Curcumin

Multi-targeting of Multigenic Cancer by
Nutraceuticals:
Role in Prevention and Treatment
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.
First ISS-ARTOI Conference on Integrative Oncology
Fifth ARTOI International Congress
Translational Medicine: From Laboratory to Clinical Evidence
Roma, Italy; November 6th-7th, 2013
Wednesday, November 6th, 2013 (14:30-14:50 PM)
Food for Thought
How complicated is the human disease?
•
•
•
•
•
•
Human body is made up of 13 trillion cells and each cell contains 24,000
different genes.
The human brain contains nearly 100 billion neurons of at least 1000
different varieties.
These nerve cells make at least a 100 trillion connections.
Just like no two human beings are alike, no two cells alike and no two
genes are alike.
All chronic diseases are mediated through dysregulation of multiple
genes.
If so, how do we expect to have a cure to any disease by targeting single
gene.
Working Hypothesis:
Dysregulated chronic
inflammation caused by life
style factors mediate chronic
diseases including cancer!
Inflammation/Flame/Fire
Controlled
Uncontrolled
Several age-related chronic diseases such as metabolic syndrome, cardiovascular
disease, and neurodegenerative disease have an inflammatory component
January 11th,
2013
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.
Potential Sources of Inflammation
Alcoholic
beverages
Environmental
pollutants
Industrial pollutant,
Diesel, Acid rain
Ultraviolet
radiation
Food Factors
Grill,
Fried,
red meat
Inflammation
Stress
pH, hypoxia,
heavy metals,
chemotherapy
Bacteria
Cigarette
smoke
Helicobacter pylori
Salmonella typhi
Chlamydia pneumoniae
Streptococcus bovis
Escherichia coli
Viruses
Herpes simplex virus 8,
Hepatitis viruses, HPVs,HIV, EBV
Inflammation as a risk factor for most cancers
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
disease
Gut pathogens
IBD
Colorectal cancer
1*
Ultraviolet light
Sunburn
Melanoma
9%
Infections, STD
PIA
Prostate cancer
?
Hodgkin’s
GA, gastric acid; GBS, gall bladder stones; HCC, hepatocellular carcinoma; STD, sexually transmitted diseases;
PIA, prostate inflammatory atrophy.
From: Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology, 72, 2006, 1605-21
Nearly 43% of patients
with ulcerative colitis
develop colorectal cancer
after 25-35 years!
Ekbom A, 1998
Inflammatory bowel disease:
a survey of the epidemiology in Asia.
Goh K, Xiao SD. Journal of Digestive Diseases. 2009 Feb;10(1):1-6.
Prevalence of rates of Ulcerative Colitis:
JAPAN
7.9 per 100,000
INDIA
44.3 per 100,000
USA
229.0 per 100,000
•
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.
Cancer Is a Preventable Disease That
Requires Major Changes in Life Style
Cancer Incidence (%)
40
35
30
30
14-20
20
18
10
7
5-10
0
Tobacco
HK 04-14-2008
Diet
Obesity
Infections
E. Pollution
Genes
& Radiations
Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009
Hypothesis!
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!
NF-kB -regulated genes
Kumar A, Takada Y, Boriek AM, Aggarwal BB. Journal of Molecular Medicine 2004;82:434-48.
Cancer genome landscapes
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW.
Science. 2013;339:1546-58.
•
•
•
•
•
Over the past decade, comprehensive sequencing efforts have revealed the
genomic landscapes of common forms of human cancer.
For most cancer types, this landscape consists of a small number of
"mountains" (genes altered in a high percentage of tumors) and a much
larger number of "hills" (genes altered infrequently).
To date, these studies have revealed ~140 genes that, when altered by
intragenic mutations, can promote or "drive" tumorigenesis.
A typical tumor contains two to eight of these "driver gene" mutations; the
remaining mutations are passengers that confer no selective growth
advantage.
Driver genes can be classified into 12 signaling pathways that regulate three
core cellular processes: cell fate, cell survival, and genome maintenance.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Science. 2013 Mar 29;339(6127):1546-58
single-base substitutions (SBS), small insertions and deletions (indels).
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Science. 2013 Mar 29;339(6127):1546-58.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Science. 2013 Mar 29;339(6127):1546-58.
Inflammatory networking in cancer
TNF
Bone loss
RANKL, IL-1, TNF
Survival &
Chemoresistance:
c-FLIP, Bcl-xL
IAP-1, IAP-2, XIAP, survivin
NF-kB
Invasion and
metastasis
Proliferation:
Cyclin D1, 5-LOX,
COX-2, IL-6
Chemokines
IL-6
STAT3
Angiogenesis
VEGF
Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology. 2006
Inflammatory bone loss:
pathogenesis and therapeutic intervention.
Redlich K, Smolen JS.
Nature Review Drug Discovery. 2012 Mar 1;11(3):234-50.
Bone is a tissue undergoing continuous building and degradation. This
remodelling is a tightly regulated process that can be disturbed by many
factors, particularly hormonal changes.
Chronic inflammation can also perturb bone metabolism and promote increased
bone loss.
Inflammatory diseases can arise all over the body, including in the
musculoskeletal system (for example, rheumatoid arthritis), the intestine (for
example, inflammatory bowel disease), the oral cavity (for example,
periodontitis) and the lung (for example, cystic fibrosis).
Wherever inflammatory diseases occur, systemic effects on bone will ensue, as
well as increased fracture risk. Here, we discuss the cellular and signaling
pathways underlying, and strategies for therapeutically interfering with, the
inflammatory loss of bone.
Constitutive activation of NF-B has been linked with most cancers
Esophageal
cancer
Colon cancer
Laryngeal
cancer
Pharyngeal
cancer
Head and neck SCC
Pancreatic
cancer
Lung cancer
Renal
carcinoma
Bladder cancer
Tobacco-linked cancers
Acute
Myelogenous
leukemia
Thyroid
cancer
Hodgkin’s
disease
Liver
cancer
Non-Hodgkin’s
lymphoma
B cell
lymphoma
Carcinogens
Breast
cancer
NF-kB
Carcinogens
Ovarian
cancer
T cell
lymphoma
Prostate
cancer
Mantle cell
lymphoma
Multiple
myeloma
UV light
Viral cancers
Acute lymphoblastic
leukemia
Adult T cell
leukemia
Cervical
cancer
Nasopharyngeal
carcinoma
Melanoma
Shishodia and Aggarwal, Biochemical Pharmacology, 2004
Role of inflammation in tumorigenesis
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
Proliferation
Invasion
VEGF
CXCR4
TWIST
Transformation
Tumor suppression
Normal cell
Transformation
Survival
10-20 Years
Angiogenesis
Metastasis
10 Years
Inflammation
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.
NF-B
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.
Working Hypothesis
Stress
NF-kappaB
Inflammation
Cancer
A Fire Extinguisher!
How to suppress NFkB activation safely?
Antiinflammatory life style
Spices
Fruits & Vegetables
Asian ginger (1)
Fennel (2)
Sesame seed (3)
Turmeric (4)
Cloves (5)
(Alpinia galanga)
(Foeniculum
vulgare)
(Sesamum
indicum)
(Curcuma
longa)
(Eugenia
caryophyllu)
Red chili (6)
Fenugreek (7)
(Capsicum
annum)
(Trigonella foenum
graecum)
Poppy seed (8)
Gamboge (9)
(Papaver somniferum)(Garcinia hanburyi)
Cauliflower (1)
Mullberry (2)
Artichoke (3)
(Brassica oleracea)
(Morus nigra)
(Cynara
cardunculus)
Holy basil (12)
(Nigella sativa)
(Ocimum sanctum)
Soybean (5)
(Glycine max)
Traditional Chinese Medicine
Onion (10)
(Allium cepa)
Lacquer tree (1)
Onion seed (11)
Grapes (4)
(Vitis vinifera)
Goldenseal (2)
(Rhus verniciflua)
(Hydrastis canadensis)
Evodia (5)
Song gen (6)
God of thunder vine (3)
Smoke tree (4)
(Tripterygium wilfordii)
(Cotinus coggygria)
Pomegranate (13)
(Punica granatum)
Ayurvedic Medicine
(Evodia rutaecarpa)
Aloe (1)
(Aloe vera)
Veldt-grape (2)
Picroliv (3)
Himalayan fir (4)
(Cissus
quadrangularis)
(Picrorhiza kurroa)
(Abies webbiana)
(Phellinus
linteus)
Magnolia (7)
(Magnolia officinalis)
Others
Chitrak (5)
(Plumbago zeylanica)
Elephant's foot (4)
Hop (5)
Cashew nut (1)
Palm (3)
Horse chestnut (2)
Iupulus L.)
)
(Aesculus hippocastanum) (Elaeis guineensis)(Elephantopus scaber Linn(Humulus
(Anacardium occidentale)
Boswellia (7)
(Boswellia serrata)
Beauty berry (7)
Pink trumpet tree (8)
(Callicarpa macrophylla) (Tabebuia avellanedae)
False pepper (11)
Rohitukine (12)
(Embelia ribes)
(Dysoxylum
binectariferum)
Ashwagandha (13)
Bloodroot (9)
(Sanguinaria
canadensis)
Indigo (14)
(Withania somnifera) (Polygonum tinctorium)
Guggulu (10)
(Commiphora mukul)
Pinecone ginger (15)
(Zingiber zerumbet)
Ginger lily (6)
Cork bush (7)
(Hedychium coronarium)
(Mundulea
sericea)
Tropical rose mallow (8) Oleander (9)
(Hibiscus vitifolius)
(Nerium oleander)
Spices
O
O
O
H 3C O
O
O
O
O
Fruits & Vegetables
O
O
O
Anethole (2)
O
O
H
O
O
Sesamin (3)
O
H
O
H
HO
Capsaicin (6)
H
H3C
O
Diosgenin (7)
O
OH
H 3C
OH
OH
OH O
N
H
O
O
H
O
O
O
O H
H
O
H
C H2O
C3 H
HO
O H HO
H
Silymarin (3)
O H
O HO
H
Resveratrol (4)
O
Genistein (5)
Traditional Chinese Medicine
O
O
HO
OH
O
O
HO
Ursolic acid (12)
HO
O
N
Berberin (2)
OH
O
OH
HO
O C H3
OH O
OH
OH
O
H 3C O
OH
O
HOOC
O
OH
HO
HO
C OOH
Thymoquinone (11)
H
Morin (2)
Butein (1)
Quercetin (10)
HO
OH
OH O
Gambogic acid (9)
H
O
O
H
O
O
O
CH3
CH3
O
O
OH
O
O
O
Noscapine (8)
CH 3
HO
HO
Indole 3carbinol (1)
OH
O
O
OH
HO
H
CH3
H
O H
CH 2 OH
Eugenol (5)
O
N
H3C
H
H
H 2C HC CH2
H
O
O
N
H
C
3
Curcumin (4)
H
O
O
H 3C
O
1’-Actoxychavicol acetate (1)
OH
O
Fisetin (4)
Celastrol (3)
Ellagic acid (13)
OH O
N
N
H
Ayurvedic Medicine
HO
O
HO
N
HO
OH
HO H
OH O
OH
OH
HO
OH
OH
O
HO
Cinnamoyl O
HO
OH
OH OH
O
O
OH
O
O
OCH3
HO
O
OH
OH
OH
Evodiamine (5)
Hispolon (6)
Honokiol (7)
CH 3
Others
OH O
OH
HO
HO
OH
O
OH
O
HO
Emodin (1)
Piceatannol (2)
Picroliv (3)
Pinitol (4)
Plumbagin (5)
O
O
O
C OOH
Acetyl-11-keto-boswellic acid (6)
O
O
O
H3 C
HO
Betulinic acid (7)
O
H
O
HO
b-Lapachone (8)
OH
NH4
O
N
H
OH O
Embelin (11)
CH3
O
O
Flavopiridol (12)
O
O
Anacardic acid (1)
O Ac O
O
OH
H
O
O
O
O
O
OH
H
O
OH
Zerumbone (15)
O
O
O
O
H
O
OH
g-Tocotrienol (3)
Escin (2)
Isodeoxyelephan
-topin (4)
O
CH 3
HO
O
O
OH
HO
H3C
O
O Ac
Indirubin 3’-monoxime Withanolide (14)
(13)
O
Guggulusterone (10)
O
O
C H3
C H3
O
OH
NH
O
HO
O
O
Sanguinarine (9)
HO
O
H
O
O
O
H
O
HO
OH
C 3H
O
H3C
N
H
N+
O H
H 3C H
O
O
H 3CO
HOOC
O
O
O
O
Xanthohumol (5)
H
O H3 C
Coronarin-D (6)
HOH 2 C
HO
HO
O
OH O
HO
OH
O
O
C H3 O
Deguelin (7)
Gossypin (8)
HO
O
OH
O
OH
OH O
O
OH
O
Oleandrin (9)
O
….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
Farmer’s Market
Fruits
Vegetables
Spices & condiments
Cereals
Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009
Hippocrates proclaimed
~2500 years ago
“Let food be thy
medicine
and medicine be thy
food”
Sept 21st, 2012
183
Sept 21st, 2012
Natural products have played a
significant role in the discovery of
cancer drugs over the years;
more than 70% of drugs have their
roots in natural products
Newman, D. J., and Cragg, G. M. (2012)
Natural products as sources of new drugs over the 30 years from 198 to 2010.
Journal Natural Products 75, 311–335
Donald Abrams:
The Integrative Oncologist
Confronts cancer with both conventional and integrative methods
(http://protomag.com/assets/donald-abrams-the-integrative-oncologist).
When the Chef Is Also a Doctor
New York Times; APRIL 12, 2012,
Doctors often tell their patients to eat healthful, nutritious food. But what do they really know about eating well?
Not enough, says Dr. David M. Eisenberg, an associate professor at Harvard Medical School and the Harvard School of Public Health, and founder of a
cooking conference for doctors and other health care workers in the business of dispensing nutrition advice. As Patricia Leigh Brown reports in The
Times’s Dining section:
“This isn’t neurosurgery,” Dr. Eisenberg said as he whacked a garlic clove with the cleaver. “This is hearty, affordable, cravenly delicious food.”
The son of a Brooklyn baker, Dr. Eisenberg is the founder and chief officiant of “Healthy Kitchens/Healthy Lives,” an “‘interfaith marriage,” as he calls it,
among physicians, public health researchers and distinguished chefs that seeks to tear down the firewall between “healthy” and “ crave-able” cuisine.
Although physicians are on the front lines of the nation’s diabetes and obesity crises, many graduate from medical school with little knowledge of nutrition,
let alone cooking….
To Dr. Eisenberg, flavor is a health issue. Now in its eighth year, the sold-out event is in the vanguard of a major shift in attitude among a young generation
of medical professionals who grew up with farmers’ markets. Their ranks include students at the Baylor College of Medicine in Houston, who have hired a
chef to teach cooking skills, and a doctor in suburban Chicago who was so inspired by “Healthy Kitchens/Healthy Lives” that he went home and installed a
demonstration kitchen in his medical office.
To learn more, read the full report, “To Heal, First Eat,” and be sure to check out the accompanying slide show, “Swapping Stethoscopes for Chefs’
Toques.”
To Heal, First Eat
Doctors Learn to Cook Healthy, ‘Crave-able’ Foods
Jim Wilson/The New York Times
Medical professionals in a cooking class at the annual “Healthy Kitchens/Healthy Lives” conference in California.
By PATRICIA LEIGH BROWN Published: April 10, 2012
Reduce your risk of
cancer by 30 to 40% by
adopting healthier eating
habits.
Visit: http://www.mdanderson.org/cancerawareness
Natural products remain quite
interesting and, often, represent
the most exquisite examples of
targeted therapiesselected for their activities
through evolution.
- Charles L. Sawyers
http://www.timtec.net/Natural-Compound-Library/Print.html
Tocotrienols, the Vitamin E
of the 21st Century:
It’s Potential Against Cancer and Other
Chronic Diseases
Aggarwal BB, Sundaram C,
Prasad S., and Kannappan R.
Biochemical Pharmacology
2010 Dec 1;80(11):1613-31.
Tocopherols
32,679 pub
Tocotrienols
749 pub
CH3
CH3
HO
CH3
3HC
CH3
CH3
CH3 HO
3HC
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
O
CH3
Beta
H
Beta
H
HO
CH3
CH3
CH3
CH3
CH3 HO
HO
CH3
CH3
Delta
Gamma
H
CH3
CH3 HO
CH3
H
O
CH3
O
CH3
Gamma
H
CH3
3HC
O
CH3
CH3
Alfa
CH3 HO
H
O
H
CH3
CH3
HO
3HC
CH3
O
CH3
Alfa
CH3
H
CH3
CH3
O
CH3
Delta
Natural Sources of Tocotrienols
http://www.tocotrienol.org/index.html
Palm
Elaeis guineensis
Rice
Oryza sativa
Barley
Hordeum distichon
Oat
Avena sativa
Wheat
Triticum vaccinium
Sources of tocotrienols
Red annatto
Palm oil
Barley
Rice bran
Grape fruit seed oil
940 mg/kg
910 mg/kg
465 mg/kg
380 mg/kg
Oat
Hazelnut
Maize
Wheat germ oil
Olive oil
210 mg/kg
209 mg/kg
200 mg/kg
189 mg/kg
180 mg/kg
Buckthorn Berry 130
Rye
Flax seed oil
Poppy seed oil
Safflower oil
mg/kg
92 mg/kg
25.1 mg/kg
20.5 mg/kg
11.8 mg/kg
From: Red annatto, Barrie, Tan; Palm oil, Schroeder,2006; Rice bran, Sookwong,2010; Grape fruit seed oil, maize, Wheat germ oil-Hassanein,
2009; Hazel nut, Amaral, 2006; Olive oil, Cunha, 2006; Buckthorn berry, Kallio, 2002; Rye-milagros Delgado-Zamarreno, 2009; Oat and
barley, Panfili, Fratianni.200; Flax oil, poopy oil, safflower oil, Bozan, 2008
From Aggarwal et al, 2010
-
tocotrienol but not tocopherol inhibits
NF-B signaling pathway through
inhibition of RIP and TAK1 leading to
suppression of antiapoptotic gene products
and potentiation of apoptosis.
Ahn KS, Sethi G, Krishnan K, Aggarwal BB.
Journal of Biological Chemistry.
2007 Jan 5;282(1):809-20.
-
tocotrienol but not - tocopherol inhibits
NF-kB signaling pathway
Ahn etal, 2007
Role of
- Tocotrienols in
Treatment of
Human Pancreatic
Cancer
Well-known pancreatic cancer victims!
Luciano Pavarotti
Marvin Zindler
Michael London Patrick Swayze
Steve Jobs
{gamma}-Tocotrienol Inhibits Pancreatic
Tumors and Sensitizes Them to
Gemcitabine Treatment by Modulating the
Inflammatory Microenvironment.
Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S,
Koca C, Yadav VR, Tong Z, Gelovani JG, Guha S, Krishnan S, Aggarwal BB.
Cancer Research
2010 Nov 1;70(21):8695-705.
NEEM tree
(Azadirachta indica)
Sanskrit“sarva roga nivarini”
(the curer of all ailments).
Nimbolide
2010
2013
2013
Azadirone, a limonoidal triterpene originally identified from the oil of the neem tree, traditionally called “nature’s
drug store” .
In east Africa, the tree is known as “Mwarobaini” in Swahili, which literally means “the tree of the 40,” because it is
considered as a treatment for 40 different diseases.
In India, the tree is known as a “village pharmacy” because of its tremendous therapeutic potential.
2013
Add spices to your life!
Dietary Spices
Targeting inflammation-induced obesity
and metabolic diseases by curcumin and
other nutraceuticals.
Aggarwal BB.
Annual Review Nutrition
2010 Aug 21;30:173-99.
Spices as NF-B Inhibitors
OCH 3
O
O
H3CO
OCH3
OH
CH
OH
CH
CH3
Foeniculum vulgare
Curcumin
Curcuma longa
Anethole
Fennel
Turmeric
Capsaicin
Capsicum annum
Eugenia caryophyllata
Eugenol
Cloves
Red chilli
C H3
H
H3C
C H3
H
C H3
C H3
H
H
H
H
C H3
O
C H3 C H3 H
O
C H3
H O
H
C H3
H O
H
T. foenum-graecum
Fenugreek
Diosgenin
C O O H
Ocimum sanctum
Holi basil
C H 3
Ursolic Acid
Red chilli
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a potent
inhibitor of NF-kB activation by diverse agents.
Singh S, Natarajan K, Aggarwal BB.
Journal of Immunology 1996 Nov 15;157(10):4412-20.
Capsaicin is a novel blocker of constitutive and
interleukin-6-inducible STAT3 activation.
Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB.
Clinical Cancer Research. 2007 May 15;13(10):3024-32.
Ginger
Zerumbone abolishes NF-kB and IkBa kinase activation
leading to suppression of antiapoptotic and metastatic
gene expression, upregulation of apoptosis, and
downregulation of invasion.
Takada Y, Murakami A, Aggarwal BB.
Oncogene.
2005 Oct 20;24(46):6957-69
Ginger
Zerumbone abolishes RANKL-induced NF-kB activation, inhibits
osteoclastogenesis, and suppresses human breast cancer-induced
bone loss in athymic nude mice.
Sung B, Murakami A, Oyajobi BO, Aggarwal BB.
Cancer Research. 2009 Feb 15;69(4):1477-84.
Black cumin
Targeting NF-kB activation pathway by thymoquinone: role in suppression of antiapoptotic
gene products and enhancement of apoptosis.
Sethi G, Ahn KS, Aggarwal BB.
Molecular Cancer Research. 2008 Jun;6(6):1059-70.
Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and
extracellular signal-regulated kinase signaling pathways.
Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB, Liu M.
Molecular Cancer Therapeutics. 2008 Jul;7(7):1789-96.
H
Fenugreek
C H
H
C H 3
C H
3
H
H
H
H
H O
H
Diosgenin inhibits osteoclastogenesis, invasion,
and proliferation through the downregulation of
Akt, IkB kinase activation and NF-kB-regulated
gene expression.
Shishodia S, Aggarwal BB.
Oncogene. 2006;25(10):1463-73.
C H
O
3
O
H
3
OCH 3
Fennel
CH
CH
CH3
Anethole blocks both early and late cellular
responses transduced by TNF: effect on
NF-kB, AP-1, JNK, MAPKK and apoptosis.
Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB.
Oncogene.
2000 Jun 8;19(25):2943-50.
Black pepper
(Piper indica)
Long pepper
(Piper longam)
Selective killing of cancer cells by a
small molecule targeting the stress
response to ROS.
Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA,
Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW.
Nature.
2011 Jul 13;475(7355):231-4. doi: 10.1038/nature10167.
Cardamom
Cardamonin Sensitizes Tumor Cells to
TRAIL Through ROS- and CHOP-Mediated
Upregulation of Death Receptors and
Downregulation of Survival Proteins.
Yadav VR, Prasad S, Aggarwal BB.
British Journal of Pharmacology
2012 Feb;165(3):741-53.
Cardamom
Curcumin:
Getting Back to
Our Roots!
Structure of Curcumin
From turmeric (curry powder)
O
O
OCH3
CH3O
OH
HO
Diferuloylmethane
Milobedzka J., von Kostnecki St, and Lampe V: Zur Kenntnis des curcumins. Ber Deutsch Chem Ges, 1910, 43, 2163-2170
Activation of transcription factor
Nuclear Factor-kappa B is suppressed
by curcumin
Singh S, and Aggarwal BB.
J Biol Chem. 1995 Oct 20;270 (42):24995-5000.
Curcumin Downregulates Expression of Cell
Proliferation, Antiapoptotic and Metastatic Gene
Products Through Suppression of IkBa Kinase and AKT
Activation
Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB.
Molecular Pharmacology
[2006 Jan;69(1):195-206]
Regulation of production and action of TNF by curcumin
Curcumin as a Proteasome Inhibitors
Inflammation-Linked MiRNA
miR-146a
miR-143
miR-155
miR-34a
miR-132
miR-210
miR-125b
NFkB/STA
T3
miR-181b
miR-19
let-7
let-7a, 7b,
7c, 7d
miR-31
miR-132
miR-181b
miR-301a
Taganov KD, .., Baltimore D.2006;
O'Connell RM, .., Baltimore D., 2007;
O'Connell RM, .., Baltimore D., 2008;
Lu LF, .., Baltimore D, 2010
Boldin MP, .. Baltimore D., 2011
Zhao JL, .., Baltimore D., 2011
Chaudhuri AA.., Baltimore D., 2011
Yang L.., Baltimore D., 2012
miR-125b
miR-21
Changes in MiRNA by Curcumin
miR-143
miR-146a
miR-200a
miR-101
miR-200b
miR-26a
miR-200c
miR-22
Curcumin
miR-16
let-7
let-7a, 7b,
7c, 7d
miR-15a
miR-199a
miR-21
miR-34a
miR-186
miR-125b
Targets shown in green are upregulated and those in blue are downregulated by curcumin
Preclinical data with curcumin
against various cancers
Gastrointestinal cancers
(Esophagus, Intestine, Liver
Hematological cancers
Stomach,Pancreas,Colorectal)
Genitourinary cancers
(Bladder, Kidney, Prostate)
(Leukemia, Lymphoma
Multiple myeloma)
Brain tumors
Bone cancer
Curcumin
Breast cancer
Melanoma
Thoracic/ H&N Cancers
(Lung, Oral, Thymus)
Gynecologic cancers
(Cervix, Ovary, Uterus)
Anand etal, Cancer Letters, 2008
Multi-targeted Approach to Prevention of Colorectal Cancer by Curcumin/Turmeric
c-Myc
AKT
NF-kB
IKK
STAT3
CREB
p21
DNA
adducts
KRAS
Curcumin /
Turmeric
COX-2
E-cadherin
TAK1
b-catenin
TGFb/S
MAD
Notch
PI3K
EGFR
p53
Curcumin
as a chemosensitizer
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 cellsignaling/survival
pathways!
Molecular targets
downregulated
Notch-1
uPA
AP-1
CREB-BP
Nrf-2
NF-B
IL-2
PPAR-
p53
HIF-1
IL-5
Hsp-70
STAT-4
MCP
STAT-5
-catenin
VCAM-1
IL-18
ERE
WT-1
Bcl-2
Molecular targets
upregulated
IL-1
STAT-3
EGR-1
Bcl-xL
STAT-1
IL-6
DEF-40
MIP
IL-8
ICAM-1
Transcriptional
factors
Cyclin D1
ELAM-1
IAP-1
MaIP
Inflammatory
cytokines
Others
MDRP
IL-12
TNF-α
AATF-1
ER-α
GCL
Fas R
IR
EPCR
Curcumin
H2R
ATFase
Desaturase
MMP
ATPase
Receptors
EGFR
GlCL
HER-2
Enzymes
DR-5
Growth
factors
IL-8 R
LDLR
CXCR4
5-LOX
NQO-1
ITR
AHR
Kinases
HGF
AR
NGF
TGF-1
Telomerase
CTGF
FPT
EGFR-K
FAK
Pp60c-tk
Ca2+PK
EGF
JNK
GST
TMMP-3
MAPK
IL-1R AK
ERK
VEGF
DNA pol
AAPK
PhP D
ODC
Src-2
FGF
TF
PDGF
COX-2
iNOS
PhK
PTK
PKB
JAK
PAK
PKA
Anand etal, CL, 2008
Multi-targeted
Mono-targeted
Inflammatory cytokines
IL-1, IL-2, IL-5, IL-6, IL-8, IL-12,
IL-8, MCP-1, MIP-1, MaIP
COX-2
Celecoxib
EGFR
Erbitux
TNF
Remicade
Humira
Enbrel
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
Curcumin
Targets
HER-2
Herceptin
Bcr-Abl
Gleevac
VEGF
Avastin
Tubulin
Paclitaxel
Topoisomerase
Camptothecin
Anti-apototic proteins
Bcl-2, BclxL, IAP-1
Protein Kinases
IKK, AAPK, Ca2+ PK, EGFR, ERK, FAK, IL1 RAK, JAK, JNK, MAPK, PhK, PK, PKA,
PKB, PKC, pp60c-src tK, PTK
Transcriptional factors
AP-1, -Catenin, CBP, ERG-1, ERE, HIF-1, Notch1, Nrf-2, NF-B, PPAR-, STAT-1, STAT-3, STAT-4,
STAT-5, WTG-1
Others
Cyclin D1, Cyclin E, HsP 70, MDR
Kunnumakkara etal, CL, 2008
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
52
Publications (#)
50
40
30
20
10
0
10
5
19371990
199120012000 July 2012
Gupta, Patchva and Aggarwal:
AAPS J. (in press)
Curcumin Clinical Trials?
Cancer
•
•
•
•
•
Colorectal cancer
Pancreatic cancer
•
Breast cancer
Prostate cancer
Multiple myeloma
•
Lung cancer
•
Cancer lesions
Head and neck cancer
Skin diseases
•
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
•
Neurodegenerative diseases
•
•
•
•
Vitiligo
Psoriasis
•
•
O
O
Cardiovascular diseases
OCH3
H3CO
Acute coronary syndrome
•
Atherosclerosis
•
OH
HO
Dejerine-Sottas disease
Alzheimer's disease
Metabolic diseases
Curcumin
•
•
•
Diabetes
Diabetic nephropathy
Diabetic microangiopathy
•
Lupus nephritis
Renal diseases
•
Renal transplantation
Viral diseases
•
OTHERS
Acquired immunodeficiency
syndrome
-Thalassemia
•
Biliary dyskinesia
Gallbladder contraction
Recurrent respiratory tract
infections
•
Cholecystitis
•
Hepatoprotection
Chronic arsenic exposure
•
Alcohol intoxication
Chronic bacterial prostatitis
•
•
•
•
•
Gupta, Patchva and Aggarwal:, AAPS J. (in
press)
Effects of dietary curcumin on glutathione S-transferase in
lymphocytes from patients with colorectal cancer
Glutathione-S-transferase
(nmol/min/mg protein)
100
N = 15
75
50
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.
25
0
Pre
Post
Curcumin (36 mg/day)
Sharma et al., 2001, Clinical Cancer Research
Combination treatment with curcumin and quercetin of
adenomas in familial adenomatous polyposis
50
8
N=5
Polyp size (mm)
Polyp number
40
30
20
10
0
Pre
Post
2
After six
months, the
mean percent
decrease in the
number and
size of polyps
from baseline
was 60.4%
0
and 50.9%,
respectively.
6
4
Pre
Post
Curcumin (1440 mg/day)
Cruz-Correa et al., 2006, Clinical Gastroenterology Hepatology
Curcumin maintenance therapy for ulcerative colitis:
randomized, multicenter, double-blind, placebo-controlled trial.
Sulfasalazine/mesalamine +/- Curcumin
50
6 months
N = 82
Recurren
ce
40
30
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.
20
10
Eighty-nine patients with quiescent UC
were recruited.
8/39
2/43
0
Furthermore, curcumin improved both
CAI (P=.038) and EI (P=.0001), thus
suppressing the morbidity associated
with UC.
Placebo Recurrence Placebo Recurrence
Curcumin (2000
mg/day)
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
Hanai et al., 2006, Clinical Gastroenterology Hepatology
Phase IIa clinical trial of curcumin for the
prevention of colorectal neoplasia
25
N = 44
Aberrant crypt
foci (#)
20
(30 days).
Neither dose of curcumin
reduced PGE₂ or 5-HETE
within ACF or normal
mucosa or reduced Ki-67
in normal mucosa.
15
10
5
0
Forty-one subjects
completed the study
Baseline
2000
Baseline
Curcumin
(mg/day)
4000
A significant 40%
reduction in ACF number
occurred with the 4-g
dose, whereas ACF were
not reduced in the 2-g
group
Carroll et al., 2011, Cancer Prevention
MDA and GSH
levels in
patients with
tropical
pancreatitis
after oral
administration
of curcumin
for 6 weeks
10
5
(nmol/gm Hb)
Glutathione
8
(nmol/gm Hb)
Malondialdehyd
e
A pilot study of the antioxidant
effect of curcumin in tropical
10
15
N = 20
pancreatitis.
6
4
2
0
0
Placebo
1500
Placebo 1500
Curcumin
(mg/day)
Durgaprasad et al., 2005, Indian Journal Medical Research
Combined inhibitory effects of soy isoflavones and
curcumin on the production of prostate-specific antigen
PSA <10 ng/ml
10
N = 85
8
Prostate specific antigen
6
4
(40 mg/day) and
curcumin
2
0
40
Serum PSA levels at
the baseline (pre) and
after administration
of isoflavones
PSA ≥10
ng/ml
30
(100 mg/day)
supplements or
placebo (post)
for 6 months in
participants with PSA
< 10 or
PSA ≥ 10
20
10
0
Placebo
Curcumin
Curcumin (100
mg/day)
Ide et al., 2010, Prostate.
Effect of turmeric oil and turmeric oleoresin on cytogenetic damage in
patients suffering from oral submucous fibrosis.
Micronuclei cells
12
3 months
10
N = 58
8
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.
6
4
It was observed that all three
treatment modalities
decreased the number of
micronucleated cells both in
exfoliated oral mucosal cells
and in circulating
lymphocytes.
2
0
Pre
Turmeric
(3g)
Turmeric
(3g)+ TO
Turmeric
(3g)+ TOR
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.
Hastak et al., 1997, Cancer Lett .
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.
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.
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, COX2, 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.
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.
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.
Curcumin & CRC patients
126 pts; 360 mg curcumin; thrice/day
Body weight
Apoptosis
TNF-a
p53
(He et al, 2011)
Cancer incidence is less in
spice consuming countries
183
Comparison of Cancer Incidence in USA and India
Cancer
USA
Cases
Breast
660
Prostate
Colon/Rectum
Lung
660
Head & Neck SCC
Liver
41
Pancreas
Stomach
Melanoma
Testis
21
Bladder
Kidney
115
Brain, Nervous system
Thyroid
Endometrial Cancers
Ovary
76
Multiple myeloma
Leukemia
Non-Hodgkin lymphoma
Hodgkin's disease
160
690
530
580
140
44
108
81
145
1
202
44
55
163
50
50
100
20
Deaths
79
130
220
38
44
12
103
50
27
3
43
65
5
41
6
47
20
40
70
180
5
India
Cases
41
20
30
37
153
13
8
33
1.8
1
15
4
12
132
2
6
19
90
7
Deaths
9
18
103
8
30
1
11
19
3
72
5
17
17
4
14
15
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.
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