P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease i P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 ADVANCESINEXPERIMENTALMEDICINEANDBIOLOGY EditorialBoard: NATHANBACK,StateUniversityofNewYorkatBuffalo IRUNR.COHEN,TheWeizmannInstituteofScience DAVIDKRITCHEVSKY,WistarInstitute ABELLAJTHA,N.S.KlineInstituteforPsychiatricResearch RODOLFOPAOLETTI,UniversityofMilan RecentVolumesinthisSeries Volume587 NEWTRENDSINCANCERFORTHE21stCENTURY EditedbyAntonioLlombart-Bosch,JoseLópez-GuerreroandVincenzoFelipe Volume588 HYPOXIAANDEXERCISE EditedbyRobertC.Roach,PeterD.Wagner,andPeterH.Hackett Volume589 NEURALCRESTINDUCTIONANDDIFFERENTIATION EditedbyJean-PierreSaint-Jeannet Volume590 CROSSROADSBETWEENINNATEANDADAPTIVEIMMUNITY EditedbyPeterD.Katsikis,BaliPulendranandStephenP.Schoenberger Volume591 SOMATICCELLNUCLEARTRANSFER EditedbyPeterSutovsky Volume592 REGULATORYMECHANISMSOFSTRIATEDMUSCLECONTRACTION EditedbySetsuroEbashiandIwaoOhtsuki Volume593 MICROARRAYTECHNOLOGYANDCANCERGENEPROFILING EditedbySimoneMocellin Volume594 MOLECULARASPECTSOFTHESTRESSRESPONSE EditedbyPeterCsermelyandLaszloVigh Volume595 THEMOLECULARTARGETSANDTHERAPEUTICUSESOFCURCUMIN INHEALTHANDDISEASE EditedbyBharatB.Aggarwal,Young-JoonSurhandShishirShishodia AContinuationOrderPlanisavailableforthisseries.Acontinuationorderwillbringdeliveryofeach newvolumeimmediatelyuponpublication.Volumesarebilledonlyuponactualshipment.Forfurther informationpleasecontactthepublisher. ii P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 Bharat B. Aggarwal Young-Joon Surh Shishir Shishodia Editors The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease With 77 Illustrations iii P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 Editors BharatB.Aggarwal,Ph.D. RansomHorne,Jr.,ProfessorofCancerResearch ProfessorofCancerMedicine(Biochemistry) andChief,CytokineResearchSection DepartmentofExperimentalTherapeutics TheUniversityofTexasM.D.AndersonCancerCenter 1515HolcombeBoulevard,BOX143,Houston,TX77030,USA [email protected] Young-JoonSurh,Ph.D. ChiefandProfessor NationalResearchLaboratoryofMolecularCarcinogenesis andChemoprevention CollegeofPharmacy SeoulNationalUniversity Shillim-dong,Kwanak-gu,Seoul151-742,SouthKorea [email protected] ShishirShishodia,Ph.D. AssistantProfessor DepartmentofBiology TexasSouthernUniversity 3100CleburneStreet,Houston,TX77004,USA [email protected] LibraryofCongressControlNumber:2006938892 ISBN-13:978-0-387-46400-8 e-ISBN-13:978-0-387-46401-5 Printedonacid-freepaper. (cid:2)C 2007SpringerScience+BusinessMedia,LLC Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten permissionofthepublisher(SpringerScience+BusinessMedia,LLC,233SpringStreet,NewYork, NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Use in connection with any form of information storage and retrieval, electronic adaptation, computer software,orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,evenifthey arenotidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyare subjecttoproprietaryrights. 9 8 7 6 5 4 3 2 1 springer.com iv P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 Dedicatedtoourgurusandparentswhoseguidancecontinuestoinspireus! Sarvebhavantusukhinahsarvesantuniramayah Sarvebhadranipasyantumakascidduhkhabhagbhavet “Mayallbehappy;mayallbehealthy; mayallenjoyprosperity;maynonesuffer.” v P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 vi P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 PREFACE Thesubjectofthismonograph,curcumin,whichgivestheyellowcolortoturmeric, bestknownasHaridrainSanskrit(meansdeartoHariorLordKrishna).Turmeric is known by several synonyms related to its appearance or use, including Pita (yellow,leadingtothenamePeethamberdhariforLordKrishnabasedonwearing onlyyellowclothes),Gauri(brilliant),Kanchani(lookslikegold),Nisha(beautiful as a full moon night), Krimighni (antibacterial and antihelmenthic), Mahaghni (antidiabetic), and Yoshit priya (gynecological disorders). In Hindi, turmeric is known as Haldi, in Japanese as Ukon or Gajyutsu, and in Korean as Ulgeum or Gangwhang. TurmericismentionedinthewritingsoftheItalianexplorerMarcoPolo,who was introduced to it during his voyage to China and India around 1290 ad. Al- thoughhegetscreditforbringingFarEastspicestoEurope,turmericwasactually introducedinEuropeinthe13thcenturyadbyArabtraders.ThePortugueseex- plorerVascodeGamavisitedtheIndiansubcontinentduringthe15thcenturyand broughtturmericandotherspicesoftheOrienttotheWest.Itwasonlyduringthe ruleoftheBritishinIndiathatturmericwascombinedwithvariousotherspices andrenamed“currypowder,”asitiscalledintheWest. Turmeric became of special importance to man with the discovery that when added to various food preparations, its dried and powdered rhizome preserved theirfreshnessandnutritivevalueandimprovedthepalatabilityandpresentation of food. The brilliant yellow color of turmeric, which persists even at very high dilutions,founditswaytocommercialuseasacoloringagentforvariousitems, includingcotton,silk,paper,wood,foodstuffs,andcosmetics.InAyurveda(science of long life), turmeric has been used internally as a stomachic, tonic, and blood purifier and topically in the prevention and treatment of skin diseases. Turmeric concoctionshavebeentraditionallyusedforthetreatmentofflatulence,dyspepsia, liverdisorder,jaundice,urinarytractdiseases,cold,chronicotorrhea,parasiticskin infection,bruises,sprain,wound,infectedwound,andinflammation. Wearecurrentlylivinginanerawhen80%oftheworld’spopulationcannotaf- fordmodernmedicine.Evenforthose20%whocan,muchofmodernmedicineis ineffectiveandhasnumeroussideeffects.Itisagoodtimetorevivethemedicinal useoftheancientmedicinecurcumin.Inthisvolumewebringtogetherthecon- tributionofmodernsciencetooneofthemostancientspicesknowntomankind. Curcumin’sbeneficialroleinhealthanddiseaseanditsmoleculartargetsarethe focusofthismonograph.Thisvolumeisdirectedatcliniciansandscientistswork- ingintheareasofexperimentalandmoleculartherapeutics,molecularmedicine, translational cancer research, Ayurveda, herbal medicine, naturopathy, and bio- medicalsciencesingeneraland,mostimportantly,totheendusersofcurcumin. Wehopethatthisbookwill“addspicetoeverybody’slife.” vii P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 viii PREFACE Wewouldliketothankallofthecontributorsfortheirvaluablecontributionsto thiswork.Wewouldalsoliketothankthosewhohavecontributedsignificantly tocurcuminresearchbutcouldnot,becauseoflimitationsonspace,beinvitedto contribute. BharatB.Aggarwal,Ph.D. Young-JoonSurh,Ph.D. ShishirShishodia,Ph.D. P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 FOREWORD ItisindeedamatterofprideandprivilegetowritetheForeword;tothisscholarly contribution on curcumin—the major constituent of turmeric. The volume has beensuccessfulinseamlesslyconnectingthetraditionalknowledgeavailableon turmeric to the findings of systematic modern research on turmeric and, based onthiseffort,buildingthepossibilitiesofdevelopingnoveldrugstotreatdiverse diseases.Turmeric(Curcumalonga)—awidelycultivatedtropicalplant—hasbeen used since ancient times as a spice, as a beauty care agent, and as a traditional medicine. Therhizomeofturmericishighlyaromaticandantiseptic.Themedicinalprop- erties of turmeric have been expounded in Ayurvedic and traditional Chinese medicine (TCM) texts. Turmeric is traditionally known as a stomachic, blood purifierandisusefulforthecommoncold,leprosy,intermittentfevers,afflictions oftheliver,indolentulcer,pyogenic(formingpus)afflictions,wound-healing,and inflammation. In recent years, the medicinal properties of turmeric have increasingly been recognized. It is being researched systematically even in the Western world. I rememberfightingthe“turmericbattle”onthewrongpatentonthewound-healing propertiesofturmericthatwasgivenbytheUSPatentOfficealmostadecadeago. AspertheUSNationalLibraryofMedicine,256researchpaperswerepublished lastyearoncurcumin.Theresearchershavefoundincurcuminanear-perfectstart- ingmaterialfordrugdiscovery.Thus,avarietyofcurcuminanalogueshavebeen preparedandevaluatedbiologically.Curcuminexhibitsawiderangeofactivities [e.g.,antibacterial,anti-inflammatory,hypolipidemic,hepatoprotective,lipoxyge- nase (LOX), cyclooxygenase (COX), protease inhibitory effects, in addition to being effective as an active oxygen scavenger and lipid peroxidase (a class of oxidoreductase enzymes) inhibitor]. Curcumin and the curcuminoids also lower cholesterol, reduce platelet aggregation, inhibit the proliferation of cancer cells, and improve digestion by increasing the flow of bile from the gallbladder. The desirablepreventiveorputativetherapeuticpropertiesofcurcuminhavebeencon- sideredtobeassociatedwithitsantioxidantandanti-inflammatoryproperties. Curcuminhasbeenfoundtomodulatetheactivityofseveralkeytranscription factorsand,inturn,thecellularexpressionprofiles.Theeffectofcurcuminhasbeen examinedonmostofthetargetsdiscoveredwithinthelastthreedecades.Curcumin modulatesseveraldifferenttranscriptionfactors,cytokines,growthfactors,kinases andotherenzymes.Theresearchresultshavebeenelaboratelycoveredinthisbook andexplanationsprovidedwouldaddtoknowledgepool. The National Institutes of Health has four clinical trials in progress on cur- cumin treatment, namely for pancreatic cancer, multiple myeloma, Alzheimer’s disease, and colorectal cancer. Curcumin has been found to possess potential ix P1:OTE/SPH P2:OTE SVNY332-Aggarwal April16,2007 13:14 x FOREWORD chemopreventiveactivities.Itshowscytotoxicpotentialagainsttumorcellsboth in vitro and in vivo. Thus, curcumin fits well in the effort of chemoprevention byediblephytochemicals,whichisnowconsideredtobeaninexpensive,readily applicable,andaccessibleapproachtocancermanagement.Theoptimizationof interventiontrialsofdiet-derivedputativechemopreventiveagentsiscurrentlyun- derdevelopmentinnormalpopulationsaswellasinhigh-riskgroups.Curcuminis alsoagoodimmunomodulator.Thesebiologicalactivitieswarrantfurtherstudies ofcurcumininthetreatmentandpreventionofhumanneoplasm. Curcuminhasenormouspotentialasanantiangiogenicdrug.Ithasbeenelabo- ratelyexplainedinthechapterdiscussingthis.Thepropertyhasbeenattributedto curcumin’sabilitytodownregulatecertaintranscriptionfactorsandproangiogenic factors.Curcuminalsohasthenecessarycharacteristicsofaneuroprotectivedrug. The activity has been proven in a variety of disease models. Thus, it has great potentialforthepreventionofmultipleneurologicalconditionsforwhichcurrent therapeuticsarelessthanoptimal.Thechapterentitled“NeuroprotectiveEffects of Curcumin” embodies the research carried out on the subject and the existing necessityforfurtherefforts.Thecurcumin-mediatedregulationofCOXandLOX enzymesforobtainingtheirbeneficialeffectsinpreventingdiverseinflammatory diseases has been dwelt upon in another chapter. Interestingly, curcumin has an edgeoverconventionalnonsteroidalanti-inflammatorydrugsandselectiveCOX-2 inhibitors.Thismightpavethewayforpath-breakingresearchinthedomain. This volume in fact covers the length and breadth of research undertaken on curcuminandresearchresultsthusfarobtained.Thediversityrangesfrommolec- ulartargets,cellgrowthregulation,antioxidantandanti-inflammatoryproperties, chemosensitivity, radio protection, and radio sensitivity to immunomodulation, anticancer effects, cardioprotective effects, nephroprotective to hepatoprotective effects,protectionfromacuteandchroniclungdiseasestopharmacokineticsand pharmacodynamics and clinical studies undertaken with curcumin. The canvas thuscoveredisindeedbrilliant. As research advances, it poses newer challenges as well. Several questions in thelightofthenewdrugdevelopmenteffortthusremaintobeansweredinorder toputcurcumininahigherorbit.Thesepertaintothesolubilityandstabilityof curcumin,itsoptimumdose,pharmacokinetics,mechanismofactionofcurcumin foragivendisease,bioavailabilityprofile,andintricaciesofpreventionandcure ofanidentifieddisease.Furtherresearchisthusnecessaryontheseaspects.There is also a need to find out whether other components of turmeric than curcumin havebeneficialeffects,eitheraloneorincombinationwithcurcumin. Iamhappytoseethatthecontributionsinthisbookhaveprovenbeyonddoubt thatcurcumin—aningredientofthetraditionalIndianspiceturmeric—hasenor- mous potential against a variety of malignant and nonmalignant diseases. I am confident that the state-of-the-art on curcumin research so nicely compiled and analyzedthroughoutthisvolumewouldprovideaninsightandlearningnotonlyto professionalsinthefieldbutalsotobuddingresearchers.Ihopethattheywouldbe inspiredtoanswertheunansweredquestionsoncurcuminbasedonnewresearch