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)
[email protected] | 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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