11

Turmeric ‐ The choice of millionsTurmeric   The choice of millions

“IF MY FATE were such that I could have IF MY FATE were such that I could have

only one medicinal plant, I would choose

turmeric. My choice would be the choice of

millions before me, from emperors to

peasants.” peasants.

C. Leigh Broadhurst, Ph.D

22USDA

33

Turmeric  Plant

Curcuma longaCurcuma longa

Herbaceous plant belonging to the familyHerbaceous plant belonging to the familyZingiberaceae.

Useful parts are the underground rhizome and p gmulti‐branched extensions from theRhizomes.Rhizomes.

Spice and Natural color usedSpice and Natural color used globally in curries……….

44

Important constituents of Curcuma longaImportant constituents of Curcuma longa

CurcuminDemethoxy curcuminBi d th iBisdemethoxy curcuminTurmeronesTurmerones 

55

Chemical structures of Curcuminoids

M O OM

CH CHCOCH CO CHCHOH

MeO

OH

OMe

CURCUMIN (Diferuloyl methane)

CH CHCOCH2CO CHCHOH OH

CURCUMIN ( f y )

OMe

CH CHCOCH2CO CHCHOH OH

DEMETHOXY CURCUMIN (p‐Hydroxy‐cinnamoyl‐feruloyl‐methane )

66

Chemical structures of CurcuminoidsChemical structures of Curcuminoids

CH CHCOCH2CO CHCHOH OH

BISDEMETHOXY CURCUMIN  (pp’ Dihydroxy dicinnamoyl methane)(pp ‐Dihydroxy‐dicinnamoyl‐methane)

CH3

CH

CH3

CHO

ar‐turmerone

CH3 CH3O

77

Curcumin C3 Complex 

fromfrom 

Turmeric RhizomesTurmeric Rhizomes

88

The structure – activity relationshipThe structure  activity relationship

OO 22

CH C CH2 C CH33

CHCH

OMeMeO

1 P h d l ti id t ti it

OHOH1 1

1.Parahydroxyl groups ‐ antioxidant activity2.Keto groups ‐ anti‐inflammatory, anticancer, antimutagen3.Double bonds ‐ anti‐inflammatory, anticancer, antimutagen

99f y, , g

Primary pharmacological actions of Curcuminoidsy p g

AntioxidantAnti‐inflammatoryAnti‐carcinogenicAnti‐carcinogenicImmunomodulatoryA ti t iAntimutagenicAnti‐thromboticHepatoprotectantAntimicrobialAntiviralAntiparasitic

1010Antiparasitic

1111

Antioxidant Profile – Rancimat Test

IN VITRO

The Rancimat Method measures the conductivity changes caused  by formation of small free fatty acid molecules, when fats and oils undergo experimentally induced accelerated rancidity or oxidative changes.

Pure lard is used for the preparation of test samples % b h f h d bcontaining  0.02% by weight of the  antioxidant being 

tested.

1212‐‐ContdContd..

Lipid peroxidation prevention by natural and synthetic i id d b R i M h d

Research report no. 786, Sabinsa Corporation, 1995

antioxidants as measured by Rancimat Method

3

xResearch report no. 786, Sabinsa Corporation, 1995

2

2.5

t inde

1.5

xidant

0.5

1

Antiox

0

1 2 3 4 5 6

A

1. BHT 2. Curcumin 3. BDMC

4 Cu u i C3 5 G a e Seed 6 Pi e Ba k1313

4. Curcumin C3  Complex

5. Grape Seed Extract

6. Pine Bark Extract

Antioxidant Profile – DPPH Scavengingg g

In the DPPH radical scavenging method, the ability f ti id t t bi d th 1 1 di h l 2of an antioxidant to bind  the 1,1 diphenyl‐2‐

picrylhydrazyl ‐radical  (a very stable free radical species) is measured, using various concentrations  of the selected antioxidants.

A compound with high antioxidant potentialA compound with high antioxidant potential effectively traps this radical thereby preventing its propagation and the resultant chain reactionpropagation and the resultant chain reaction.

1414

DPPH scavenging ability of Curcuminoidssca e gi g abi ity o Cu cu i oids

Concentration (μg/ml)

1515Research Report No. 786, Sabinsa Corporation, 1995

Antioxidant Profile – ORAC value

The Oxygen Radical Absorbance Capacity (ORAC) yg p y ( )assay depends on the free radical damage to a fluorescent probe through the change in itsfluorescent probe through the change in its fluorescence intensity. 

In the presence of antioxidant, the inhibition of free di l d hi h i fl t d i th t tiradical damage, which is reflected in the protection 

against the change of probe fluorescence, is a measure of its antioxidant capacity against the free radical.

1616

ORAC value of CurcuminoidsORAC value of Curcuminoids

12000

10000

6000

8000

4000

0

2000

Coffee Bean Extract

Curcumin C3 Complex

Grape Seed Extract

Green tea Extract

1717Research Report No. 786, Sabinsa Corporation, 1995

Proposed antioxidant mechanismsProposed antioxidant mechanisms

PREVENTION f f di l f tiPREVENTION of free radical formation.

INTERVENTION whereby already preformedradicals are quenched by the Curcuminoids.q y

1818

1919

Saga of InflammationSaga of Inflammation

Almost all of the degenerative diseases are d i b h i b li i l i fl tidriven by chronic subclinical inflammation.

Essentially, nearly every condition that walks into a doctor’s office is driven at least in part byinto a doctor s office is driven, at least in part, by inflammation.

Co td2020

Contd……

Saga of InflammationSaga of Inflammation

The old view of the inflammation is that it represents the healing process This is true to arepresents the healing process. This is true to a certain extent; however when the inflammation, b h i it b dibecomes chronic, it becomes a disease.

Literature strongly recommends that there is a need to halt the chronic inflammation and itsneed to halt the chronic inflammation and its induction.

Co td2121

Contd……

Saga of InflammationSaga of Inflammation

Today the study of inflammation has gone fromToday the study of inflammation has gone from the tissue levels deeper into the nuclear level.

Cell‐signaling molecules have been identified g gwhich stimulate the gene that induce the expression of the COX enzyme which in turnexpression of the COX enzyme which in turn induce inflammation.

2222

TIME Feb. 23, 2004

2323

Nuclear factor Kappa B (NF kB)Nuclear factor Kappa B (NF‐kB)

NF kB i th “Bi h ” ll i liNF‐kB is the “Big cheese” cell‐signaling molecule for inflammation; 

its activation induces the expression of COX 2its activation induces the expression of COX‐2, which leads to tissue inflammation.

2424

What activates NF kB?What activates NF‐kB?

ROI inducersCarcinogens

ACytokines

f l I

ROI inducers(H2O2)

( eg: TNF, CSC, DMBA)(TNF family, IL‐1, IL‐17, IL‐18, EGF)

NF-κBTumor 

PromotersInfectionb l/ l (PMA)(bacterial/viral; e.g HIV, EBV‐LMP,HTLV1)

Stress(pH, hypoxia,stress 

h l )Apoptosis inducers heavy metals)

Endotoxin(LPS)

Apoptosis‐inducersChemotherapeutic 

agents & g‐irradiation

25(LPS)

Aggarwal BB, Cancer Cell, 2004

25

NF kB i I fl tiNF‐kB in Inflammation

NF‐kB resides in the cytoplasm of the cell and is bound to its inhibitorbound to its inhibitor.

I j i d i fl t ti li h fInjuries and inflammatory stimuli, such as free radicals, release NF‐kB from its inhibitor.

The free NF‐kB, now moves into the nucleus and ti t th ibl f iactivates the genes responsible for expressing 

COX‐2.

This leads to inflammation.2626

Stress and NF‐kBe a

Stress and carcinogens activate NF kBStress and carcinogens activate NF‐kB.

Ch i NF kB i i di i fl i /Chronic NF‐kB activation mediates inflammation/ carcinogenesis/ tumorigenesis .

Inhibition of NF‐kB activation suppresses ppinflammation/ tumorigenesis.

2727

Central dogma for most type of inflammationsCentral dogma for most type of  inflammations

TNF/CarcinogensTNF/CarcinogensTNF/CarcinogensTNF/Carcinogens

NF‐kB

COXCOX‐‐222828

Drug‐discovery from natural sourcesDrug‐discovery from natural sources

There are 121 prescription drugs in use today, which      come from 90 plant species. About 74% came from following folklore claims. g

(Benowitz S, The Scientist 10, 1996, 1‐7).

Approximately 25% of the drug prescription in the USA are compounds derived from plants and were p pdiscovered through scientific investigation of folklore claimsfolklore claims .

(Reynold T, J. Natl. Cancer Inst. 183, 1991, 594‐596).2929

3030

Therapeutic potential of curcuminTherapeutic potential of curcuminC di l di

Di b t

Cardiovasuclar diseasesCholestrol, platelet aggregation, inhibition of smooth muscle cell 

proliferation

Multiple sclerosis Alzheimer 

diseaseDiabetes

ChemotherapeuticNephrotoxicity

C

ChemopreventiveSkin, liver, colon, stomach

Antioxidant

p y

CurcuminAntiflammatory

Gall‐stones 

Arthritisformation

Lung fibrosisCataract formation

31Cardiotoxicity

Wound healingHIV replication 31

Different stages of cancer progression and its suppression by curcumin

Overexpression ofOncogenes HER2  Overexpression ofGrowth factors 

(e.g; EGF, PDGF, FGF)Growth factor receptorsSurvival factors

( S i i B l 2 d B l l)

Overexpression ofMatrix metalloproteasesCyclooxygenase‐2Adhesion moleculesChemokine 

Tumor Suppressor genes

Constitutive activation of transcription factors 

AP‐1& NF‐kB(e.g; Survivin,Bcl‐2 and Bcl‐xl) Cyclin D1Decoy receptor

TNF

Tumor MetastasisNormal cells Tumor cells Tumor growth

Proliferation InvasionTransformation

32Curcumin BlocksFrom Aggarwal B et al, Anticancer Research 23, 2003, 363-398

32

Curcumin helps fights diseasesCurcumin helps fights diseases…..

So if we take care to reduce the NF‐kB ti it t ti l factivity, we  are protecting ourselves from 

a host of diseases, including Cancer.

Cu u i ha a o iti e ole i thiCurcumin has a positive role in this.

K. Kohli, J. Ali, M. J. Ansari, Z. Raheman Curcumin: A natural anti‐inflammatory agenty gIndian J Pharmacol | June 2005 | Vol 37 | Issue 3 | 141‐147( and references cited therein)

3333

NFkB‐Zero™NFkB Zero  

Inhibition of NF‐kB can help prevent/delay the onset ofthe disease.

This is the basic premise on which NFkB‐Zero™ haspbeen developed.

3434

Effect of curcuminoids application in patients with external cancerous lesions

100

* 62 Subject Study

708090

100

n

506070

educ

tion

203040

% r

e

010

Reduction in fould f l i

Drying lesions Reduction in lesioni d i

Itching

35odor of lesions size and pain

Ref: Kuttan et al., (1987) Tumori, 2, 28-29.

Effect of turmeric administration on levels of urinary mutagensEffect of turmeric administration on levels of urinary mutagens in smokers

300

350

Load

28.5% decrease

(p < 0.001) 40% decrease

200

250

utag

en L 40% decrease

(p < 0.001)

100

150

200

nary

Mu

50

100

Urin

00 15 days 30 days

Time elapse from turmeric administration 16 smokers36

Time elapse from turmeric administration 16 smokers + 6 non-smokers

Ref: Polasa, et al., Mutagenesis, 7, 107 (1992)

D d d t tith b ti ff t f i

Antithrombotic activity of curcumin

Dose dependent antithrombotic effect of curcumin and aspirin

60708090

tion

2030405060

prot

ect

Curcumin

Aspirin

* Platelet0

1020

15 25 50 100 200

% Platelet

aggregation

* PGI2Dose mg/kg PGI2synthesis

37Srivastava, R. et al. (1985) . Thrombosis Res., 40, 413-417.

Effect of curcuminoids on the hepatotoxicity produced by Aflatoxin B1 (AFB) in ducklings

2.5

ty

1.5

2

T ac

tivit

0.5

1

ver G

PT 1 2 3

0

0.5

Liv

1. Normal 2. AFB 3. AFB + Curcuminoids

Treatment regimens38

Treatment regimensSoni et. al. (1992), Cancer Lett, 66, 115

3939

Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials

Since the first article referring to the use of curcumin was  published in “The Lancet in 1937” more than 2 600published in  The Lancet in 1937 , more than 2,600 research studies using curcumin or turmeric have been published in English language journalspublished in English language journals. 

Thi i ti l id i f th t iThis review article  provides an overview of the extensive published literature on the use of curcumin as a therapy for malignant and inflammatory diseases and its potentialfor malignant and inflammatory diseases and its potential use in the treatment of degenerative neurologic diseases, cystic fibrosis and cardiovascular diseasescystic fibrosis and cardiovascular diseases.

4040Strimpakos AS, Sharma RA., Antioxid Redox Signal. 2008 Mar; 10(3); 511‐545Department of Medicine, Royal Marsden Hospital, London, England

Curcumin C3 Complex® and Cancer PreventionCurcumin C Complex and Cancer Prevention

41414141

Curcumin C3 Complex® and Cancer PreventionCurcumin C Complex and Cancer Prevention

M.D. Anderson Cancer Center is currently conducting numerous studies to determine the effects of curcumin, an extract of turmeric root, in fighting against several 

ftypes of cancers. 

S bi C ti ʹ C i C3 C l ®Sabinsa Corporationʹs Curcumin C3 Complex® was named as the curcumin ingredient of choice by M.D. A de o Ca e Ce te at the U i e ity of Te aAnderson Cancer Center at the University of Texas. 

42424242

Curcumin Analogues in Cancer PreventionCurcumin Analogues in Cancer Prevention

In a pre‐clinical study, the authors investigated whether analogs of curcumin (Cur), such as demethoxy curcuminanalogs of curcumin (Cur), such as demethoxy curcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate y ( ) ,inflammatory signaling and cell proliferation to the same extent as curcumin. 

The results demonstrated that different analogs ofThe results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti‐inflammatory and anti‐proliferative activities.inflammatory and anti proliferative activities.

4343Sandur SK, Aggarwal BB et al, Carcinogenesis. 2007 Aug; 28(8); 1765‐1773

Curcuminoids and their analogues  on production of ll l ROS d GSHcellular ROS and GSH

44cSandur SK, Aggarwal BB et al, Carcinogenesis. 2007 Aug; 28(8); 1765‐1773

44

Comparison of Cancer Incidence  ‐1U.S [curcumin non‐users] vs. India [curcumin users]

Cancer US IndiaCancer US  IndiaCases Deaths Cases Deaths

Breast 600 160 79 41Breast 600 160 79 41Prostate 690 130 20 9Colon/Rectum 530 220 30 18Colon/Rectum 530 220 30 18Lung 660 580 38 37Head and Neck SCC 140 44 153 103Head and Neck SCC 140 44 153 103Liver 44 41 13 12Pancreas 108 103 8 8Pancreas 108 103 8 8Stomach 81 50 33 30Melanoma 145 27 1 8 1Melanoma 145 27 1.8 1Testis 21 1 3 1

Showing cases per 1 million persons calculated on the basis of current consensus:4545

Showing cases per 1 million persons calculated on the basis of current consensus: GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence 

Worldwide, Version 1.0. IARC Cancer Base No. 5, Lyon, IARC Press, 2001.

Comparison of Cancer Incidence  ‐2U S [curcumin non users] vs India [curcumin users]U.S [curcumin non‐users] vs. India [curcumin users]

Cancer US IndiaCancer US  IndiaCases Deaths Cases Deaths

Bladder 202 43 15 11Bladder 202 43 15 11Kidney 115 44 6 4Brain Nervous Systems 65 47 19 14Brain, Nervous Systems 65 47 19 14Thyroid 55 5 12 3Endometrial Cancer 163 41 132 72Endometrial Cancer 163 41 132 72Ovary 76 50 20 12Multiple Myelome 50 40 6 5Multiple Myelome 50 40 6 5Leukemia 100 70 19 17Non‐Hodgkin’s lymphoma 180 90 17 15Non Hodgkin s lymphoma 180 90 17 15Hodgkin’s disease 20 5 7 4

Showing cases per 1 million persons calculated on the basis of current consensus:4646

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.

Curcumin C3 Complex® ‐ Researchp

Diabetic Nephropathy Lichen planusDiabetic Nephropathy Lichen planus

Melanoma Cystic fibrosis

Colorectal cancer Multiple myeloma

Pancreatic cancer Oral cancer

COPD [ Lung inflammation ] Rheumatoid arthritis

Alzheimer’s Disease Head and Neck CancerAlzheimer s Disease Head and Neck Cancer

474747Sabinsa Corporation

Curcumin Bioavailability enhanced by Bioperine®

0.18

0.2

Curcumin + Bioperine

Curcumin

0.14

0.16

0.18

(g/m

l)

0 08

0.1

0.12

DoseC ien

trat

ion

0.04

0.06

0.08 Curcumin 2000 mgBioperine 20 mg

um c

once

0

0.02

0 25 0 5 0 75 1 2 3 4 5

Ser

0.25 0.5 0.75 1 2 3 4 5

Serum concentration of curcumin in healthy  volunteers  (n=8) after 4848

yadministration of curcumin with and without Bioperine

Curcumin BioavailabilityCurcumin Bioavailability

Sabinsa Corporation is currently working with a US b d h i t d Ph ti l tbased, research oriented Pharmaceutical company  to effect studies with Curcumin in the form of nanosomes  and liposomes in patients with various forms of cancerand liposomes in patients with various forms of cancer, particularly  pancreatic cancer.

Nano‐liposomes can act as both encapsulation and delivery systems with new and exciting applications, particularly in the pioneering of anti‐aging research.

4949

5050