10/4/2016

1

Anti-Inflammatory Lifestyle for

Prevention & Treatment of

Cancer: Facts & Fiction

Sahdeo Prasad, Ph.D. Department of Experimental Therapeutics

Division of Cancer Medicine

The University of Texas, M.D. Anderson Cancer Center

Houston, Texas, U.S.A.

Presented in

the 4th Annual International Plant-Based Nutrition Healthcare Conference

September 21- September 23, 2016

Anaheim Marriott ~ Anaheim, CA

Conflict of Interest Statement

No potential conflict of interest declared in

this presentation

War on Cancer

“I will ask for an appropriation of an extra $100 million to

launch an extensive campaign to find a cure for cancer.

Let us make a total national commitment to conquer this

dread disease. America has long been the wealthiest

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

healthiest nation in the world”.

--President Richard Nixon, 1971

State of the Union address

Change in the US Death Rates* by Cause,

1950 & 2002

* Age-adjusted to 2000 US standard population.

Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.

2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and

Prevention, 2004

22.5

180.7

48.1

586.8

193.9

56.0

193.4

240.1

0

100

200

300

400

500

600

Heart

Diseases

Cerebrovascular

Diseases

Pneumonia/

Influenza

Cancer

1950

2002

10

16

20

7

10

14

0

5

10

15

20

25

2002 2020 2030

New Cases Deaths

Millio

ns

Year

Projection for Global

Cancer Incidence and Cancer Deaths Global Cancer Incidence

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

10/4/2016

2

Lifestyle and cancer

Chinese from Shanghai 2

Chinese in USA for five years 23

Chinese born in USA 37

Caucasian born in USA 58

Prostate cancer per 100,000

Ho E, 2007; IJC

0

10

20

30

40

Tobacco Diet Obesity Infections Genes

Cancer Is a Preventable Disease That

Requires Major Changes in Lifestyle

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

Working Hypothesis:

Inflammation and Cancer:

Role of lifestyle

What is Inflammation?

Cornelius Celsus,

a physician in first century Rome:

Heat (calor)

Pain (dolor)

Redness (rubor)

Swelling (tumour)

Inflammation is part of the complex biological response of body tissues

to harmful stimuli, such as pathogens, damaged cells, or irritants.

TIME Feb. 23, 2004

10/4/2016

3

Inflammation/Flame/Fire

Controlled

Uncontrolled

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

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” Nearly 43% of patients

with ulcerative colitis

develop colorectal

cancer after

Ekbom A, 1998

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

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.

10/4/2016

4

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-B -regulated genes

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

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.

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.

10/4/2016

5

Requirements of Chemopreventive agent

Should be non-toxic to normal and healthy people.

Should have high efficacy against multiple sites.

Should be orally bio-available.

Should have known mechanism of action.

Should be easily available.

Should be low-cost.

Should be acceptable most human population.

Plant based diets

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

TNF Family

Bacteria

Fungus

Alcohol Heavy metals

Interleukins

Cytokines

Sun exposure

Chemo drugs

Growth factors

Hormones Oxidative stress

Obesity

Mitogens

Viruses

Environmental

pollutants

Carcinogens

-radiation

Leishmania

Glucose

Receptor ligands

Physiological stress

Tobacco

Ascorbic acid

Apigenin

Allicin

Anethole

Avenanthramide

Betulinic acid

Berberine

Catechin

Caffeic acid Capsaicin

Silymarin

Indole-3-carbinol

Kaempferol

Luteolin

Lycopene

Ursolic acid

Tocotrienol

Lupeol

Mangiferine

Morin

Myrcetin

Plumbagin

Piperine

Pantothenic acid

Zerumbone

Gambogic acid

Gingerol

Genistein

Curcumin

Delphinidine

Diosgenin

Ellagic acid

Eugenol

Glycyrrhizic acid Geraniol

Thymoquinone

Tocopherol

Sulphoraphane

Stigmasterol

Phytic acid

Sanguinarine

Quercetin

Rutin

Resveratrol

Gossypin

Fisetin

Celastrol

Xanthohumol

NF-B

Inflammation

Inducers

Chemopreventive

agents

Inhibitors of NF-B from our lab

Inhibitors of NF-B from our lab

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.

Long pepper (Piper longam)

10/4/2016

6

Long pepper (Piper longam)

Piperlongumine blocked NF-κB activated by TNF-α and

various other cancer promoters.

Han et al 2014

Multi-targeted nature of piperlongumine

Black pepper (Piper indica) Piperine

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.

10/4/2016

7

Sources of tocotrienols

Palm oil 940 mg/kg

Barley 910 mg/kg

Rice bran 465 mg/kg

Grape fruit seed oil 380 mg/kg

Oat 210 mg/kg

Hazelnut 209 mg/kg

Maize 200 mg/kg

Wheat germ oil 189 mg/kg

Olive oil 180 mg/kg

Buckthorn Berry 130

mg/kg

Rye 92 mg/kg

Flax seed oil 25.1 mg/kg

Poppy seed oil 20.5 mg/kg

Safflower oil 11.8 mg/kg

Red annatto

From Aggarwal et al, 2010

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

- tocotrienol but not - tocopherol

inhibits NF-kB signaling pathway

Ahn etal, 2007

Tocotrienol in colorectal

cancer

In a nude mouse xenograft model of human CRC, γ-

T3 inhibited tumor growth and enhanced the anti-

tumor efficacy of capecitabine.

Prasad et al 2016

Role of

- Tocotrienols in

Treatment of

Human

Pancreatic

Cancer

{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.

10/4/2016

8

Ursolic acid

Ursolic acid is a pentacyclic triterpene acid, present in many plants,

including apples, basil, bilberries, cranberries, elder flower, peppermint,

rosemary, lavender, oregano, thyme, hawthorn, and prunes.

It is capable of inhibiting various types of cancer cells by inhibiting the

NF-kB and STAT3 activation pathway.

Ursolic Acid in the Treatment

of Human Pancreatic Cancer

UA inhibited proliferation, induced apoptosis, and

proliferative, metastatic, and angiogenic proteins in

human pancreatic cancer cells.

Prasad et al 2016

In the nude mouse model, oral administration of UA (250

mg/kg) suppressed tumor growth and enhanced the effect of

gemcitabine (25 mg/kg).

Prasad et al 2016

Ursolic Acid in the Treatment

of Human Colorectal Cancer

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

10/4/2016

9

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.

Role of Ginger and its components in the treatment

of gastrointestinal cancer

Molecular targets of Ginger and its components

against gastrointestinal cancer

Prasad &

Tyagi 2015

Boswellia Serrata (Indian frankincense, Salai)

Boswellia Serrata Boswellic acid

Oral administration of acetyl- 11-keto-beta boswellic acid

(AKBA) dose-dependently inhibited the growth of CRC

tumors in mice, resulting in decrease in tumor volumes

10/4/2016

10

Boswellic Acid in the Treatment

of Human Pancreatic Cancer

In the orthotopic nude mouse model of PaCa, AKBA

alone inhibited the tumor growth; this activity was

enhanced by gemcitabine.

Nimbolide

NEEM tree

(Azadirachta indica)

Sanskrit-

“sarva roga nivarini” (the curer of all ailments).

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.

10/4/2016

11

Diosgenin inhibits osteoclastogenesis,

invasion, and proliferation through the

downregulation of Akt, IkB kinase activation

and NF-kB-regulated gene expression.

Shishodia S, et al Oncogene. 2006;25(10):1463-73.

Fenugreek

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.

Fennel OCH3

CH

CH

CH3

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.

Red chilli Capsazepine

Capsazepine is a synthetic analogue of capsaicin.

capsazepine sensitizes human colon cancer cells to

TRAIL-induced apoptosis through the upregulation

of death receptors DR4 and DR5

Cardamom

10/4/2016

12

Cardamonin, a chalcone isolated from Alpinia

katsumadai Hayata that can affect

osteoclastogenesis through modulation of RANKL. 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

Garcinol has been isolated from several Garcinia species;

including Garcinia indica.

Garcinol Garcinol, the active component of Garcinia indica, increases

the sensitivity of cancer cells to TRAIL, a cytokine currently

in phase II clinical trial.

Garcinol potentiated TRAIL-induced apoptosis of cancer

cells

Trends Pharmacol Sci. 2014 Aug 13.

pii: S0165-6147(14)00115-1. doi:

10.1016/j.tips.2014.07.004. [Epub ahead of print]

Curcumin:

Getting Back

to Our Roots!

10/4/2016

13

OH

O O

OCH3 CH3O

HO

Diferuloylmethane

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

aaaa

aaaa

BBA

Activation of transcription factor

Nuclear Factor-kappa B is

suppressed by curcumin

Singh S et al, J Biol Chem. 1995 Oct 20;270

(42):24995-5000.

Curcumin Downregulates Expression of Cell

Proliferation, Antiapoptotic and Metastatic Gene

Products Through Suppression of IBa Kinase and AKT Activation

Aggarwal S, et al. Molecular Pharmacology

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

10/4/2016

14

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

AP-1

-catenin

CREB-BP

EGR-1

Notch-1

ERE

NF-B

HIF-1 WT-1

Nrf-2

PPAR-

STAT-1

STAT-3

STAT-4 STAT-5

Curcumin

Transcription

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

Multitargeting by curcumin

as revealed by molecular

interaction studies.

Gupta SC, Prasad S, Kim JH, Patchva S,

Webb LJ, Priyadarsini IK, Aggarwal BB.

Natural Products Reports

2011;28(12):1937-55.

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

Effect of curcumin in HIV infection mediated

disorders

10/4/2016

15

Design of curcumin-loaded PLGA

nanoparticles formulation with enhanced

cellular uptake, and increased bioactivity in

vitro and superior bioavailability in vivo.

Anand P, Nair HB, Sung B, Kunnumakkara AB, Yadav VR, Tekmal RR,

Aggarwal BB.

Biochem Pharmacol. ,2010;79(3):330-8.

Cyclodextrin-complexed curcumin exhibits

anti-inflammatory and antiproliferative

activities superior to those of curcumin

through higher cellular uptake

Yadav VR, Prasad S, Kannappan R, Ravindran J, Chaturvedi

MM, Vaahtera L, Parkkinen J, Aggarwal BB

Biochem Pharmacol. 2010;80(7):1021-32.

Add spice to

your life, not

years to your

life!

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!

10/4/2016

16

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 et al, AAPS J. 2013

Curcumin &

Cancer

Clinical Trials

Glu

tath

ion

e-S

-tra

nsfe

rase

(nm

ol/

min

/mg

pro

tein

)

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

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 = 41

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

Ma

lon

dia

lde

hy

de

(nm

ol/g

m H

b)

Glu

tath

ion

e

(nm

ol/g

m H

b)

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

10/4/2016

17

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), Quercetin (20mg)

Post

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

After six

months as

shown by

endoscopy, the

mean percent

decrease in the

number and

size of polyps

from baseline

was 60.4%

and 50.9%,

respectively. Pre

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

pecif

ic a

nti

gen

N = 85

Curcumin (100 mg/day)

Placebo Curcumin+

Isoflavones

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

uc

lei c

ells

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.

Study was 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-aBody 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, et al Blood 2007;110(11):357a.

10/4/2016

18

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

-Re

ac

tiv

e 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).

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-

Re

ac

tiv

e 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

mill

test

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

D40L

(n

g/m

L)

40

30

20

10

0

Ery

thro

cyte

sed

imen

tati

on

rate

(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.

Treatment Control

Pre Post Pre Post Pre Post

Duration of treatment 8 months

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

10/4/2016

19

Curcumin & Skin Diseases Curcumin-induced suppression of phosphorylase kinase activity

correlates with resolution of psoriasis as assessed by clinical,

histological and immunohistochemical parameters

MC 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

Transferrin receptors on keratinocytes

Untreated Calcipotriol Curcumin

Management of chronic anterior uveitis relapses:

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

120

100

80

60

40

20

0 Rela

pse (

# p

ts)

Pre

Post

N = 106 pts; 12 months follow up

Curcumin

(120 mg/day)

Meriva, 600 mg/day X2

Administered 600 mg Meriva, 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.

Meriva was well tolerated and could

reduce eye discomfort symptoms and

signs after a few weeks of treatment in

more than 80% of patients.

An ongoing therapy with systemic drugs

(steroids, immune-suppressants,

antiherpetic, and antitoxoplasmic drugs)

or eye drops (steroids, mydriatics, and

cycloplegics nonsteroidal anti-

inflammatory drug) was maintained, and

Norflo tablets were added as an adjunctive

treatment.

The therapy was only administered to

patients who had frequent relapses in the

last 2 years of follow-up and was started

at the time of a relapse.

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

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

/10

0 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

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.

10/4/2016

20

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 le

ve

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-a (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

aaaa

aaaa

BBA

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

beti

c p

ati

en

ts (

#)

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)

Insu

lin

AU

C (

mU

/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

nary

IL

-8 (

pg

/ml)

Control Trial Control Trial

10000

8000

6000

4000

2000

0

Uri

nary

Pro

tein

uri

a

Pre

Post

800

600

400

200

0

Seru

m

TG

F-β

(p

g/m

l)

250

200

150

100

50

0

Seru

m

IL-8

(p

g/m

l)

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

10/4/2016

21

Hippocrates proclaimed

~2500 years ago

“Let food be thy

medicine

and medicine be

thy food”

National Cancer Institute

Eat 8 servings of fruits and vegetables every day!

“You are

what

you eat”