Anti-Inflammatory Life Style for

Prevention and Treatment of

Cancer: Facts and Fiction

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.

The Society for Integrative Oncology

Host; Laura Vecchio

Albany, New York (1SIO)

info@integrativeonc.org | www.integrativeonc.org

(Webinar on Tuesday; August 13th, 12:00-1:00 PM)

A yin-yang symbol superimposed on a scanning electron micrograph of a mouse tissue alveolar macrophage.

Macrophages are immune cells that mediate inflammation, but they often play protective roles as well.

Several age-related chronic diseases such as metabolic syndrome,

cardiovascular disease, and neurodegenerative disease have an

inflammatory component

January

11th, 2013

Sick Societies: Responding to the

global challenge of chronic disease

David Stuckler (Author),

Karen Siegel (Author)

(Oxford Press)

Sept 21st, 2012

Inflammation, Lifestyle

and Chronic Diseases:

The Silent Link

Bharat B. Aggarwal, Ph.D. (Editor),

Sunil Krishnan, M.D. (Editor),

Sushovan Guha, M.D. (Editor)

(Francis and Taylor)

Aggarwal-638

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

Aggarwal BB.

Nature Reviews Immunology

2003 Sep;3(9):745-56.

Historical perspectives on

tumor necrosis factor and its superfamily: twenty-five years later, a golden journey.

Aggarwal BB, Gupta SC, Kim JH.

Blood. 2012 Jan 19;119(3):651-65.

TIME Feb. 23, 2004

TIME Feb. 23, 2004

Inflammation/Flame/Fire

Controlled

Uncontrolled

Life style Carcinogens/Risk factors

HK 04-14-2008

0

10

20

30

40

Tobacco Diet Obesity Infections Genes

Cancer Is a Preventable Disease That

Requires Major Changes in Life Style

E. Pollution

& Radiations

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

Reduce your risk of

cancer by 30 to 40%

by adopting healthier

eating habits. Visit: http://www.mdanderson.org/cancerawareness

Bacteria

Helicobacter pylori

Salmonella typhi

Chlamydia pneumoniae

Streptococcus bovis

Escherichia coli

Viruses Herpes simplex virus 8,

Hepatitis viruses, HPVs,HIV, EBV

Stress pH, hypoxia,

heavy metals,

chemotherapy

Cigarette

smoke

Food Factors

Grill,

Fried,

red meat

Environmental

pollutants Industrial pollutant,

Diesel, Acid rain Ultraviolet

radiation

Alcoholic

beverages

Potential Sources of Inflammation

Inflammation

Working Hypothesis:

Dysregulated chronic

inflammation caused by

life style factors mediate

chronic diseases

including cancer!

Inflammation and cancer

Rudolf Virchow (1821-1902; in 1850)

His Pathology laboratory in Wurzburg, Germany

Redness, swelling, heat and pain

From Heidland A et al, History of Nephrology, 2006

Linked Inflammation with atherosclerosis, rheumatoid arthritis, multiple sclerosis, cancer, asthma, Alzheimer’s

22

Arthritis is inflammation of the joints

Bronchitis………………. Bronchus

Sinusitis………………… Sinus

Gastritis………………. Stomach

Esophagitis…………….. Esophagus

Pancreatitis…………….. Pancreas

Meningitis…………………Brain

Rhinitis…………………… Rhina

Gingivitis………………… Gum

Inflammation is “itis”

Adenitis

Adrenalitis

Allergic rhinitis

Appendicitis

Arachnoiditis

Arteritis

Arthritis

Blepharitis

Bronchiolitis

Bronchitis

Bursitis

Capsulitis

Carditis

Cellulitis

Cerebellitis

Cerebritis

Cervicitis

Cheilitis

Cholecystitis

Chondritis

Chorditis

Choroiditis

Colitis

Conjunctivitis

Cystitis

Dermatitis

Dermatomyositis

Diverticulitis

Duodenitis

Pancreatitis

Panophthalmitis

Pansinusitis

Paracolpitis

Paraglottitis

Paradenitis

Parahepatitis

Parametritis

Paranephritis

Parasalpingitis

Parodontitis

Parotitis

Periadenitis

Periangitis

Periarteritis

Periarthritis

Pericarditis

Periodontitis

Peritonitis

Pharyngitis

Phlebitis

Pleuritis

Pneumonitis

Poikilodermatomyositis

Proctitis

Pyelonephritis

Retinitis

Rhinitis

Rheumatoid arthritis

Salpingitis

Salpingo-oophoritis

Sialoadenitis

Sinusitis

Sphenoiditis

Splenitis

Spondylitis

Stomatitis

Syndesmitis

Synovitis

Tendonitis

Temporal arteritis

Tenosynovitis

Thrombophlebitis

Thyroiditis

Typlitis

Tonsillitis

Urethritis

Uveitis

Vaginitis

Valvulitis

Vulvitis

Vulvovaginitis

Encephalitis

Endocarditis

Endotracheitis

Endometritis

Enteritis

Enterocolitis

Epididymitis

Epididymo-orchitis

Fibrositis

Epiglottiditis

Epiphysitis

Episcleritis

Esophagitis

Ethmoiditis

Fascitis

Fibromyositis

Folliculitis

Funiculitis

Gastritis

Gastroenteritis

Gingivitis

Glossitis

Glottitis

Glomerulonephritis

Hepatitis

Hidradenitis

Ileitis

Iritis

Iridocyclitis

JejunitisKeratitis

Keratodermatitis

Laminitis

Laryngitis

Lymphadenitis

Lymphangitis

Mastitis

Mastoiditis

Meningitis

Meningomyelitis

Myelitis

Myeloencephalitis

Myocarditis

Myositis

Myringitis

Nephritis

Neuritis

Neuroretinitis

Omphalitis

Onychitis

Oophoritis

Oophorosalpingitis

Ophthalmitis

Orchitis

Osteochondritis

Osteitis

Otitis

Optic neuritis

Osteoarthritis

Inflammation-mediated diseases

Inducer Inflammation Cancers % predisposed

progress to cancer

Tobacco smoke Bronchitis Lung Cancer 11-24

Helicobacter pylori Gastritis Gastric Cancer 1 - 3

Human papilloma virus Cervicitis Cervical cancer <1

Hepatitis B & C virus Hepatitis HCC 10

Bacteria, GBS Cholecystitis Gall bladder cancer 1 – 2%

Gram- uropathogens Cystitis Bladder cancer <1

Tobacco, genetics Pancreatitis Pancreatic cancer 10%

GA, alcohol, tobacco Esophagitis Esophageal cancer 15

Asbestos fibers Asbestosis Mesothelioma 10–15

Epstein-Barr virus Mononucleosis Burkitt’s lymphoma <1

Hodgkin’s disease

Gut pathogens IBD Colorectal cancer 1*

Ultraviolet light Sunburn Melanoma 9%

Infections, STD PIA Prostate cancer ?

From: Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology, 72, 2006, 1605-21

Inflammation as a risk factor for most cancers

GA, gastric acid; GBS, gall bladder stones; HCC, hepatocellular carcinoma; STD, sexually transmitted diseases;

PIA, prostate inflammatory atrophy.

NF-B activation is a major

mediator of inflammation in

most chronic diseases

(including cancer) &

inhibition of NF-B can

prevent/delay the onset of

the chronic diseases!

Hypothesis!

NF-B -regulated genes

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

TNF

Angiogenesis VEGF

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

COX-2, IL-6

Invasion and

metastasis Chemokines

Survival &

Chemoresistance: c-FLIP, Bcl-xL

IAP-1, IAP-2, XIAP, survivin

Bone loss RANKL, IL-1, TNF

Inflammatory networking in cancer

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

NF-kB

STAT3

Radiation

..nib

..mab

Chemo

Regulation of Inflammatory Network

NF-kB

B cell

lymphoma

Hodgkin’s

disease

T cell

lymphoma

Acute lymphoblastic

leukemia

Breast

cancer

Liver

cancer

Thyroid

cancer

Prostate

cancer

Melanoma

Head and neck SCC Colon cancer

Multiple

myeloma

Ovarian

cancer

Bladder cancer Lung cancer

NF-B

Acute

Myelogenous

leukemia

Cervical

cancer

Nasopharyngeal

carcinoma

Mantle cell

lymphoma

Non-Hodgkin’s

lymphoma

Viral cancers

Tobacco-linked cancers

UV light

Carcinogens Carcinogens

Esophageal

cancer

Pharyngeal

cancer

Renal

carcinoma

Laryngeal

cancer

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

Shishodia and Aggarwal, Biochemical Pharmacology, 2004

Adult T cell

leukemia

Pancreatic

cancer

NF-κB 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-B and other transcription factors

Chaturvedi etal, 2010

Normal cell Transformation Survival Proliferation Invasion Angiogenesis Metastasis

Transformation

Tumor suppression

Inflammation

NF-B

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

10-20 Years 10 Years

Role of inflammation in tumorigenesis

Aggarwal etal, CCR, 2010

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.

Cigarette Smoke Activates

Nuclear Factor-B and Induces

Cyclooxygenase-2

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

Aggarwal B. B.,

Carcinogenesis, 23, 1511, 2002

NF- B

1 4 4 3.5 4 3 3 3.2 Fold

0 0.5 1 2 4 8 12 24 t (h)

Cigarette smoke

Cigarette smoke-induced NF-B

activation is persistent

Shishodia S, and Aggarwal BB.

Cancer Research. 2004;64:5004-12.

Normal Epithelium Hyperplasia

Moderate Dysplasia Carcinoma In SituSquamous Metaplasia

AAH Normal Epithelium Hyperplasia

Moderate Dysplasia Carcinoma In SituSquamous Metaplasia

AAH

NF-B expression in the pathogenesis

of lung cancer

Tang et al, 2006

F5

Esophageal cancer

Colon cancer

Renal cancer

Multiple myeloma

Liver cancer

Breast cancer

Ovarian cancer Pancreatic cancer

Rectal cancer

Non-Hodgkin’s

lymphoma

Cervical cancer

Gall bladder cancer

Gastric cancer

Obesity 14%

20%

Uterine cancer

Endometrial cancer

♂ ♀

Obesity and Cancer

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

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

NF-B : a friend or a foe in cancer? Shishodia S, Aggarwal BB.

Biochem Pharmacol. 2004;68:1071-80.

NF-κB in Cancer:

A Matter of Life and Death. Aggarwal BB, Sung B.

Cancer Discovery. 2011 Nov;1(6):469-71.

NF-B

Characterization of receptors for human TNF and their

regulation by IFN-g. Aggarwal BB, Eessalu TE, Hass PE.

Nature. 1985 Dec 19-1986 Jan 1;318(6047):665-7.

T-helper-1-cell cytokines (TNF-a and IFN-g) drive cancer

into senescence. Braumüller H, .., Röcken M.

Nature. 2013 Feb 21;494(7437):361-5.

Impaired interferon signaling is a common immune defect

in human cancer. Critchley-Thorne RJ, .., Lee PP.

Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9010-5.

Hypothalamic programming of systemic ageing involving

IKK-β, NF-κB and GnRH. Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D.

Nature. 2013 May 9;497(7448):211-6.

NF-B

Hypothalamic inflammation

NF-B

Overweight

Glucose intolerance

Hypertension

Aging

IKKb/NF-kB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Li, J., .. Nature Cell

Biol. 14, 999–1012 (2012).

Hypothalamic IKKb/NF-kB and ER stress link overnutrition to energy imbalance and obesity. Zhang, X. et al. Cell 135, 61–73 (2008).

Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Purkayastha,S.etal. PNAS 108, 2939–2944 (2011).

Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-b and NF-kB. Purkayastha,S.,..Nature Med. 17, 883–887 (2011).

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

NF-B : a friend or a foe in cancer? Shishodia S, Aggarwal BB.

Biochem Pharmacol. 2004;68:1071-80.

NF-κB in Cancer:

A Matter of Life and Death. Aggarwal BB, Sung B.

Cancer Discovery. 2011 Nov;1(6):469-71.

NF-B

NF-B: a pivotal transcription factor in

chronic inflammatory diseases.

Barnes PJ, Karin M.

New England Journal of Medicine.

1997 Apr 10;336(15):1066-71.

NF-kB in cancer development

and progression Karin M.

Nature. 2006 May 25;441(7092):431-6.

NF-B & Cancer NFKBIA deletion in glioblastomas.

Bredel, 2011; N Engl J Med. 2011 Feb 17;364(7):627-37.

Monoallelic deletion of NFKBIA in glioblastoma: when less is more.

Rinkenbaugh AL, Baldwin AS.Cancer Cell. 2011 Feb 15;19(2):163-5.

Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that

promotes chemotherapy resistance.

Tanaka K,. Cancer Discov. 2011 Nov;1(6):524-38.

FAS and NF-κB signalling modulate dependence of lung cancers on

mutant EGFR.

Bivona TG,... Nature. 2011 Mar 24;471(7339):523-6.

Requirement for NF-kappaB signalling in a mouse model of lung

adenocarcinoma.

Meylan E, …….Jacks T. Nature. 2009 Nov 5;462(7269):104-7.

Stress

NF-kappaB

Inflammation

Cancer

Working Hypothesis

Nearly 43% of patients

with ulcerative colitis

develop colorectal

cancer after

Ekbom A, 1998

Prevalence of rates of Ulcerative Colitis:

JAPAN 7.9 per 100,000

INDIA 44.3 per 100,000

USA 229.0 per 100,000

Inflammatory bowel disease:

a survey of the epidemiology in Asia. Goh K, Xiao SD. Journal of Digestive Diseases. 2009 Feb;10(1):1-6.

• Migrant studies of South Asians in the UK, where second-generation immigrants have assumed incidence rates as

high as the indigenous whites and Asian Jews who develop high incidence rates comparable to Jews from Europe

or North America in Israel point to the role of environmental factors.

• Studies have suggested a change in diet to a more Westernized one may underlie this epidemiological change in

the Asian population.

• It is likely that there are racial groups amongst Asians who are more susceptible to IBD and who will demonstrate

a higher frequency of IBD when exposed to putative environmental factors.

A Fire Extinguisher!

How to suppress

NF-B activation

safely?

Wonders of Modern Medicine

Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much?

Fojo T, Parkinson DR. Clinical Cancer Research. 2010 Dec 15;16(24):5972-80. Medical Oncology Branch, Center for Cancer Research, Bethesda, Maryland, USA.

Neutralizing tumor-promoting

chronic inflammation:

a magic bullet?

Coussens LM, Zitvogel L, Palucka AK.

Science.

2013 Jan 18;339(6117):286-91.

Neutralizing tumor-promoting chronic inflammation: a magic bullet? Coussens LM, Zitvogel L, Palucka AK.

Science. 2013 Jan 18;339(6117):286-91.

Steroids

NSAID

Celebrex

Metformin

Statins

Natural Products &

Traditional Medicine

Aspirin (Salicylic acid; bark and leaves of willow tree)

The Greek physician Hippocrates wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and

pains and reduce fevers. Fruits and vegetables are natural sources of salicylic acid, particularly blackberries, blueberries, cantaloupes,

dates, raisins, guavas, apricots, green pepper, olives, tomatoes, radish, mushrooms and chicory. Some herbs and spices contain quite

high amounts. Of the legumes, seeds, nuts, and cereals, only almonds, water chestnuts and peanuts have significant amounts.

Galega name derives from gale (milk) and ega (to bring on), as Galega has been used as a galactogogue in small domestic animals

(hence the name "Goat's rue").

Carl Djerassi worked on a new synthesis of cortisone based on diosgenin, a steroid sapogenin derived from a Mexican wild yam.

Metformin ( Galega officinalis; goat's rue )

Steroids (Fenugreek; Diosgenin)

Statins

(Aspergillus terreus)

Prevention by Aspirin

Aspirin Ischemic

stroke

Myocardial

infarction

Cancer

Haemorrhagic

stroke

• Women who take aspirin regularly for 20 years have an increased chance of developing pancreatic

cancer, according to a survey of 90,000 females.

• Scientists studied thousands of American women, finding that those who took two or more tablets

each week for two decades had a 58% increased chance of developing the disease.

• The risk of developing pancreatic cancer increased as the dose got bigger up to 86% higher for

those who took the drug twice a day. Aspirin has been hailed as a wonder drug and is commonly

recommended as a preventative treatment for heart disease.

• It has also been suggested as a preventative drug against Alzheimer's disease and can prevent

deep vein thrombosis during long haul flights.

• The researchers, based at the Brigham and Women's Hospital and Harvard Medical School in

Boston, warned in their study that doctors and patients must balance the benefits of aspirin with

the risks suggested by the new study. The scientists studied nearly 90,000 women.

• Among them, 34% were defined as regular users, taking two or more 325mg aspirin tablets per

week.

• The regular users, over the next two decades, were found to be 58% more likely to develop cancer

of the pancreas.

• Those who took two tablets a day for 20 years were 86% more likely to get the cancer, said the

report, published in the Journal of the National Cancer Institute.

• Read more: http://www.dailymail.co.uk/news/article-205523/Aspirin-ups-risk-cancer--survey.html#ixzz2GO2zEob3

• Follow us: @MailOnline on Twitter | DailyMail on Facebook

Aspirin ups risk of cancer’ – survey

TNF Blockers ( $20 billion/year)

Crohn’s

Disease

Ulcerative colitis

Rheumatoid

arthritis

Ankylosing

spondylitis Juvenile idiopathic

arthritis

FDA approved uses

of TNF blockers

Psoriasis

Drug Mechanism Disease

Infliximab mAbs RA, PA, psoriasis, ALS, ulcerative colitis,

Crohn's disease

Etanercept RD RA, PA, psoriasis, ALS, juvenile RA

Adalimumab mAbs RA, PA, psoriasis, ALS, juvenile RA,

Crohn's disease

Certolizumab mAbs RA, Crohn's disease

Golimumab mAbs RA, PA, AS

Aggarwal et al., 2011,

Blood

Selected FDA approved TNF blockers

Aggarwal et al., 2011, Blood

TNF-α

Ankylosing spondylitis

Autoimmune diseases

Atopic dermatitis

Atherosclerosis

Hidradenitis suppurativa

Inflammatory

bowel disease

Multiple sclerosis

Rheumatoid arthritis

Psoriasis

Sarcoidosis

Scleroderma

Systemic lupus erythematosus

Eczema

Myocardial infarction

Cancer

Non-alcoholic fatty liver disease

Asthma

Pulmonary diseases

Diabetes, type 2

Obesity

Metabolic diseases

Chronic obstructive

pulmonary disease

Cardiovascular diseases

Alzheimer's disease

Neurologic diseases

Epilepsy

Bipolar disorder

Depression

Parkinson's disease

Osteoporosis

Various diseases that have been closely linked to TNF-α and members of its family.

TNF blockade:

an inflammatory issue

Aggarwal BB, Shishodia S, Takada Y, Jackson-

Bernitsas D, Ahn KS, Sethi G, Ichikawa H.

Ernst Schering Res Found Workshop.

2006;(56):161-86. Review.

Deepak, 2012; Askling, 2005a, 2005b; Siegel, 2009; Herrinton, 2011; Parakkal, 2011; Adams, 2004; Dalle, 2005; Michot, 2009;

Dauendorffer, 2007; Lourari, 2009; Schmidt, 2009; Mackey, 2007

TNF Blockers ( $20 billion/year)

Lymphoma

T cell

Non-Hodgkins

Lymphoma

Develop

resistance

Cutaneous T Cell

lymphoma Sezary syndrome

Black label

warning

Infections

Injectable

only

Evidence that curcumin is an orally

bioavailable TNF-a blocker in human

Usharani,

2008

Placebo

Curcumin (150 mgx2 daily)

TN

F-

(p

g/m

l)

6.0

4.0

2.0

0.0

Pre Post

6.0

4.0

2.0

0.0

8 wks

N=21

N=23

Se

rum

TN

F-

(p

g/m

l)

Regulation of production and action of TNF by curcumin

….Sloan School of

Management at M.I.T. and

the Harvard Business

School has created

Pharmer’s Market,

however, we need a

Farmer’s Market…

New York Times, November, 2009

Fruits Spices & condiments

Cereals Vegetables

Farmer’s Market

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

Farmer’s Market

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

Farmer’s Market

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

Farmer’s Market

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

Sept 21st, 2012

Fruits & Vegetables

Traditional Chinese Medicine

Ayurvedic Medicine

Others

Spices

Fennel (2) (Foeniculum vulgare)

Asian ginger (1) (Alpinia galanga)

Red chili (6) (Capsicum annum

)

Sesame seed (3) (Sesamum

indicum)

Turmeric (4) (Curcuma longa)

Gamboge (9) (Garcinia hanburyi)

Onion seed (11) (Nigella sativa)

Holy basil (12) (Ocimum sanctum)

Onion (10) (Allium cepa)

Poppy seed (8) (Papaver somniferum)

Fenugreek (7) (Trigonella foenum

graecum)

Cloves (5) (Eugenia

caryophyllu)

Pomegranate (13) (Punica granatum)

Boswellia (7) (Boswellia serrata)

Aloe (1) (Aloe vera)

Guggulu (10) (Commiphora mukul)

Chitrak (5) (Plumbago zeylanica)

Ashwagandha (13) (Withania somnifera)

Indigo (14) (Polygonum tinctorium)

Picroliv (3) (Picrorhiza kurroa)

False pepper (11) (Embelia ribes)

Rohitukine (12) (Dysoxylum binectariferu

m)

Himalayan fir (4) (Abies webbiana)

Pinecone ginger (15) (Zingiber zerumbet)

Veldt-grape (2) (Cissus

quadrangularis)

Bloodroot (9) (Sanguinaria

canadensis)

Pink trumpet tree (8) (Tabebuia avellanedae)

Beauty berry (7) (Callicarpa macrophylla)

Mullberry (2) (Morus nigra)

Grapes (4) (Vitis vinifera)

Cauliflower (1) (Brassica oleracea)

Soybean (5)

(Glycine max)

Artichoke (3) (Cynara cardunculus)

Lacquer tree (1) (Rhus verniciflua)

God of thunder vine (3) (Tripterygium wilfordii)

Evodia (5) (Evodia rutaecarpa)

Smoke tree (4) (Cotinus coggygria)

Magnolia (7) (Magnolia officinalis)

Song gen (6) (Phellinus

linteus)

Goldenseal (2) (Hydrastis canadensis)

Ginger lily (6) (Hedychium coronarium)

Tropical rose mallow (8) (Hibiscus vitifolius)

Cork bush (7) (Mundulea

sericea)

Oleander (9) (Nerium oleander)

Cashew nut (1)

(Anacardium occidentale)

Horse chestnut (2) (Aesculus hippocastanum)

Elephant's foot (4)

(Elephantopus scaber Linn) Palm (3)

(Elaeis guineensis)

Hop (5) (Humulus Iupulus L.)

Antiinflammatory life style

Spices

O

O

O

O H3C O

O

O

O

O

O

O

H O

N H

OO

OH3C O

H O

O C H3

O H

O

O

H

HH

HHHO

N

O

O

OH3C

CH3

OOCH3

OH3C

HH

OH

H2C C H

CH2

O O

O H O

O

O H

OO

OHO

OH O

OH

OH

OH CH 3

CH 3

O

OH3C

HO

COOH

H O

OO

OH

OH

O

HO

HO

N H

CH 2OHO

O H

O HO

HO

HO

O H

O

O

O

O H

O C H3

C H2O H

H

HO H

H O

O H

H

OO H

O HHO

O

OO H

O H

H O

Fruits & Vegetables

O H

O H

C H3

OO

O

O

O

O

H

O

H

H

OHO

HO

HO

O

OH

HO

OH

OHO

O

O

OH

OH

HO

HO

OH

HO

O

H O

O

O

O

O

O

O

OH

CH3H3C

HO

OH3C

O

OH O O O

OOH3C

CH3O

CH3

CH3

H

O OHO

O

O H

O H

O H

O H

O

HO

OHO H2CHO

HOO HO

O

OOHO

OHO

O

O

Others

OH

HO

OH

OH

O

HOOC

O

HO

N

OO

H3CO

OCH3

O

OHOH

OHO

HO

NN H N

O HO

HOOOH

OH

HO

Traditional Chinese Medicine

O HO O H

O HO

HOHO

OH

OHOH O

CH3

OOH

O

OO

HHO

O

OHHO OH

O

HO

Cinnamoyl

OH OH

OCH3OH

OH

OH

H3COHOOC

O

HO

COOHN+

OO

O

O O

H3C H

O

O H

O

O

O H

O

N

HO

OH O

O

N H

NH

NH4

OH

O

OOAc

OO

OAcO

O

O

O

O

H3C CH3

Ayurvedic Medicine

Anethole (2) Sesamin (3)

Capsaicin (6)

Curcumin (4) 1’-Actoxychav-

icol acetate (1)

Diosgenin (7) Noscapine (8)

Eugenol (5)

Gambogic acid (9)

Quercetin (10) Thymoquinone (11) Ursolic acid (12) Ellagic acid (13)

Indole 3-

carbinol (1)

Morin (2) Silymarin (3) Resveratrol (4) Genistein (5)

Anacardic acid (1) Escin (2) g-Tocotrienol (3) Isodeoxyelephan

-topin (4)

Xanthohumol (5) Deguelin (7) Coronarin-D (6) Gossypin (8) Oleandrin (9)

Butein (1) Celastrol (3) Berberin (2) Fisetin (4)

Evodiamine (5) Honokiol (7) Hispolon (6)

Emodin (1) Piceatannol (2) Picroliv (3) Plumbagin (5) Pinitol (4)

Acetyl-11-keto--boswellic acid (6)

Betulinic acid (7) Sanguinarine (9) Guggulusterone (10)

Embelin (11) Flavopiridol (12) Indirubin 3’-

monoxime (13)

Withanolide (14) Zerumbone (15)

-Lapachone (8)

Add spices to your life!

Spice Route

Dietary Spices

TNF blockers

TNF blockers

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.

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.

Curcumin:

Getting Back

to Our Roots!

Pharmacological basis for the role

of curcumin in chronic diseases:

an age-old spice with modern

targets.

Aggarwal BB, Sung B.

Trends Pharmacological Sciences.

2009 Feb;30(2):85-94.

Discovery of curcumin, a component of golden spice, and its miraculous biological activities.

Gupta SC, Patchva S, Koh W, Aggarwal BB.

Clinical and Experimental Pharmacology and Physiology. 2012 Mar;39(3):283-99.

OH

O O

OCH3 CH3O

HO

Diferuloylmethane

Structure of Curcumin From turmeric (curry powder)

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

Antibacterial action of

curcumin and related

compounds.

SCHRAUFSTATTER E, BERNT H.

Nature. 1949 Sep 10;164(4167):456.

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.

Curcumin Downregulates Expression of Cell

Proliferation, Antiapoptotic and Metastatic Gene

Products Through Suppression of IB Kinase and AKT Activation

Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB.

Molecular Pharmacology

[2006 Jan;69(1):195-206]

Preclinical data with curcumin

against various cancers

Gynecologic cancers (Cervix, Ovary, Uterus) Thoracic/ H&N Cancers

(Lung, Oral, Thymus)

Breast cancer

Curcumin

Melanoma

Bone cancer

Brain tumors

Gastrointestinal cancers (Esophagus, Intestine, Liver

Stomach,Pancreas,Colorectal)

Genitourinary cancers (Bladder, Kidney, Prostate)

Hematological cancers (Leukemia, Lymphoma

Multiple myeloma)

Anand etal, Cancer Letters, 2008

Spicy approach to cancer

treatment.

Nath S.

Journal of National Cancer Institute

2011 Dec 21;103(24):1817-8.

Curry compound fights

cancer in the clinic

Carter A.

Journal of National Cancer Institute

2008 May 7;100(9):616-7.

STAT3

c-Myc

EGFR

-catenin

COX-2

PI3K

TAK1

E-cadherin

p21

NF-B

IKK

CREB

DNA

adducts

AKT

p53

KRAS

TGF/S

MAD Notch

Curcumin /

Turmeric

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

Curcumin

as a chemo-

sensitizer

Curcumin, the golden spice from

Indian saffron, is a

chemosensitizer and

radiosensitizer for

tumors and

chemoprotector and

radioprotector for

normal organs.

Goel A, and Aggarwal BB.

Nutrition and Cancer

2010 Oct;62(7):919-30.

Cancer treatment

requires suppression

of multiple cell-

signaling/survival

pathways!

AP-1

-catenin

CREB-BP

EGR-1

Notch-1

ERE

NF-B

HIF-1 WT-1

Nrf-2

PPAR-g

STAT-1

STAT-3

STAT-4 STAT-5

Curcumin

Transcriptional

factors

IL-1

IL-2

IL-5

IL-6

IL-8

IL-12

MCP

MIP

MaIP

TNF-α

IL-18

AATF-1

ATFase

ATPase

COX-2

5-LOX

Desaturase

DNA pol

FPT

GST

GCL

iNOS

MMP

NQO-1

ODC

PhP D

Src-2

Telomerase

TMMP-3

GlCL

AAPK Ca2+PK

EGFR-K

ERK

FAK

IL-1R AK

JAK

JNK

MAPK PhK

PAK PKA

PKB

Pp60c-tk

PTK

CTGF

EGF

FGF

HGF

NGF PDGF

TF

TGF-1

VEGF

AR

AHR

CXCR4

EGFR

EPCR

ER-α Fas R

H2R

HER-2

IL-8 R

ITR

IR

LDLR

DR-5

ELAM-1

ICAM-1

VCAM-1

Bcl-2

Bcl-xL

IAP-1

Cyclin D1

Hsp-70

MDRP

uPA

DEF-40

p53

Inflammatory

cytokines

Kinases

Enzymes

Growth

factors

Receptors

Others

Molecular targets

upregulated

Molecular targets

downregulated

Anand etal, CL, 2008

Multi-targeted

Transcriptional factors AP-1, -Catenin, CBP, ERG-1, ERE, HIF-1,

Notch-1, Nrf-2, NF-B, PPAR-g, STAT-1,

STAT-3, STAT-4, STAT-5, WTG-1

Inflammatory cytokines IL-1, IL-2, IL-5, IL-6, IL-8, IL-12,

IL-8, MCP-1, MIP-1, MaIP

Protein Kinases IKK, AAPK, Ca2+ PK, EGFR, ERK, FAK,

IL-1 RAK, JAK, JNK, MAPK, PhK, PK,

PKA, PKB, PKC, pp60c-src tK, PTK

Enzymes ATFase, ATPase, Desaturase, FPTase, GST,

GCL, HO-1, iNOS, MMPs, NQO-1, ODC,

PhPD, TIMP-3, 5-LOX, Telomerase

Growth factors TGF , FGF, HGF,

PDGF, TF

Receptors AR, AHR, CXCR4, DR, EGFR, ER-, FasR,

H2R, IL-8R, ITPR, IR, LD-R

Adhesion molecules ELAM-1, ICAM-1, VCAM-1

Anti-apototic proteins Bcl-2, BclxL, IAP-1

Others Cyclin D1, Cyclin E, HsP 70, MDR

Avastin

Celecoxib COX-2

VEGF

TNF

Remicade

Humira

Enbrel

Herceptin HER-2

Bcr-Abl Gleevac

Topoisomerase

Tubulin Paclitaxel

Camptothecin

Mono-targeted

EGFR Erbitux

Curcumin

Targets

Kunnumakkara etal, CL, 2008

Curcumin: gene profile

Performed gene expression profiling study to identify novel targets of curcumin action.

A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated, and

untreated, MDA-1986 cells for differential gene expression.

Identified 202 up-regulated mRNAs and 505 transcripts decreased 2 fold or more.

The pro-apoptotic activating transcription factor 3 (ATF3) was induced over 4 fold. Two negative regulators of

growth control (antagonizer of myc transcriptional activity, Mad, and p27kip1) were induced 68 and 3 fold respectively.

Additionally, two dual-activity phosphatases (CL 100 and MKP-5) which inactivate the JNKs showed augmented

expression, coinciding with reduced expression of the upstream activators of JNK (MEKK and MKK4).

Of the repressed genes, the expression of Frizzled-1, (Wnt receptor), was most strongly attenuated (8 fold).

Growth control genes (K-sam, encoding the KGF receptor and HER3) as well as the E2F-5 transcription factor, which

regulates genes controlling cell proliferation also showed down-regulated expression.

Treatment of MDA-1986 cells, yielded a rapid, dose-dependent increase in ATF3 protein. Moreover, expression of an

exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis.

In conclusion, we have identified several putative, novel biological targets of curcumin and demonstrated that one

(ATF3) contributes to the pro-apoptotic effects of this compound.

Gene expression profiling identifies activating transcription factor 3 as a

novel contributor to the proapoptotic effect of curcumin.

Yan C, Jamaluddin MS, Aggarwal B, Myers J, Boyd DD.

Mol Cancer Ther. 2005 Feb;4(2):233-41.

Curcumin is an

Orally

Bioavailable

TNF Blocker

Regulation of production and action of TNF by curcumin

JNK

TNF-

NF-B AP-1

TNFR1

TRADD

TRAF2

NF-B ERK P38 MAPK AP-1

RIP

IL-6 IL-6R STAT3

INOS

EGR-1

PI3K/AKT

IL-8

CREB C/EBP/ NFAT Sp-1 ATF2/Jun Nrf-1 Ets

IKK

TAK1

MMP-9 COX2

TNF-

TNFR2

Docking Prediction of TNF-a and

curcumin

Wua ST etal;; International Journal of Engg Science and

Technology; Vol 2 (9), 2010; 4263-4277.

• The 3 main binding regions for curcumin

were identified.

• Curcumin docked at the receptor-binding

sites of TNF-α.

• Covalent π–π aromatic interactions or π–

cation interactions were found between

and curcumin and the TNF-α.

• Curcumin is the strong inhibitor of TNF-α

because of the covalent bonds it forms

with TNF-α.

• Curcumin bound to Cys129–in TNF-α.

Evidence that curcumin is an orally

bioavailable TNF-a blocker in human

Usharani,

2008

Placebo

Curcumin (150 mgx2 daily)

TN

F-

(p

g/m

l)

6.0

4.0

2.0

0.0

Pre Post

6.0

4.0

2.0

0.0

8 wks

N=21

N=23

Se

rum

TN

F-

(p

g/m

l)

Metformin vs Curcumin

Curcumin increased the phosphorylation of

AMP-activated protein kinase (AMPK) and

its downstream target acetyl-CoA

carboxylase (ACC) with 400 times

(curcumin) to 100,000 times (THC) the

potency of metformin (Kim, 2009).

White vs Yellow Curcumin

Sandur, 2007

Curcumin

As Antioxidant

Vitamin C Vitamin E

BHT BHA

Curcumin

Curcumin is a better antioxidant than most vitamins

Curcumin is more potent antioxidant

than Vitamin C or Vitamin E

Antioxidant NBT superoxide DPPH free radical

scavenging activity (IC50 in um)

scavenging activity (IC50 in uM)

Curcumin 41 21

Demethoxycurcumin 40 34

Bis demethoxycurcumin 38 33

Curcumin (no hydroxyl) 810 >500

Curcumin (hexahydroxy) 4.8 4.6

Vitamin C 852 25.1

Vitamin E 726 >100

Butylated hydroxyanisol (BHA) 966 34

Butylated hydroxyltoluene (BHT) 381 22.5

Venkateswarlu S, 2005

Curcumin

Clinical Trials?

To date, more than 65 human

clinical trials of curcumin,

which included more than 1000

patients, have been completed,

and as many as 35 clinical

trials are underway!

Therapeutic Role of Curcumin:

Lessons Learned from Clinical trials

60

0

10

20

30

40

50

5

10

52

Pu

bli

cati

on

s (

#)

1937-

1990

1991-

2000

2001-

July 2012

Gupta, Patchva and Aggarwal:

AAPS J. (in press)

Curcumin Clinical Trials?

Inflammatory diseases • Crohn disease

• Ulcerative proctitis

• Ulcerative colitis

• Inflammatory bowel disease

• Irritable bowel syndrome

•Rheumatoid arthritis

• Osteoarthritis

• Chronic anterior uveitis

• Recurrent anterior uveitis

•Post operative Inflammation

• Gastric ulcer

• Peptic ulcer

• H. pylori infection

• Idiopathic orbital inflammatory

Pseudotumor

Skin diseases • Vitiligo

• Psoriasis

Neurodegenerative diseases • Dejerine-Sottas disease

• Alzheimer's disease

Cardiovascular diseases • Acute coronary syndrome

• Atherosclerosis

Metabolic diseases • Diabetes

• Diabetic nephropathy

• Diabetic microangiopathy

• Lupus nephritis

Renal diseases • Renal transplantation

Viral diseases • Acquired immunodeficiency

syndrome OTHERS • -Thalassemia

• Biliary dyskinesia

• Gallbladder contraction

• Recurrent respiratory tract

infections

• Cholecystitis

• Hepatoprotection

• Chronic arsenic exposure

• Alcohol intoxication

• Chronic bacterial prostatitis

O O

H3CO

HO

OCH3

OH

Curcumin

Cancer • Colorectal cancer

• Pancreatic cancer

• Breast cancer

• Prostate cancer

• Multiple myeloma

• Lung cancer

• Cancer lesions

• Head and neck cancer

Gupta, Patchva and Aggarwal:, AAPS J. (in

press)

Loeber C.C.. De curcuma officinarum. & c., Halae . 1748. Shortt T.. Madras quart. J. med. Sci. 1867; 12: 170.

Guttenberg A.. Z. ges. exp. Med. 1927; 54: 542.

Koch R.. Münch. med. Wschr. 1927; 74: 972.

Kalk H., Nissen K.. Dtsch. med. Wschr. 1931; 62: 1613.

Fähndrich H.A.. Fortschr. Ther. 1932; 8: 606.

Franquelo E.. Münch. med. Wschr. 1933; 80: 524.

Henning N., Künzel O.. Münch. med. Wschr. 1934; 81: 1611.

Potter van Loon J.. Geneesk. Tijdschr. van Ned.-Ind. 1934; 74: 782.

von den Velden R.. Fortschr. Ther. 1934; 10: 725.

Helmy W.. Med. Welt 1935; 9: 90.

Stefan, R. (1934) Quoted by Vetterlein.

Vetterlein S.. Dtsch. med. Wschr. 1935; 61: 964.

TURMERIC (CURCUMIN) IN BILIARY DISEASES

Albert Oppenheimer M.D.

(ASSISTANT PROFESSOR OF ROENTGENOLOGY TO THE AMERICAN UNIVERSITY OF BEIRÛT, LEBANON)

The Lancet, Volume 229, Issue 5924, Pages 619 - 621, 13 March 1937

1Ahmed T, 2009

2Zsila F, 2004

3Reddy S, 1994

4Matsunaga T, 2009

5Lin R, 2008

6 Muthenna P, 2009

7Sneharani AH, 2009

8Bilmen JG, 2001

9Yanagisawa D, 2010

10Luthra PM, 2009

11Bourassa P, 2010

12ShimJS, 2004

13Innocenti A, 2010

14Sahu A, 2008

15Shim JS, 2003

16Gafner S, 2004

17Baum L, 2004

18Takeuchi T, 2006

19Leung MM, 2009

20Rai D, 2008

21Hayeshi R, 2007

22Bustanji Y, 2009

23Awasthi S, 2000

24Leu TH, 2003

25Liu M, 2010

26Jung Y, 2007

27Sahoo BK, 2009

28Sui Z, 1993

29Mazumder A, 1995

30Hu, 2010

31Jung KH, unpublished

32Dairaku I, 2010

33Liu Y, 2008

34Jankun J, 2006

35Wang SS, 2009

36Kulkarni SK, 2008

37Gradisar H, 2007

38Wortelboer HM, 2003

39Gupta KK, 2006

40Nafisi S, 2009

41Sahoo BK, 2009

42Ji HF, 2009

43Hafner-Bratkovic I, 2008

44Chearwae W, 2004

45Marcu MG, 2006

46Jutooru I, 2010

47Martin-Cordero C, 2003

48Fang J, 2005

49Pullakhandam R, 2009

50Mullally JE, 2002

51Shen L, 2009

Curcumin

Interactors

AChE1

ALR26

ATPase8

αS1-Casein7

β-amyloid9

BSA11

Bcl-210

Casein14

COX-216

CD13-AN15

DNA polIλ18

Fibrinogen19

GSH23 FAK24 GST-P121

GLO125 GSK-3β22

HIV-1IN29

Her226

Lysozyme35

HIV-1&2 PR28

DNA& RNA40

Pgp44

PhK3

PrP43

PKA3

Pp60-srcTK3

RNase A41

HSA27

IMPDH32

IVIG33

MDP-237

LOX34

MRP 1,238

TrxR48

Microtubulin39

Topo-II47 TTR49

XO51 UIP50

MAO36

Fe2+17

Cu2+17

Zn2+17

Mn2+5

cPK3

PfATP642

AGP2

Docking studies

p30045

ICDH31

Ca2+/CalM12

FtsZ20

Sp46

CAIs13

17β-HSD330

AKR1B104

Kim 11-03-2010

Curcumin binders

Evidence that curcumin is an orally

bioavailable TNF-a blocker in human

Usharani,

2008

Placebo

Curcumin (150 mgx2 daily)

TN

F-

(p

g/m

l)

6.0

4.0

2.0

0.0

Pre Post

6.0

4.0

2.0

0.0

8 wks

N=21

N=23

Se

rum

TN

F-

(p

g/m

l)

Curcumin &

Cancer

Clinical Trials

Glu

tath

ion

e-S

-tra

ns

fera

se

(nm

ol/m

in/m

g p

rote

in)

100

75

50

25

0

Curcumin (36 mg/day)

Pre Post

N = 15

Ingestion of 440 mg

of Curcuma extract (36

mg curcumin) for 29

days was

accompanied by a

59% decrease in

lymphocytic

glutathione S-

transferase activity.

At higher dose levels,

this effect was not

observed.

Effects of dietary curcumin on glutathione S-transferase in

lymphocytes from patients with colorectal cancer

Sharma et al., 2001, Clinical Cancer Research

Combination treatment with curcumin and quercetin of

adenomas in familial adenomatous polyposis

50

40

30

20

10

0

8

6

4

2

0

Pre

Po

lyp

siz

e (

mm

)

Po

lyp

nu

mb

er

N = 5

Post

Curcumin (1440 mg/day)

Post

Cruz-Correa et al., 2006, Clinical Gastroenterology Hepatology

After six

months, the

mean percent

decrease in the

number and

size of polyps

from baseline

was 60.4%

and 50.9%,

respectively.

Pre

Curcumin maintenance therapy for ulcerative colitis:

randomized, multicenter, double-blind, placebo-controlled trial.

50

40

30

20

10

0

Rec

urr

en

ce

Recurrence Placebo

Curcumin (2000 mg/day)

N = 82

Recurrence Placebo

6 months

Hanai et al., 2006, Clinical Gastroenterology Hepatology

Eighty-nine patients with quiescent UC

were recruited.

Forty-five patients received curcumin,

1g after breakfast and 1g after the

evening meal, plus sulfasalazine (SZ) or

mesalamine, and 44 patients received

placebo plus SZ or mesalamine for 6

months.

Of 43 patients who received curcumin,

2 relapsed during 6 months of therapy ,

whereas 8 of 39 patients in the placebo

group relapsed.

Furthermore, curcumin improved both

CAI (P=.038) and EI (P=.0001), thus

suppressing the morbidity associated

with UC.

A 6-month follow-up was done during

which patients in both groups were on

SZ or mesalamine.

Curry for the cure?

Inflammatory Bowel Disease. 2007

2/43

8/39

Sulfasalazine/mesalamine +/- Curcumin

Phase IIa clinical trial of curcumin for the

prevention of colorectal neoplasia

25

20

15

10

5

0

2000 4000

Ab

err

an

t cry

pt

foci

(#)

Baseline

Curcumin (mg/day)

N = 44

Baseline

Carroll et al., 2011, Cancer Prevention

Research

Forty-one subjects

completed the study

(30 days).

Neither dose of curcumin

reduced PGE₂ or 5-HETE

within ACF or normal

mucosa or reduced Ki-67

in normal mucosa.

A significant 40%

reduction in ACF number

occurred with the 4-g

dose, whereas ACF were

not reduced in the 2-g

group

A pilot study of the antioxidant effect of

curcumin in tropical pancreatitis.

15

10

5

0

Malo

nd

iald

eh

yd

e

(nm

ol/

gm

Hb

)

Glu

tath

ion

e

(nm

ol/

gm

Hb

)

10

8

6

4

2

0

Placebo

N = 20

Curcumin (mg/day)

1500 1500 Placebo

Durgaprasad et al., 2005, Indian Journal Medical Research

MDA and GSH

levels in

patients with

tropical

pancreatitis

after oral

administration

of curcumin

for 6 weeks

Combined inhibitory effects of soy isoflavones and

curcumin on the production of prostate-specific antigen

Ide et al., 2010, Prostate.

10

8

6

4

2

0

PSA <10 ng/ml

40

30

20

10

0

PSA ≥10 ng/ml

Pro

sta

te s

pe

cif

ic a

nti

ge

n

N = 85

Curcumin (100 mg/day)

Placebo Curcumin

Serum PSA levels at

the baseline (pre) and

after administration

of isoflavones

(40 mg/day) and

curcumin

(100 mg/day)

supplements or

placebo (post)

for 6 months in

participants with PSA

< 10 or

PSA ≥ 10

Effect of turmeric oil and turmeric oleoresin on cytogenetic damage in

patients suffering from oral submucous fibrosis.

Hastak et al., 1997, Cancer Lett .

12

10

8

6

4

2

0

Mic

ron

ucle

i cells

N = 58

Pre

3 months

Patients suffering from

submucous fibrosis were

given a total oral dose of

turmeric oil (600 mg TO

mixed with 3 g turmeric/day).

Turmeric oleoresin (600 mg +

3 g turmeric/day) and 3 g

turmeric/day as a control for

3 months.

It was observed that all three

treatment modalities

decreased the number of

micronucleated cells both in

exfoliated oral mucosal cells

and in circulating

lymphocytes.

Turmeric oleoresin was

found to be more effective in

reducing the number of Mn

in oral mucosal cells, but in

circulating lymphocytes the

decrease in Mn was

comparable in all three

groups.

Turmeric

(3g)+ TO

Turmeric

(3g)+ TOR

Turmeric

(3g)

Effect of turmeric on urinary mutagens

in smokers. Polasa K, Raghuram TC, Krishna TP, Krishnaswamy K.

Mutagenesis. 1992 Mar;7(2):107-9.

National Institute of Nutrition, Jamai-osmania, Hyderabad, India.

Curcumin, the active principle of turmeric, is known to act as an anti-oxidant,

anti-mutagen and anti-carcinogen in experimental animals. In the present

study, anti-mutagenic effects of turmeric were assessed in 16 chronic

smokers.

It was observed that turmeric, given in doses of 1.5 g/day for 30 days,

significantly reduced the urinary excretion of mutagens in smokers.

In contrast, in six non-smokers, who served as control, there was no change in

the urinary excretion of mutagens after 30 days.

Turmeric had no significant effect on serum aspartate aminotransferase and

alanine aminotransferase, blood glucose, creatinine and lipid profile.

These results indicate that dietary turmeric is an effective anti-mutagen and it

may be useful in chemoprevention.

p53 Apoptosis

Curcumin & CRC patients 126 pts; 360 mg curcumin; thrice/day

(He et al, 2011)

TNF- Body weight

29 patients with asymptomatic, relapsed, or plateau phase multiple myeloma.

Curcumin was given either alone (orally at 2, 4, 6, 8, or 12 g/d in two divided doses) or in combination with bioperine

(10 mg in two divided doses) for 12 weeks.

Peripheral blood mononuclear cells from 28 patients examined at baseline showed constitutively active NF-κB, COX-

2, and STAT3.

Furthermore, oral administration of curcumin was associated with significant down-regulation in the constitutive

activation of NF-κB and STAT3, and it suppressed COX-2 expression in most of the patients. These observations

suggest the potential of curcumin against multiple myeloma.

Curcumin downregulates NF-КB and related

genes in patients with multiple myeloma:

Results of a phase 1/2 study.

Vadhan-Raj S, Weber D, Wang M, Giralt S, Alexanian R,

Thomas S, …Aggarwal BB

Blood

2007;110(11):357a.

Constitutive activation of NF-B in PBMC from MM Patients

and its Suppression by Curcumin (2g/day)

NF-B

- + - + - + - + - + TNF

Pre 4w Patient #4

(482480)

8w 12w 20w

Patient #6

(337641)

NF-B

- + - + - + - + - + TNF

4w Pre 12w 16w 20w

A, B, C, D, E, F, and G represents Pre, 4, 8, 12, 16, 20 and 24 wks after curcumin administration

•The only FDA-approved therapies- gemcitabine and erlotinib- produce objective responses in less than 10% of

patients.

•The objectives of this trial were to evaluate the toxicity and activity of curcumin, as well as its impact on survival

and biologic correlates.

•Patients were treated with 8 grams of curcumin (Sabinsa Corp.) daily by mouth for two months and evaluated

radiographically using the RECIST criteria.

•Maintenance therapy was continued at the same dose and schedule until disease progression.

•RESULTS: Seventeen patients were enrolled as of the date of analysis.

•Six were inevaluable: noncompliance (n=1), never dosed (n= 1), noted to have gastric obstruction after one dose

(n=1), and too early (n=3).

•Eleven patients were evaluable for response and 15 were evaluable for toxicity.

•To date, four patients have stable disease (2+, 2+, 3+ and 7 months) and one patient had a brief partial

remission (73% reduction in tumor size by RECIST) that lasted one month.

•No toxicity was observed. Serum was available for evaluation of pre-and post-dose cytokine levels in thirteen

patients. Interestingly, the patient with the partial remission had marked increases in (4-35 fold) in serum IL-1

receptor antagonist, IL-6, IL-10 and IL-8 levels. One to three other patients also had post-treatment increases one

or more of the above cytokines, albeit to a lesser extent (2-6 folds).

•CONCLUSIONS: We conclude that curcumin is well tolerated and our preliminary results

suggest biologic activity in pancreatic cancer. From ASCO-2006

Phase II Trial of Curcumin in Patients with

Advanced Pancreatic Cancer

N. Dhillon, B. B. Aggarwal, R. A. Wolff, J. L. Abbruzzese, D. S. Hong, L. H. Camacho, L. Li, F. S.Braiteh, R. Kurzrock

A Gift of Time "If you want to do something, do it now. Don't wait."

This advice come from a patient with end-stage pancreatic

cancer who was given an unexpected gift of time, thanks to

curcumin, the main ingredient in the spice tumeric. When

Duane Jacobson first came to the Clinical Center for Targeted

Therapy (CCTT) at M. D. Anderson, he had less than three

months to live, estimated his oncologist Razelle Kurzrock,

M.D., principal investigator of the curcumin trial and also chair

of the Department of Investigational Cancer Therapeutics

(Phase I Clinical Trials Program). More than two years later,

he is traveling around the world with his wife Hildrud while

enrolled in an NIH-sponsored, phase II clinical trial of

curcumin in advanced pancreatic cancer.

Phase II trial of curcumin in patients

with advanced pancreatic cancer.

Dhillon N, Aggarwal BB, Newman RA, Wolff RA,

Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V,

Kurzrock R.

Clin Cancer Res.

2008 Jul 15;14(14):4491-9.

Curcumin &

Arthritis

Clinical Trials

Randomized, Pilot Study to Assess the Efficacy and Safety of

Curcumin in Patients with Active Rheumatoid Arthritis

10

8

6

4

2

0 C

-Reacti

ve P

rote

in (

mg

/l)

N = 45

Curcumin

(500 mg/day) Baseline

8 wks

Diclofenac +/- Curcumin Levels of C-reactive protein in

patients with active rheumatoid

arthritis at baseline and after

curcumin treatment

Forty-five patients diagnosed with RA

were randomized into three groups with

patients receiving curcumin (500 mg)

and diclofenac sodium (50 mg) alone or

their combination.

The primary endpoints were reduction in

Disease Activity Score (DAS) 28.

The secondary endpoints included

American College of Rheumatology

(ACR) criteria for reduction in

tenderness and swelling of joint scores.

Patients in all three treatment groups

showed statistically significant changes

in their DAS scores.

Interestingly, the curcumin group

showed the highest percentage of

improvement in overall DAS and ACR

scores (ACR 20, 50 and 70) and these

scores were significantly better than the

patients in the diclofenac sodium group.

Chandran and Goel, 2012, Phytother Res

Efficacy and safety of curcumin-phosphatidylcholine complex, during

extended administration in osteoarthritis patients

200

150

100

50

0

0 8 12 0 8 12

C-

Rea

cti

ve p

rote

in

(mg

/L)

Curcumin

(200 mg/day)

N = 50

Weeks

Control 3 months

After three months of

treatment, the global

WOMAC score decreased by

58%, walking distance in the

treadmill test was prolonged

from 76 m to 332 m, and

CRP levels decreased from

168 +/- 18 to 11.3 +/-. 4.1

mg/L in the subpopulation

with high CRP.

In comparison, the control

group experienced only a

modest improvement in

these parameters (2% in the

WOMAC score, from 82 m to

129 m in the treadmill test,

and from 175 +/- 12.3 to 112

+/- 22.2 mg/L in the CRP

plasma concentration),

while the treatment costs

(use of anti-inflammatory

drugs, treatment and

hospitalization) were

reduced significantly in the

treatment group.

Belcaro et al., 2010, Panminerva Med

Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex,

during extended ( 8 months) administration in osteoarthritis patients

50

40

30

20

10

0

WO

MA

C s

co

re 400

300

200

100

0

Tre

ad

mil

l te

st

1.5

1.0

0.5

0

IL-6

(p

g/m

L)

1.0

0.8

0.6

0.4

0.2

0

IL-1

β (

pg

/mL

)

3

2

1

0

sC

D4

0L

(n

g/m

L)

40

30

20

10

0

Ery

thro

cy

te

se

dim

en

tati

on

ra

te

(mm

/hr)

Pre Post

N = 100 Curcumin (200 mg/day)

Treatment Control

Belcaro et al., 2010, Alternate Medicine Review

The treatment consisted of two

500-mg tablets daily, one after

breakfast and one after dinner

(1,000 mg/day, corresponding to

200 mg curcumin/ day).

The composition of the test

material was a natural curcuminoid

mixture (20%), phosphatidyl-

choline (40%), and microcrystalline

cellulose (40%).

The composition of the

curcuminoid mixture was

75% curcumin,

15% demethoxycurcumin, and

10% bisdemethoxycurcumin.

Curcumin &

Psoriasis

Clinical Trials

Treatment of psoriasis

with Psoria-Gold

After 4 weeks

Before

R Knee L Knee L Leg L Elbow

12-05-2003

11-07-2003

Courtesy of Dr. Madeline Heng from UCLA

http://www.psoria-gold.com/RESEARCH.html

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

Drug-induced suppression of phosphorylase kinase activity correlates

with resolution of psoriasis as assessed by clinical, histological and

immunohistochemical parameters.

1600

1200

800

400

0 P

ho

sp

ho

ryla

se k

inase

(Un

its/m

g p

rote

in)

Vehicle Curcumin

N = 12

1 % in gel

4 weeks

Heng et al., 2000, British Journal Dermatology

Eelevated PhK activity correlates with psoriatic

activity. PhK activity was assayed in four groups,

each with 10 patients:

(i) active untreated psoriasis;

(ii) resolving psoriasis treated by calcipotriol, a

vitamin D3 analogue and an indirect inhibitor

of PhK;

(iii) curcumin, a selective PhK inhibitor;

(iv) 10 normal non-psoriatic subjects.

PhK activity in units mg-1 protein was highest in

active untreated psoriasis (1204 +/- 804.3; mean

+/- SD), lower in the calcipotriol-treated group

(550.7 +/- 192. 9), lower in curcumin-treated group

(207.2 +/- 97.6), and lowest in normal skin (105.4

+/- 44.6).

One-way analysis of variance performed on log-

transformed PhK activity measure showed

significant differences among the four groups,

F3,36 = 48.79, P < 0.0001.

Our results demonstrate that drug-induced

suppression of PhK activity is associated with

resolution of psoriatic activity

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

Uveitis Uveitis is the inflammation of uvea.

Symptoms include red eye, injected conjunctiva, pain and decreased

vision.

Uveitis is estimated to be responsible for approx 10% of the blindness in

the USA

Treated with steroids, topical cycloplegics, such as atropine or

homatropine, methotrexate, anti-TNFs' infusions.

Management of chronic anterior uveitis

relapses: efficacy of oral phospholipidic

curcumin treatment. Long-term follow-up.

Allegri P, Mastromarino A, Neri P. Genova, Italy.

Clin Ophthalmol. 2010 Oct 21;4:1201-6.

Administered 600 mg curcumin, twice a day, orally.

Consisted of 106 patients.

More than 80% of patients responded.

Benefits in eye inflammatory and degenerative conditions,

such as dry eye, maculopathy, glaucoma, and diabetic

retinopathy.

Pts with relapse

No of relapse

Management of chronic anterior uveitis relapses:

efficacy of oral phospholipidic curcumin treatment. Long-term follow-up.

120

100

80

60

40

20

0 Re

lap

se

(#

pts

) 300

200

100

0 To

tal re

lap

se

nu

mb

er

Pre

Post

N = 106 pts; 12 months follow up

Curcumin

(120 mg/day)

Meriva, 600 mg/day X2

group 1 (autoimmune

uveitis),

group 2 (herpetic uveitis),

group 3 (different

etiologies of uveitis).

The primary end point of

our work was the

evaluation of relapse

frequency in all treated

patients, before and after

Norflo treatment, followed

by the number of relapses

in the three etiological

groups.

The secondary end points

were the evaluation of

relapse severity and of the

overall quality of life.

The results showed that

Norflo was well tolerated

and could reduce eye

discomfort symptoms and

signs after a few weeks of

treatment in more than

80% of patients.

Allegri et al., 2010, Clinical Ophthalmology

Indicates therapeutic role of curcumin and its efficacy in eye relapsing diseases, such as anterior

uveitis, and points out other promising curcumin-related benefits in eye inflammatory and degenerative

conditions, such as dry eye, maculopathy, glaucoma, and diabetic retinopathy.

Curcumin &

Heart

Clinical Trials

145

Effect of oral curcumin administration on serum peroxides

and cholesterol levels in human volunteers

8

6

4

2

0

300

200

100

0

100

75

50

25

0

MD

A (

nm

ole

s/m

l)

To

tal ch

ole

ste

rol

(mg

/100 m

l)

HD

L c

ho

leste

rol

(m

g/1

00

ml)

Pre Post

N = 10

Curcumin

(500 mg/day)

7 day trial

33%

12% 29%

Soni KB, Kuttan R. Indian J Physiol Pharmacol. 1992

“Diverse effects of a low dose supplement of lipidated

curcumin in healthy middle aged people.” Nutrition Journal 2012, 11:79, 26 September 2012.

Robert A DiSilvestro, Elizabeth Joseph, Shi Zhao, Bomser Joshua.

Enrolled 19 healthy men and women, ages 40 to 60 years, in a four-

week long study. Subjects received a supplement containing 80 mg

curcumin, daily; an age-matched group of 19 other subjects were

given placebo and served as controls.

Curcumin supplementation significantly lowered plasma triglyceride

levels, lowered salivary amylase while raised salivary radical

scavenging capacities, raised plasma catalase activities, lowered

plasma soluble intercellular adhesion molecule levels, and increased

plasma nitric oxide.

Collectively, these results demonstrate that a low dose of a curcumin-

lipid preparation can produce a variety of potentially health promoting

effects in healthy middle aged people.”

Curcumin &

Diabetes

Clinical Trials

Effect of curcumin on

blood sugar as seen in

a diabetic subject.

Srinivasan M.

Indian J Med Sci.

1972 Apr;26(4):269-70.

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, placebo-

controlled, 8-week study.

Usharani P, Mateen AA, Naidu MU, Raju YS, Chandra N.

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

Bio

ma

rke

rs l

eve

l

ET-1 (pg/ml)

Placebo

Atorvastatin (10 mg/day)

Curcumin (NCB-02

150 mgx2 daily)

Curcumin decreases serum inflammatory biomarkers in DM2 Patients

TNF- (pg/ml)

IL-6 (pg/ml)

2.0

1.5

1.0

0.5

0.0

8.0

6.0

4.0

2.0

0.0

6.0

4.0

2.0

0.0

MDA (nmol/ml)

6.0

4.0

2.0

0.0

6.0

4.0

2.0

0.0

4.5

3.0

1.5

0.0

6.0

4.0

2.0

0.0

Pre Post

6.0

4.0

2.0

0.0

Pre Post

6.0

4.0

2.0

0.0

Pre Post

2.0

1.5

1.0

0.5

0.0

Pre Post

4.5

3.0

1.5

0.0

2.0

1.5

1.0

0.5

0.0

Usharani,

2008

8 wks

N=21

N=23

N=23

Curcumin extract for prevention of type 2 diabetes

0 3 6 9 0 3 6 9

Months

140

120

100

80

60

40

20

0 Dia

be

tic

pa

tie

nts

(#

)

Placebo

N = 240

Curcumin

(1500 mg/day)

Number of newly diagnosed diabetic subjects after treatment with curcumin

Chuengsamarn et al., 2012, Diabetes Care.

After 9 months of

treatment, 16.4% of

subjects in the placebo

group were diagnosed

with T2DM, whereas none

were diagnosed with

T2DM in the curcumin-

treated group.

In addition, the curcumin-

treated group showed a

better overall function of

β-cells, with higher

changes in β-cell

functions (homeostasis

model assessment

[HOMA]-β (61.58 vs.

48.72; P < 0.01) and lower

C-peptide (1.7 vs. 2.17; P <

0.05).

The curcumin-treated

group showed a lower

level of HOMA-IR (3.22 vs.

4.04; P < 0.001) and higher

adiponectin (22.46 vs.

18.45; P < 0.05) when

compared with the

placebo group. A 9-month curcumin intervention in a prediabetic population significantly lowered the number of prediabetic

individuals who eventually developed T2DM.

curcumin treatment appeared to improve overall function of β-cells, with very minor adverse effects.

This study demonstrated that the curcumin intervention in a prediabetic population may be beneficial

Curcumin upregulates serum insulin levels

in healthy subjects (n=14)

Time (min)

Ins

uli

n A

UC

(m

U/L

)

Placebo

C. longa (6 gm/day)

Wickenberg J, 2010

0

1000

2000

3000

4000

5000

15 30 45 60 90 120

Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-β

and interleukin-8 levels in patients with overt type 2 diabetic nephropathy:

a randomized, double-blind and placebo-controlled study.

250

200

150

100

50

0

Uri

na

ry IL

-8 (

pg

/ml)

Control Trial Control Trial

10000

8000

6000

4000

2000

0

Uri

na

ry P

rote

inu

ria

Pre

Post

800

600

400

200

0

Se

rum

T

GF

-β (

pg

/ml)

250

200

150

100

50

0

Se

rum

IL

-8 (

pg

/ml)

N = 40

Turmeric

(1500 mg/day)

40 patients with overt type 2

diabetic nephropathy,

randomized into a trial group (n

= 20) and a control group (n =

20).

Each patient in the trial group

received one capsule with each

meal containing 500 mg

turmeric, of which 22.1 mg was

the active ingredient curcumin

(three capsules daily) for 2

months.

The control group received

three capsules identical in

colour and size containing

starch for the same 2 months.

Serum levels of TGF-β and IL-8

and urinary protein excretion

and IL-8 decreased significantly

comparing the pre- and post-

turmeric supplementation

values.

Short-term turmeric

supplementation can attenuate

proteinuria, TGF-β and IL-8 in

patients with overt type 2

diabetic nephropathy and can

be administered as a safe

adjuvant therapy for these

patients. Khajehdehi et al., 2011, Scand J Urol Nephrol

Curcuma longa and Tinospora cordifolia formulation to prevent anti-

tuberculosis treatment induced hepatotoxicity

400

300

200

100

0

120

100

80

60

40

20

0

10

8

6

4

2

0

50

40

30

20

10

0

80

60

40

20

0

As

pa

rtate

tra

ns

am

ina

se

Ala

nin

e t

ran

sa

min

ase

Bilir

ub

in

We

igh

t (K

g)

Ery

thro

cy

te

se

dim

en

tati

on

ra

te

N = 528

Curcumin (1000 mg/day)

Control

Trial

Curcumin enriched (25%) CL and a hydro-

ethanolic extract enriched (50%) TC 1 g each

divided in two doses comprised the herbal

adjuvant.

Hemogram, bilirubin and liver enzymes were

tested initially and monthly till the end of

study to evaluate the result.

Incidence and severity of hepatotoxicity was

significantly lower in trial group (incidence:

27/192 vs 2/316, P<0.0001).

Mean aspartate transaminase (AST) (195.93+/-

108.74 vs 85+/-4.24, P<0.0001), alanine

transaminase (ALT) (75.74+/-26.54 vs 41+/-

1.41, P<0.0001) and serum bilirubin (5.4+/-3.38

vs 1.5+/-0.42, P<0.0001).

A lesser sputum positivity ratio at the end of 4

wk (10/67 vs 4/137, P=0.0068) and decreased

incidence of poorly resolved parenchymal

lesion at the end of the treatment (9/152 vs

2/278, P=0.0037) was observed.

Improved patient compliance was indicated

by nil drop-out in trial vs 10/192 in control

group (P<0.0001).

The herbal formulation prevented

hepatotoxicity significantly and improved the

disease outcome as well as patient

compliance without any toxicity or side

effects.

Adhvaryu et al., 2008, World J Gastroenterol.

Cancer incidence is less in

spice consuming countries

183

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.

Comparison of Cancer Incidence in USA and India

Cancer USA India

Cases Deaths Cases Deaths Breast 660 160 79 41

Prostate 690 130 20 9

Colon/Rectum 530 220 30 18

Lung 660 580 38 37

Head & Neck SCC 140 44 153 103

Liver 41 44 12 13

Pancreas 108 103 8 8

Stomach 81 50 33 30

Melanoma 145 27 1.8 1

Testis 21 1 3 1

Bladder 202 43 15 11

Kidney 115 44 6 4

Brain, Nervous system 65 47 19 14

Thyroid 55 5 12 3

Endometrial Cancers 163 41 132 72

Ovary 76 50 20 2

Multiple myeloma 50 40 6 5

Leukemia 100 70 19 17

Non-Hodgkin lymphoma 180 90 17 15

Hodgkin's disease 20 5 7 4

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