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

0 48.9 193.CDC/NCHS. 2002 Mortality Data: US Mortality Public Use Data Tape.5 Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer * Age-adjusted to 2000 US standard population. 2002. NVSS.4 56.1 22. Mortality Revised.7 193. Centers for Disease Control and Prevention.8 1950 500 400 300 200 100 0 2002 240. NCHS. Sources: 1950 Mortality Data .1 180. 1950 & 2002 600 586.Change in the US Death Rates* by Cause. 2004 .

EJC. 2000.Global Cancer Incidence From Parkin DM. 37. 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 7 2002 2020 2030 Year .

Harikumar K and Aggarwal BB. 2009 .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. Pharmaceutical Research.

Life style Carcinogens/Risk factors .

pork. Dietary modification can reduce this cancer burden by 70%. veal. lamb. high protein cholesterol and salt contents and heme iron are some of the components of meat linked with CRC. and offal) intake is closely linked with the risk of CRC.Colorectal Cancer and Red Meat! Colorectal cancer is the second most common cause of cancer deaths in affluent countries. Bastide NM. Heterocyclic amines. CAPR. high saturated fat. mutton. 2011 . Processed red meat (beef. carcinogenic Nnitroso compounds.

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

a physician in first century Rome: Heat (calor) Pain (dolor) Redness (rubor) Swelling (tumour) 21 .What is Inflammation? Cornelius Celsus.

Germany Linked Inflammation with atherosclerosis. multiple sclerosis. History of Nephrology. in 1850) His Pathology laboratory in Wurzburg. asthma. cancer.Inflammation and cancer Redness. swelling. 2006 22 . rheumatoid arthritis. heat and pain Rudolf Virchow (1821-1902. Alzheimer’s From Heidland A et al.

. Pancreas Meningitis…………………Brain Rhinitis…………………… Rhina Gingivitis………………… Gum ..Inflammation is “itis” Arthritis is inflammation of the joints Bronchitis………………. Stomach Esophagitis……………. Esophagus Pancreatitis……………. Bronchus Sinusitis………………… Sinus Gastritis……………….

gastric acid. gall bladder stones. GBS. prostate inflammatory atrophy. Inflammation and cancer: How hot is the link? Biochemical Pharmacology. 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 10–15 Burkitt’s lymphoma <1 1* 9% ? Bronchitis Gastritis Cervicitis Hepatitis Cholecystitis Cystitis Pancreatitis Esophagitis Asbestosis Mononucleosis Hodgkin’s disease IBD Colorectal cancer Sunburn Melanoma PIA Prostate cancer GA. et al. From: Aggarwal BB. HCC.Inflammation as a risk factor for most cancers Inducer Tobacco smoke Helicobacter pylori Human papilloma virus Hepatitis B & C virus Bacteria. PIA. GBS Gram. 2006. alcohol. 1605-21 . sexually transmitted diseases.uropathogens Tobacco. STD. 72. genetics GA. hepatocellular carcinoma.

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! .

Journal of Molecular Medicine 2004.82:434-48.NF-kappa B activation has been linked to most major diseases Kumar A. . Boriek AM. Aggarwal BB. Takada Y.

Hepatitis viruses. Fried. HPVs. chemotherapy Bacteria Helicobacter pylori Salmonella typhi Chlamydia pneumoniae Streptococcus bovis Escherichia coli Cigarette smoke Viruses Herpes simplex virus 8. heavy metals. Diesel. red meat Stress pH. Acid rain Ultraviolet radiation Food Factors Grill. EBV .HIV. hypoxia.Potential Sources of Inflammation Alcoholic beverages Environmental pollutants Industrial pollutant.

et al.HCV. HBV. Fried.and psychological) Environmental pollutants (Cigarette smoke. EBV ) Food Factors (Grill. 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.Different faces of inflammation and its role in tumorigenesis Stress (Chemical. Inflammation and cancer: How hot is the link? Biochem Pharmacol. HPV.g. 2006 . 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. Diesel) Viruses (HTLV1. physical.

Working Hypothesis Stress NF-kappaB Inflammation Cancer .

2002 . Mukhopadhyay A. J.. and Aggarwal B. B. G. 1511. Carcinogenesis.. Gairola C.Cigarette Smoke Activates Nuclear Factor-kB and Induces Cyclooxygenase-2 Anto R. 23..

2 Fold Shishodia S.5 4 3 3 3.Cigarette smoke-induced NF-kB activation is persistent Cigarette smoke 0 0. .64:5004-12. 2004. and Aggarwal BB. Cancer Research.kB 1 4 4 3.5 1 2 4 8 12 24 t (h) NF.

NF-kB expression in the pathogenesis of lung cancer AAH Normal Epithelium Hyperplasia Squamous Metaplasia Moderate Dysplasia Carcinoma In Situ Tang et al. 2006 .

Harikumar K and Aggarwal BB. Pharmaceutical Research.Obesity and Cancer Esophageal cancer Multiple myeloma Renal cancer Gastric cancer Non-Hodgkin’s 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. 2009 .

Mohanty P. .110(12):1564-71. Circulation. Syed T. 2004 Sep 21. Dandona P. Aljada A.Circulating mononuclear cells in the obese are in a proinflammatory state Ghanim H. Hofmeyer D.

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 0 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 .

Chaudhuri A.79(4):682-90. 2004 Apr. Abdo T. Aljada A. American Journal of Clinical Nutrition. Ghanim H. Mohanty P. . Tripathy D. Dandona P.kB and decrease in IkB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect.Increase in intranuclear NF.

sausage. 51g fat. 2 hash browns (81g CHO. 29-38y) fasted overnight. BMI=24. BMI=25.3. muffin sandwiches. 32 g protein=910 kcal) finished in 15 min. 3 h after the meal. came to clinic between 8-9 AM. 2. 26-50 y) given 300ml water Blood samples: 1. Aljada A. Control subject: (N=8. 2004 .Protocol Expt subjects:(N=9. Mixed meals: Egg muffin. non-diabetic.

6(3):203-8. 2004. NF-kB : a friend or a foe in cancer? Shishodia S. Signalling pathways of the TNF superfamily: a double-edged sword. Aggarwal BB.68:1071-80. Aggarwal BB. Cancer Cell. Biochem Pharmacol. Aggarwal BB. Nature Rev Immunol. . 2004 Sep. 2003.NF-kB NF-kB: the enemy within.3:745-56.

COX-2. survivin Bone loss RANKL. et al.Inflammatory networking in cancer TNF Survival & Chemoresistance: c-FLIP. Bcl-xL IAP-1. 5-LOX. IL-1. XIAP. IAP-2. TNF NF-kB IL-6 Invasion and metastasis Chemokines Proliferation: Cyclin D1. IL-6 STAT3 Angiogenesis VEGF Aggarwal BB. 2006 . Inflammation and cancer: How hot is the link? Biochemical Pharmacology.

2010 . CCR.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.

Biochemical Pharmacology.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 Hodgkin’s disease Non-Hodgkin’s 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. 2004 .

Yadav VR. . and Aggarwal BB Oncogene. Kannappan R.30(14):1615-30. Sung B.NF-κB addiction and its role in cancer: “One size does not fit all” Chaturvedi MM. 2011 Apr 7.

Cross Talk between NF-kB and other transcription factors Chaturvedi et al. 2011 .

Jove R.Persistently activated Stat3 maintains constitutive NF-kB activity in tumors. Kujawski M. .15(4):283-93. Deng JH. Herrmann A. 2009 Apr 7. Pardoll DM. Cancer Cell. Niu G. Lee H. Yu H. Li Z. Forman S.

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 X mTOR Afinitor Torisel Proteasome Velacade NF-kB Chaturvedi et al. 2011 .

. Pusztai L. Esteva FJ.11(23):8398-402.15(6):405-11. . Current Opinion of Oncology 2003 Nov. Sahin AA. Sahin AA.The NF-kB/bcl-2 pathway correlates with pathologic complete response to doxorubicinbased neoadjuvant chemotherapy in human breast cancer. Review. Aggarwal BB. Buchholz TA. Chakravarti N. Hortobagyi GN. Singletary SE. Clinical Cancer Research 2005 Dec 1. NF-kB as a predictor of treatment response in breast cancer. Buchholz TA. Kuerer HM. Cristofanilli M. Garg AK. Aggarwal BB. Garg AK. Hortobagyi GN.

2003. 2004. Nakopoulou. Wincewicz. Zeeneldin. 2008. 2007 . 2003. 2009. Chow. 2008. 2005 STAT3 Dolled-Filhart. Younis. Buchholz. 2005.Inflammatory biomarkers have been linked to survival of breast cancer pts COX-2 Ahn. Guo. 2009 NF-kB Hou. Haffty. 2005.

Boriek AM. Journal of Molecular Medicine 2004.NF-kB -regulated genes Kumar A. Aggarwal BB.82:434-48. Takada Y. .

How to suppress NF-kB activation safely! .

Chronic diseases caused by chronic inflammation requires chronic treatment! .

Harikumar K and Aggarwal BB. Pharmaceutical Research.Farmer’s Market Fruits Spices & condiments Vegetables Cereals Anand P. 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 .

Reverse Pharmacology .Drug Development High Throughput Screen vs.

.10:87-118. 2006.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.

This is an ancient medical system primarily practiced in India for over 6000 years. .Ayurveda (Sushruta Samhita) Ayurveda means “science of long life”.

.

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 O H O O H 1’-Actoxychavicol acetate (1) Anethole (2) Sesamin (3) O Curcumin (4) Eugenol (5) O H 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 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 O COOH O O C3 H O O O O OH OH O H3 C CH3 H3CO HOOC HO O 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 O O O O CH3 CH3 O HO H2 C HO HO O O HO HO OH O OH OH O O OH OH O O OH3C H OH O O OAc H 3C CH3O Embelin (11) Flavopiridol (12) Indirubin 3’monoxime (13) HO O O Withanolide (14) Zerumbone (15) Xanthohumol (5) Coronarin-D (6) Deguelin (7) Gossypin (8) Oleandrin (9) .

2004 .Resveratrol can block NF-kB Activation Aggarwal etal.

2004 .Indole-3-Carbinol can block NF-kB activation Aggarwal etal.

2010 . Bozan.2010. Rice bran. Flax oil. Schroeder. Hazel nut. 2009. 2009.200. Fratianni. Panfili. 2006. Cunha. Olive oil. Buckthorn berry. Amaral.5 mg/kg Safflower oil 11. poopy oil. maize. Grape fruit seed oil. Sookwong. Rye-milagros DelgadoZamarreno. Palm oil. 2006.2006. 2008 From Aggarwal et al. safflower oil. Oat and barley.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. Kallio. Tan. Wheat germ oil-Hassanein.8 mg/kg From: Red annatto. 2002. Barrie.

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 O CH3 Delta Delta .

- . Krishnan K. Sethi G.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.282(1):809-20. Aggarwal BB. 2007 Jan 5. Ahn KS. Journal of Biological Chemistry.

Azadiracta indica (neem. Azad Dirakht) Over 300 bioactive compounds have been identified .

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

Neem .

Thunder of God’s 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.

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

and TNF-a-induced NF-kB activation and interleukin-8 release in alveolar epithelial cells.Ergothioneine inhibits oxidative stress. Gilmour PS. Biochem Biophys Res Commun.302(4):860-4. Antonicelli F. 2003 Mar 21. Aruoma OI. . Jimenez LA. Rahman I. Biswas SK.

Obesity Crotepoxide . Diarrhea.Pneumonia. Abdominal pain. Cold. Dysentery. Bronchitis.

Crotepoxide .

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

Dietary Spices .

TNF blockers Spice book Curcumin book .

Add spices to your life! .

Spice Route .

Dietary Spices .

CL.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 N HO HO Piperine Yakuchinone A [6]-Paradol Black Pepper Kunnumakkara etal. 2008 .

Harikumar KB.Molecular Targets of Nutraceuticals Derived from Dietary Spices Potential Role in Suppression of Inflammation and Tumorigenesis Aggarwal B. Iyer LH. . Sung B Experimental Biology & Medicine 2009 234(8):825-49. Van Kuiken ME.

foenum-graecum Fenugreek Diosgenin Ocimum sanctum Holi basil Ursolic Acid .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.

. Kunnumakkara AB. Natarajan K. 2007 May 15. Guha S. Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation.13(10):3024-32. Bhutani M.157(10):4412-20. Pathak AK. Sethi G.Red chilli Capsaicin (8-methyl-N-vanillyl-6nonenamide) is a potent inhibitor of NF-kB activation by diverse agents. Clinical Cancer Research. Singh S. Aggarwal BB. Nair AS. Aggarwal BB. Journal of Immunology 1996 Nov 15.

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

Cho SG. Aggarwal BB. Sethi G. Sethi G. .6(6):1059-70.Black cumin Targeting NF-kB activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Liu M. 2008 Jun. Yi T. Wang Y. Yi Z. Aggarwal BB.7(7):1789-96. Molecular Cancer Research. Pang X. 2008 Jul. Molecular Cancer Therapeutics. Ahn KS. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Rodriguez M.

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

JNK. 2000 Jun 8. Oncogene. MAPKK and apoptosis.19(25):2943-50. Aggarwal BB. AP-1. Chainy GB. . Manna SK..OCH 3 Fennel CH CH CH3 Anethole blocks both early and late cellular responses transduced by TNF: effect on NF-kB. Chaturvedi MM.

Black pepper .

Structure of Curcumin From turmeric (curry powder) O O CH3O OCH3 HO OH Diferuloylmethane Milobedzka J. von Kostnecki St. 1910. Ber Deutsch Chem Ges.. 43. and Lampe V: Zur Kenntnis des curcumins. 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

Mateen AA. 8-week study. Usharani P. Drugs R D. 2008.9(4):243-50. oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized. Chandra N. atorvastatin and placebo on endothelial function. . Raju YS. placebocontrolled. parallel-group. Naidu MU.Effect of NCB-02 (Curcumin).

0 6.0 1.0 0.0 1.0 4.5 Biomarkers level 0.5 N=23 3.0 6.0 MDA (nmol/ml) 8 wks (pg/ml) 2.0 4.5 0.0 0.0 6.0 0.0 2.0 0.0 2.0 2.0 0.0 4.0 1.5 0.0 2.5 6.0 0.0 2.0 0.0 6.0 1.5 1.0 Pre Post Pre Post Pre Post Pre Post Usharani.0 2.0 0.0 1.0 4.0 4.0 2.5 Atorvastatin (10 mg/day) N=23 3.Low doses of curcumin can decreases serum inflammatory biomarkers in patients ET-1 IL-6 (pg/ml) 8.0 0.0 6.0 1.0 2.0 N=21 Placebo 4.5 4.5 0. 2008 .0 2.0 0.0 TNF- (pg/ml) 6.0 4.0 Curcumin (NCB-02 150 mgx2 daily) 1.5 0.0 4.

360 mg curcumin.Curcumin & CRC patients 126 pts. 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 .

IARC Cancer Base No. 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. 2001. . IARC Press. Mortality and Prevalence Worldwide. Lyon. Version 1. GLOBOCAN 2000: Cancer Incidence.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.0.8 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. 5.

Thank you! Arigato! Teşekkür ederim! Obrigado! Thank you! Namaste! Merci! Gamsa hamnida! Terima Kasih! Kiitos! Gracias! Shalom! Shei-shei! Do Jeh! Danke! .