38y) fasted overnight, came to clinic between 8-9 AM. Mixed meals: Egg muffin, sausage, muffin sandwiches, 2 hash browns (81g CHO, 51g fat; 32 g protein=910 kcal) finished in 15 min. Control subject: (N=8; BMI=24.3; 26-50 y) given 300ml water Blood samples: 1, 2, 3 h after the meal.

Aljada A, 2004

NF-kB
NF-kB: the enemy within.
Aggarwal BB. Cancer Cell. 2004 Sep;6(3):203-8.

NF-kB : a friend or a foe in cancer?

Shishodia S, Aggarwal BB. Biochem Pharmacol. 2004;68:1071-80.

Signalling pathways of the TNF superfamily: a double-edged sword.

Aggarwal BB. Nature Rev Immunol. 2003;3:745-56.

Inflammatory networking in cancer

TNF
Survival & Chemoresistance:
c-FLIP, Bcl-xL IAP-1, IAP-2, XIAP, survivin

Bone loss
RANKL, IL-1, TNF

NF-kB
IL-6

Invasion and metastasis

Chemokines

Proliferation:
Cyclin D1, 5-LOX, COX-2, IL-6

STAT3

Angiogenesis
VEGF

Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology. 2006

Role of inflammation in tumorigenesis

NF-kB

DNA damage Oncogenes

Bcl-xl Bcl-2 Survivin C-FLIP cIAP-1 cIAP-2 XIAP

Cyclin D1 C-myc TNF IL-1 IL-6 COX2

MMP-9 uPA ICAM-1 ELAM-1 VCAM-1

VEGF

CXCR4 TWIST

Transformation

Tumor suppression

Normal cell

Transformation

Survival

Proliferation

Invasion

Angiogenesis

Metastasis

10-20 Years

10 Years

Inflammation
Aggarwal etal, CCR, 2010

Constitutive activation of NF-kB has been linked with most cancers

Esophageal cancer Colon cancer Laryngeal cancer Pharyngeal cancer Pancreatic cancer Renal carcinoma

Head and neck SCC

Lung cancer

Bladder cancer

Tobacco-linked cancers
Acute Myelogenous leukemia Hodgkins disease Non-Hodgkins lymphoma B cell lymphoma T cell lymphoma Mantle cell lymphoma Multiple myeloma Acute lymphoblastic leukemia Thyroid cancer Liver cancer

Carcinogens

NF-kB

Breast cancer

Carcinogens
Ovarian cancer

Prostate cancer

Viral cancers
Adult T cell leukemia Cervical cancer Nasopharyngeal carcinoma

UV light
Melanoma

Shishodia and Aggarwal, Biochemical Pharmacology, 2004

NF-B addiction and its role in cancer:

One size does not fit all
Chaturvedi MM, Sung B, Yadav VR, Kannappan R, and Aggarwal BB Oncogene. 2011 Apr 7;30(14):1615-30.

Cross Talk between NF-kB and other transcription factors

Chaturvedi et al, 2011

Persistently activated Stat3 maintains constitutive NF-kB activity in tumors.

Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H. Cancer Cell. 2009 Apr 7;15(4):283-93.

NF-kB and FDA Approved Anticancer Drugs

Herceptin Tykerb Erbitux Iressa Vectibix Humira Remicade Revlimid Enbrel Sutent Sprycel Avastin Sutent Nexavar Gleevec Sprycel Tasigna

HER2

EGFR

TNF

PDGFR

VEGFR

Bcr-Abl

mTOR

Afinitor Torisel

Proteasome

Velacade

NF-kB
Chaturvedi et al, 2011

The NF-kB/bcl-2 pathway correlates with pathologic complete response to doxorubicinbased neoadjuvant chemotherapy in human breast cancer.
Buchholz TA, Garg AK, Chakravarti N, Aggarwal BB, Esteva FJ, Kuerer HM, Singletary SE, Hortobagyi GN, Pusztai L, Cristofanilli M, Sahin AA. Clinical Cancer Research 2005 Dec 1;11(23):8398-402.

NF-kB as a predictor of treatment response in breast cancer.

Garg AK, Hortobagyi GN, Aggarwal BB, Sahin AA, Buchholz TA. Current Opinion of Oncology 2003 Nov;15(6):405-11. Review.

Inflammatory biomarkers have been linked to survival of breast cancer pts

COX-2
Ahn, 2004; Chow, 2005; Nakopoulou, 2005; Guo, 2008; Haffty, 2008; Younis, 2009; Zeeneldin, 2009

NF-kB
Hou, 2003; Buchholz, 2005

STAT3
Dolled-Filhart, 2003; Wincewicz, 2007

NF-kB -regulated genes

Kumar A, Takada Y, Boriek AM, Aggarwal BB. Journal of Molecular Medicine 2004;82:434-48.

How to suppress NF-kB activation safely!

Chronic diseases caused by chronic inflammation requires chronic treatment!

Farmers Market

Fruits

Spices & condiments

Vegetables

Cereals
Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009

Hippocrates proclaimed ~2500 years ago

Let food be thy medicine and medicine be thy food

183

Identification of inhibitors of NF-kB from natural sources

Drug Development
High Throughput Screen vs. Reverse Pharmacology

Golden Triangle
Modern Technology

Traditional Knowledge
(Traditional Chinese Medicine Ayurvedic Medicine Egyptian Medicine Kampo)

Modern Knowledge
(Allopathic Medicine)

Aggarwal BB, et al Expert Opin Ther Targets. 2006;10:87-118.

Ayurveda (Sushruta Samhita)

Ayurveda means science of long life.

This is an ancient medical system primarily practiced in India for over 6000 years.

Therapeutic Uses of Ayurvedic plants

Guggul
Commiphora mukul

Salai Guggul
Boswellia Serrata

Ashwagandha
Withania Somnifera

Amla
Emblica Officinalis

Vitis Vinifera

Grapes

Piper Longum

Pipalli

Bala
Sida cordifolia

Guduchi
Tinospora cardifolia

Terminalia-chebula

Hareetaki

Bhumiyamalaki
Phyllantus amarus

Shilajit
Asphaltum

Isabgol
Plantago Ovata

Spreading Hogweed

Punarnava

Ocimum sanctum

Basil

Vanshalochan
Bamboosa arundinacea

Cinnamomum zeylanicum

Dalchini

Therapeutic Uses of Ayurvedic plants

Jeevanti
Leptadenia reticulata

Kachur
Curcuma zedoary

Karkatakashringi
Pistacia integerriama

Kushta
Saussurea lappa

Laghu Kantakari
Solanum xanthocarpum

Mustaka
Cyprus rotundus

Sterospermum suaveolens

Patala

Kokum
Garcinia indica

Clove
Syzygium aromaticum

Ashok
Saraca indica

Yastimadhu
Glycyrrhiza glabra

Saunf
Foeniculum vulgare

Neem
Azadirachta indica

Bakul
Erythrina Indica

Chemo drugs Receptor ligands Cytokines Growth factors Tobacco Obesity Fungus Interleukins Oxidative stress -radiation Physiological stress Hormones Viruses TNF Family Bacteria Sun exposure

F10

Glucose
Environmental pollutants

Carcinogens

Carcinogens Heavy metals Mitogens Alcohol Leishmania

Glycyrrhizic acid
Berberine Lycopene Morin Stigmasterol Apigenin Mangiferine Thymoquinone Kaempferol

NF-kB Inflammation

Fisetin Allicin Tocotrienol

Geraniol Caffeic acid

Plumbagin

Capsaicin

Zerumbone Silymarin

Chemopreventive agents
Genistein Celastrol Catechin

Quercetin Myrcetin Anethole

Piperine Xanthohumol Diosgenin

Indole-3-carbinol
Ascorbic acid

Tocopherol Ursolic acid Phytic acid Rutin Gossypin

Pantothenic acid

Betulinic acid Gingerol Curcumin Luteolin

Ellagic acid Lupeol

Sanguinarine

Delphinidine Gambogic acid Sulphoraphane Avenanthramide Eugenol

Resveratrol

Antiinflammatory life style

Spices Fruits & Vegetables
Asian ginger (1)
(Alpinia galanga)

Fennel (2)
(Foeniculum vulgare)

Sesame seed (3)

(Sesamum indicum)

Turmeric (4)
(Curcuma longa)

Cloves (5)
(Eugenia caryophyllu)

Cauliflower (1)
(Brassica oleracea)

Mullberry (2)
(Morus nigra)

Artichoke (3)
(Cynara cardunculus)

Grapes (4)
(Vitis vinifera)

Soybean (5) (Glycine max)

Red chili (6)

(Capsicum annum )

Fenugreek (7)
(Trigonella foenum graecum)

Poppy seed (8)

Gamboge (9)

Onion (10)
(Allium cepa)

Traditional Chinese Medicine

(Papaver somniferum) (Garcinia hanburyi)

Lacquer tree (1)

(Rhus verniciflua)

Goldenseal (2)
(Hydrastis canadensis)

God of thunder vine (3)

(Tripterygium wilfordii)

Smoke tree (4)

(Cotinus coggygria)

Onion seed (11)

(Nigella sativa)

Holy basil (12)

(Ocimum sanctum)

Pomegranate (13)
(Punica granatum)

Ayurvedic Medicine
Evodia (5)
(Evodia rutaecarpa)

Song gen (6)

(Phellinus linteus)

Magnolia (7)
(Magnolia officinalis)

Aloe (1)
(Aloe vera)

Veldt-grape (2)
(Cissus quadrangularis)

Picroliv (3)
(Picrorhiza kurroa)

Himalayan fir (4)

(Abies webbiana)

Chitrak (5)
(Plumbago zeylanica)

Others

Elephant's foot (4) Hop (5) Cashew nut (1) Palm (3) Horse chestnut (2) (Aesculus hippocastanum) (Elaeis guineensis) (Elephantopus scaber Linn)(Humulus Iupulus L.) (Anacardium occidentale) Boswellia (7)
(Boswellia serrata)

Beauty berry (7)

Pink trumpet tree (8)

Bloodroot (9)
(Sanguinaria canadensis)

Guggulu (10)
(Commiphora mukul)

(Callicarpa macrophylla) (Tabebuia avellanedae)

Ginger lily (6)

(Hedychium coronarium)

Cork bush (7)

(Mundulea sericea)

Tropical rose mallow (8) Oleander (9)

(Hibiscus vitifolius) (Nerium oleander)

False pepper (11)

(Embelia ribes)

Rohitukine (12)

Ashwagandha (13)

Indigo (14)

Pinecone ginger (15)

(Zingiber zerumbet)

(Dysoxylum binectariferu (Withania somnifera) (Polygonum tinctorium) m)

Spices
O O O O
H3C O
O O O O O O

Fruits & Vegetables

OH

O O H C 3 H O O O O
3

C
H2C C CH2 H H

H
CH 2 OH N H

HO HO O O H O HO

H O H O OH O H O O

H H O O C 2O H H

O O
3

H C H HO

O H O

1-Actoxychavicol acetate (1)

Anethole (2)

Sesamin (3)
O

Curcumin (4)

Eugenol (5)
O

HH O

H
O O H O N H

O
H3C O H

N H O O O O CH3

CH3
O O O

OH O

Indole 3carbinol (1)

Morin (2)

Silymarin (3)

Resveratrol (4)

Genistein (5)

H H HO H

H3 C

OH O

Traditional Chinese Medicine

OH
O

Capsaicin (6)
OH OH HO O OH OH O

Diosgenin (7)

Noscapine (8)

Gambogic acid (9)

O

HOOC
O

OH OH HO O OH O

O H 3C O

CH 3 CH 3
HO

H COOH

HO HO

O OH O O OH

HO OH O

OH H3CO
N OCH 3

O HO

Butein (1) Thymoquinone (11) Ursolic acid (12) Ellagic acid (13)

Berberin (2)
OH O

Celastrol (3)
H O H O

Fisetin (4)

Quercetin (10)

Ayurvedic Medicine
HO H

N H

N N

O
HO OH

O HO HO O

OH OH

OH OH
O HO O OH O OH O

OH OH OH OCH3 OH OH

Evodiamine (5)
O CH3 OH O

Hispolon (6)

Honokiol (7)

HO OH

Cinnamoyl O HO

Others
HO HO OH OH HO O O HO O O OH H OH H H O O O OH

O
H O O

Emodin (1)

Piceatannol (2)

Picroliv (3)
O O

Pinitol (4)
O N+

Plumbagin (5)
H3C H O

O O O

H H

HO HO

O O O O

O
COOH
O

C3 H
O O O O OH OH

O
H3 C CH3

H3CO HOOC

HO

Anacardic acid (1)

O

Escin (2)

-Tocotrienol (3)

Isodeoxyelephan -topin (4)

Acetyl-11-keto-boswellic acid (6)

O O O O H H

Betulinic acid (7)

N O HO O

-Lapachone (8)
OH NH 4 N H NH O

Sanguinarine (9) Guggulusterone (10)

H3C
OAc O O O

O
CH 3 OH HO O OH O

HO

O O

CH3 CH3 O

HO H2 C HO HO

O O HO HO OH O OH OH O

O
OH

OH O

OH3C
H

OH O

O OAc

H 3C

CH3O

Embelin (11)

Flavopiridol (12)

Indirubin 3monoxime (13)

HO O

Withanolide (14)

Zerumbone (15)

Xanthohumol (5) Coronarin-D (6)

Deguelin (7)

Gossypin (8)

Oleandrin (9)

Resveratrol can block NF-kB Activation

Aggarwal etal, 2004

Indole-3-Carbinol can block NF-kB activation

Aggarwal etal, 2004

Sources of tocotrienols

Red annatto

Palm oil
940 mg/kg

Barley
910 mg/kg

Rice bran
465 mg/kg

Grape fruit seed oil

380 mg/kg

Oat
210 mg/kg

Hazelnut
209 mg/kg

Maize
200 mg/kg

Wheat germ oil

189 mg/kg

Olive oil
180 mg/kg

Buckthorn Berry 130

mg/kg

Rye
92 mg/kg

Flax seed oil

25.1 mg/kg

Poppy seed oil

20.5 mg/kg

Safflower oil
11.8 mg/kg

From: Red annatto, Barrie, Tan; Palm oil, Schroeder,2006; Rice bran, Sookwong,2010; Grape fruit seed oil, maize, Wheat germ oil-Hassanein, 2009; Hazel nut, Amaral, 2006; Olive oil, Cunha, 2006; Buckthorn berry, Kallio, 2002; Rye-milagros DelgadoZamarreno, 2009; Oat and barley, Panfili, Fratianni.200; Flax oil, poopy oil, safflower oil, Bozan, 2008

From Aggarwal et al, 2010

Tocopherols >20,000 pub

CH3 HO
3HC

Tocotrienols <500 pub

CH3 CH3 HO
3HC

CH3 O CH3 CH3

CH3

CH3

CH3 O CH3 CH3

CH3

CH3

CH3

Alfa
CH3 O CH3 CH3 CH3 HO H

Alfa
CH3 O CH3 CH3 CH3

HO H CH3 H

Beta
CH3 O

CH3 H

Beta
CH3 O

HO
3HC

CH3

CH3

CH3 HO
3HC

CH3

CH3

CH3

CH3 H HO H CH3

Gamma
CH3 CH3 CH3 CH3 HO H

CH3 H

Gamma
CH3 CH3 CH3 CH3

O
CH3

Delta

Delta

tocotrienol but not toocpherol inhibits NF-kB signaling pathway through inhibition of RIP and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis.
Ahn KS, Sethi G, Krishnan K, Aggarwal BB.
Journal of Biological Chemistry. 2007 Jan 5;282(1):809-20.

Azadiracta indica
(neem; Azad Dirakht)

Over 300 bioactive compounds have been identified

Neem
Systemic purifier Antibacterial Antifungal Blood purifying properties are useful in skin disorders and keeps the skin healthy. Tonic and astringent that promotes wound healing. Detoxifying benefits that help maintain healthy circulatory, digestive, respiratory, and urinary systems. Possesses anti-diabetic, and anti-viral properties. Beneficial in treating malarial fever and cutaneous diseases

Neem

Thunder of Gods Vine

(Tripterygium wilfordii Hook F.)

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kB-regulated gene products and TAK1-mediated NF-kB activation.

Sethi G, Ahn KS, Pandey MK, Aggarwal BB. Blood. 2007 Apr 1;109(7):2727-35.

Ergothioneine

Although ET was isolated a century ago, its physiologic function has not been clearly established.
Foods with highest concentrations of ergothioneine are mushrooms, kidney, liver, black and red beans, and oat bran. (Ey J, 2007)

Ergothioneine (2-mercaptohistidine trimethylbetaine) is a naturally occurring amino acid analogue found in up to millimolar concentrations in several tissues and biological fluids.

The unusual amino acid L-ergothioneine is a physiologic cytoprotectant

Paul BD, Snyder SH. Cell Death Differ. 2010 Jul;17(7):1134-40. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ergothioneine (ET) is an unusual sulfur-containing derivative of the amino acid, histidine, which is derived exclusively through the diet. Recently, a highly specific transporter for ET (ETT) was identified in mammalian tissues, which explains abundant tissue levels of ET and implies a physiologic role. Using RNA interference, we depleted cells of its transporter. Cells lacking ETT are more susceptible to oxidative stress, resulting in increased mitochondrial DNA damage, protein oxidation and lipid peroxidation. ETT is concentrated in mitochondria, suggesting a specific role in protecting mitochondrial components such as DNA from oxidative damage associated with mitochondrial generation of superoxide. In combating cytotoxic effects of pyrogallol, a known superoxide generator, ET is as potent as glutathione. Because of its dietary origin and the toxicity associated with its depletion, ET may represent a new vitamin whose physiologic roles include antioxidant cytoprotection.

Ergothioneine inhibits oxidative stress- and TNF-a-induced NF-kB activation and interleukin-8 release in alveolar epithelial cells.

Rahman I, Gilmour PS, Jimenez LA, Biswas SK, Antonicelli F, Aruoma OI.

Biochem Biophys Res Commun. 2003 Mar 21;302(4):860-4.

Pneumonia, Bronchitis, Abdominal pain, Dysentery, Diarrhea, Cold, Obesity

Crotepoxide

Crotepoxide

From exotic spice to modern drug?

Singh S. Cell. 2007 Sep 7;130(5):765-8.
The global demand for more affordable therapeutics and concerns about side effects of commonly used drugs are refocusing interest on Eastern traditional medicines, particularly those of India and China.

Dietary Spices

TNF blockers
Spice book

Curcumin
book

Add spices to your life!

Spice Route

Dietary Spices

Turmeric
O CH3O O CH3O O

Zingiber cassumunar
O CH3O OH CH3O N H O

Red chilli

HO

Curcumin
O O

OH

HO

Cassumuin A
O

CH3O CH3O

Capsaicin

CH3O O CH3O

HO

Demethoxycurcumin
O O

OH

HO CH3O HO

OH

CH3O CH3O O O

Glycorrhiza

Cassumuin B

OH

Bisdemethoxycurcumin
HO O CH3O O O OH CH3O

Ginger Dibenzoylmethane

Cyclocurcumin

CH3O HO CH3O

[6]-Gingerol
HO

Alpinia
O CH3O CH3O

Guinea pepper
O O

Clove

Isoeugenol
O

O O

HO HO

Piperine

Yakuchinone A

[6]-Paradol

Black Pepper

Kunnumakkara etal, CL, 2008

Molecular Targets of Nutraceuticals Derived from Dietary Spices

Potential Role in Suppression of Inflammation and Tumorigenesis

Aggarwal B, Van Kuiken ME, Iyer LH, Harikumar KB, Sung B

Experimental Biology & Medicine 2009 234(8):825-49.

Spices as NF-kB Inhibitors

OCH 3
O H3CO OH O OCH3 OH

CH CH CH3

Curcuma longa
Turmeric

Curcumin

Foeniculum vulgare Anethole

Fennel

Capsicum annum
Red chilli

Capsaicin

Eugenia caryophyllata Eugenol

Cloves

T. foenum-graecum
Fenugreek

Diosgenin

Ocimum sanctum
Holi basil

Ursolic Acid

Red chilli
Capsaicin (8-methyl-N-vanillyl-6nonenamide) is a potent inhibitor of NF-kB activation by diverse agents.
Singh S, Natarajan K, Aggarwal BB. Journal of Immunology 1996 Nov 15;157(10):4412-20.

Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation.

Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB. Clinical Cancer Research. 2007 May 15;13(10):3024-32.

Ginger
Zerumbone abolishes NF-kB and IkBa kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion.
Takada Y, Murakami A, Aggarwal BB. Oncogene. 2005 Oct 20;24(46):6957-69

Black cumin
Targeting NF-kB activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis.
Sethi G, Ahn KS, Aggarwal BB. Molecular Cancer Research. 2008 Jun;6(6):1059-70.

Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways.
Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB, Liu M. Molecular Cancer Therapeutics. 2008 Jul;7(7):1789-96.

Fenugreek
Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IkB kinase activation and NF-kB-regulated gene expression.
Shishodia S, Aggarwal BB. Oncogene. 2006;25(10):1463-73.

OCH 3

Fennel

CH CH CH3

Anethole blocks both early and late cellular responses transduced by TNF: effect on NF-kB, AP-1, JNK, MAPKK and apoptosis.
Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB.
Oncogene. 2000 Jun 8;19(25):2943-50..

Black pepper

Structure of Curcumin
From turmeric (curry powder)
O O

CH3O

OCH3

HO

OH

Diferuloylmethane
Milobedzka J., von Kostnecki St, and Lampe V: Zur Kenntnis des curcumins. Ber Deutsch Chem Ges, 1910, 43, 2163-2170

Activation of transcription factor Nuclear Factor-kappa B is suppressed by curcumin

Singh S, and Aggarwal BB. J Biol Chem. 1995 Oct 20;270 (42):24995-5000.

Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets.

Aggarwal BB, Sung B.

Trends in Pharmacological Sciences 2009 Feb;30(2):85-94.

Different stages of cancer progression and its suppression by curcumin

Constitutive activation of transcription factors
AP-1& NF-kB

Overexpression of
Oncogenes HER2 Growth factors (e.g; EGF, PDGF, FGF) Growth factor receptors Survival factors (e.g; Survivin,Bcl-2 and Bcl-xl) Cyclin D1 Decoy receptor

Overexpression of
Matrix metalloproteases Cyclooxygenase-2 Adhesion molecules Chemokine TNF

Tumor Suppressor genes

Transformation Normal cells Tumor cells

Proliferation Tumor growth

Invasion Tumor Metastasis

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

Effect of NCB-02 (Curcumin), atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebocontrolled, 8-week study.
Usharani P, Mateen AA, Naidu MU, Raju YS, Chandra N.

Drugs R D. 2008;9(4):243-50.

Low doses of curcumin can decreases serum inflammatory biomarkers in patients

ET-1 IL-6
(pg/ml)
8.0 1.5 6.0 6.0 4.0 4.0 2.0 0.0 2.0 0.0 2.0

TNF-
(pg/ml)
6.0

MDA
(nmol/ml)

8 wks

(pg/ml)
2.0

N=21

Placebo

4.0

1.0 0.5

Biomarkers level

0.0 2.0

0.0 6.0

6.0 1.5 1.0 0.5 0.0 2.0 1.5 4.0 1.0 0.5 0.0 2.0 4.0

4.5

Atorvastatin
(10 mg/day)

N=23
3.0 1.5 0.0 4.0

2.0

2.0

0.0 6.0

0.0

6.0 4.0 2.0 0.0

4.5

N=23
3.0

Curcumin
(NCB-02 150 mgx2 daily)

1.5

0.0

0.0

Pre Post

Pre Post

Pre Post

Pre Post

Usharani, 2008

Curcumin & CRC patients

126 pts; 360 mg curcumin; thrice/day

Body weight

TNF-

Apoptosis

p53

(He et al, 2011)

Multi-targeted Approach to Prevention of Colorectal Cancer by Curcumin/Turmeric

AKT c-Myc IKK NF-kB STAT3

CREB

p21

DNA adducts

KRAS

COX-2

Curcumin / Turmeric

E-cadherin

-catenin TGF/S MAD PI3K p53

TAK1

Notch

EGFR

Comparison of Cancer Incidence in USA and India

Cancer USA India

Cases
Breast Prostate Colon/Rectum Lung Head & Neck SCC Liver Pancreas Stomach Melanoma Testis Bladder Kidney Brain, Nervous system Thyroid Endometrial Cancers Ovary Multiple myeloma Leukemia Non-Hodgkin lymphoma Hodgkin's disease 660 690 530 660 140 41 108 81 145 21 202 115 65 55 163 76 50 100 180 20

Deaths
160 130 220 580 44 44 103 50 27 1 43 44 47 5 41 50 40 70 90 5

Cases
79 20 30 38 153 12 8 33 1.8 3 15 6 19 12 132 20 6 19 17 7 1

Deaths
41 9 18 37 103 13 8 30 1 11 4 14 3 72 2 5 17 15 4

Showing cases per 1 million persons calculated on the basis of current consensus: Endometrial cancers include Cervix uteri and Corpus uteri. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARC Cancer Base No. 5. Lyon, IARC Press, 2001.

Thank you!
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