Review Article Curcumin: A Potential Candidate in Prevention ...curcumin [ ]. Another report in human breast cancer cell line showed that CD induces G-G arrest and apoptosis via regulation

Review ArticleCurcumin A Potential Candidate in Prevention of Cancer viaModulation of Molecular Pathways

Arshad H Rahmani1 Mohammad A Al Zohairy1 Salah M Aly12 and Masood A Khan3

1 Department of Medical Laboratories College of Applied Medical Sciences Qassim University Buraida Saudi Arabia2Department of Pathology Faculty of Vet Medicine Suez Canal University Ismailia Egypt3 Department of Basic Health Science College of Applied Medical Sciences Qassim University Saudi Arabia

Correspondence should be addressed to Arshad H Rahmani rehmaniarshadgmailcom

Received 19 June 2014 Revised 25 August 2014 Accepted 25 August 2014 Published 10 September 2014

Academic Editor Goutam Ghosh Choudhury

Copyright copy 2014 Arshad H Rahmani et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cancer is the most dreadful disease worldwide in terms of morbidity and mortality The exact cause of cancer development andprogression is not fully known But it is thought that cancer occurs due to the structural and functional changes in the genesThe current approach to cancer treatment based on allopathic is expensive exhibits side effects and may also alter the normalfunctioning of genes Thus a safe and effective mode of treatment is needed to control the cancer development and progressionSomemedicinal plants provide a safe effective and affordable remedy to control the progression of malignant cellsThe importanceof medicinal plants and their constituents has been documented in Ayurveda Unani medicine and various religious booksCurcumin a vital constituent of the spice turmeric is an alternative approach in the prevention of cancer Earlier studies haveshown the effect of curcumin as an antioxidant antibacterial antitumor and it also has a noteworthy role in the control of differentdiseases In this review we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer viathe regulation of various cell signaling and genetic pathways

1 Introduction

Population growth and aging may contribute to a dramaticincrease in the numbers of cancer cases The exact causeof the cancer development and progression is still not wellknown But it is thought to be as a result from alterationsin the various genetic [1ndash3] and metabolic pathways Thepresent regime to cancer treatment based on synthetic drugsand chemotherapyradiotherapy is expensive and also altersthe various mechanisms of the normal actions of genesPresently several medicinal plants and their constituentsare in use to manage the development and progression ofvarious diseases and have been found effective safe andless expensive The importance of medicinal plants has beendiscussed in different religious books including ChristianityHinduism and Islam Our Prophet Mohammad (PBUH)used and recommended various plants and their products inthe cure of diseases [4 5] In the present scenario variousparts of the world are using different types of local plants

or products like turmeric in Indian cuisine and oregano inItaly olive in Spain and Ajwa dates in Saudi Arabia in thetreatment and prevention of various diseases Earlier studieshave reported that olive dates and black seed show role incancer prevention through modulation of various activities[6ndash8]

Curcumin is a polyphenolic compound derived fromthe popular Indian spice turmeric plant It is a memberof the Zingiberaceae (ginger) family which is native toSoutheast Asia [9] chemical structure was characterizedin 1910 by Milobedeska and colleagues and synthesis wasconfirmed by Lampe and colleagues in 1913 [10 11]Curcuminis lipophilic in nature which shows low solubility and stabilityin aqueous solution It is extensively used in AyurvedaUnani Siddha and Chinese medicine for the managementof various diseases such as wound inflammation and cancer(Figure 1) and used in curries and dishes especially in spicydishes in India Pakistan Bangladesh and other countriesof Asia Curcumin because of its special properties such

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 761608 15 pageshttpdxdoiorg1011552014761608

2 BioMed Research International

Liver cancer

Breast cancer

Arthritis Cataract

Diabetes

Lung cancer

Turmericcurcumin

Pancreas cancer

Bladder cancer

Oral cancerColorectal cancer

Stomach cancer

Cardiovasculardisease

Figure 1 Turmericcurcumin shows pivotal role in the prevention of diseases including cancer

as being antiprotozoal and antioxidant and this uniquenessmight have a significant effect on several types of diseasesanticipation [12 13] Important reviews based on curcuminprovide an overview of the history chemistry analogs andmechanism of action of curcumin [14] and another studydiscussed in detail the therapeutic implications of curcuminin patients with pancreatic cancer [15]

2 Curcumin Modulator ofMolecular Pathways

Tumorigenesis and tumor progression are thought to be asa result of some changes in the different types of geneticpathways [16 17] Curcumin chief constituents of turmericshows a vital role in cancer prevention and treatmentthrough modulation of various biological activities includingmolecular cascades However understanding the turmericrsquosmechanism of action in the activation or inactivation ofgenetic pathways will provide significant information todevelop therapeutic approaches to manage various types ofcancers

21 Effect of Curcumin on Tumor Suppressor Genes Tumorsuppressor genes play a vital and significant role in theinhibition of cancer formation and its progression Whenan alteration or mutation occurs in a gene then tumorsuppressor gene lost its ability to perform normal functionTumor suppressor gene p53 is the guardian of all genesand regulates the various cellular and molecular pathwaysand prevents cancer formation Numerous in vivo and invitro reports showed that turmeric and its constituents havea significant role in cancer prevention or inhibition Animportant study showed that curcumin down-regulates theexpression of p53 as well as the survival genes egr-1 c-myc and bcl-XL in B cells [18] Another report has alsoindicated that curcumin inhibits cell cycle progression ofimmortalized human umbilical vein endothelial cells viaupregulating the CDK inhibitors p21WAF1CIP1 p27KIP1

and p53 [19] Further studies reported that curcumin mainlyacts in p53-dependent manner and also showed that wild p53was highly susceptible to curcumin toxicity [20]

Another tumor suppressor gene phosphatase and tensinhomolog deleted on chromosome ten (PTEN) has a role inthe progression of the cell cycle and apoptosis The alterationor mutation of PTEN gene has been noticed in several typesof cancers A study of the curcumin has shown that PTENincreases the curcumin-induced apoptosis whereas inactivePTEN decreasesinhibits the curcumin-induced apoptosis[21] A study showed that difluorinated curcumin (CDF) anontoxic analog modulates the expression of miR-21 andPTEN in pancreatic cancer [22ndash25]

The retinoblastoma is a type of tumour suppressor geneand shows an important role in the control of cell cyclepRb the protein coded for by the RB1 gene shows animportant role in cell cycle regulation promoting G1S arrestand growth restriction via inhibition of the E2F transcriptionfactors [26] It is inactivated through hyperphosphorylationcatalyzed by the cyclin D-cyclin-dependent kinase 4 (cyclinD-cdk4) and cyclin E-cdk2 complexes [27ndash29] Variousmedicinal plants and their constituents show a vital role in theregulation of Rb genes via regulation of phophorylation Inthis vista curcumin chief constituents of turmeric also showsan important role in modulation of Rb gene via reductionin hyperphosphorylation An important study based onprostate cancer cells has revealed that curcumin induced theexpression of cyclin-dependent kinase (CDK) inhibitors p16p21 and p27 and inhibited the expression of cyclin E andcyclin D1 and hyperphosphorylation of retinoblastoma (Rb)protein [30] and another study has shown that suppression ofcyclin D1 by curcumin led to inhibition of CDK4-mediatedphosphorylation of retinoblastoma protein [31]

22 Effect of Curcumin on Apoptotic Genes Apoptosis is oneof the prerequisites to maintain the normal and healthy inter-nal milieu Any alteration or change in the normal process ofapoptosis may increase cell survival and support the tumor

BioMed Research International 3

development and progression [32 33] Curcumin plays a vitalrole in the upregulation of different proapoptotic genes and atthe same time downregulates some of the antiapoptotic genesand by this way balances the apoptosis process (Figure 2) Aninteresting study showed that curcumin induces apoptosis inscleroderma lung fibroblasts (SLF) without affecting normallung fibroblasts [34] Furthermore curcumin has shownan antitumor activity and was involved in the apoptosisinduction and the modulation of key apoptotic proteins suchas Bax and bcl-2 [35] A study has reported that growth arrestand apoptosis of B cell lymphoma occur through the downregulation of c-myc bcl-XL and p53 with the treatment ofcurcumin [36] Another report in human breast cancer cellline showed that CD437 induces G0-G1 arrest and apoptosisvia regulation of p21WAFICIPI Bcl-2 and Bax in a p53independentmanner [37] Another study on p53-null cells aswell as TR9-7 cells reported that curcumin induces apoptosisin tumor cells via a p53-dependent pathway and Bax act asdownstream effectors of p53 [38]

Curcumin induces apoptosis in a range of tumor cell linesthrough activation of caspase-3 cytochrome c release anddownregulation of bcl-2 [39ndash42] Curcumin has shown anapoptotic effect by inhibiting various genes such as proteintyrosine kinase protein kinase C c-myc mRNA expressionand bcl-2 mRNA expression [43] and also mitochondrialpathway Earlier studies have shown that curcumin possessesan apoptotic activity in different types of cancer cell suchas human colon cancer cells stomach and skin tumorsbreast cancer cells and prostate cancer cells [44ndash47] Studyof colon cancer cell line showed that apoptosis was increasedin response to curcumin [48 49] Curcumin also showed avital role in decreasing cell proliferation in a dose dependentmanner [48ndash50] Curcumin may lower the incidence ofvarious cancers including urothelial malignancies [51 52]and also may induce apoptosis inMBT-2 cells [53] and G2Marrest of T24 cells [54] Experimental studies showed thatthe downregulation of the expression of antiapoptotic proteinoccurs with curcumin treatment [55 56]

23 Effect of Curcumin on Angiogenesis Angiogenesis is acomplex process involving widespread interaction betweenthe cells soluble factors and ECM components [57] It alsoshows a vital effect in tumor growth and is triggered by chem-ical signals from tumor cells in a phase of rapid growth [58]There are several angiogenic factors such as vascular endothe-lial growth factor (VEGF) basic fibroblast growth factor(bFGF) angiogenin transforming growth factor (TGF-120572TGF-120573) and epidermal growth factor These factors show acritical role in tumor angiogenesis via cancerous tumor cellsby releasing molecules and sending signals to surroundingnormal host tissue [59] VEGF is a crucial survival factorfor endothelial cells in the process of physiological tumorangiogenesis and induces the expression of antiapoptoticproteins in the endothelial cells [60]There are certain drugslike Bevacizumab (Avastin) available as an inhibitor of VEGFaction in the treatment of cancer These drugs are expensiveand a large group of the population cannot afford their costHowever a safe and affordable natural product is needed tocontrol the cancer development

Earlier studies have shown that curcumin is an inhibitorof VEGF in different types of cancer including orthotopicallyimplanted pancreatic tumors [61] Important record via invitro and in vivo studies showed that curcumin suppressesthe proliferation of human vascular endothelial cells and alsoabrogates the FGF-2-induced angiogenic response [62 63]Moreover curcumin has the ability to inhibit both VEGFand its receptor in various cancer types it might be usefulas an antiangiogenic agent [64 65] Besides curcumin playsa major role in the suppression of transcriptional activity ofAP62 and HIF-1 and causes a reduction in the expressionof VEGF [66] An important study results suggested thatcurcumin potentiates the antitumor effects of gemcitabine inpancreatic cancer via suppressing proliferation angiogenesisNF-120581B and NF-120581B-regulated gene products [61] A study ofadenoid cystic carcinoma cells showed that curcumin signifi-cantly inhibited the growth survivalmigrationinvasion anddownregulates VEGF and MMP-29 or inhibits the mTORand NF-120581B pathways [67]

24 Effect of Curcumin on Phase I and Phase II GenesEnzymes Xenobiotics are molecules introduced into thebody from the environment and not produced inside thebody The body then metabolizes them through two phasesof transformation Phase I and Phase II

The turmeric has shown a significant effect on the regu-lation of xenobiotic metabolism via inhibition of the phase Iand activates the phase II geneenzymes In the phase I reac-tions addition of a functional polar group normally resultsin a relatively small increase in hydrophilicity and may causemetabolic activation Cytochrome P450 (CYP) is the mainenzymes in phase I and shows the vital effect on the activationof carcinogens So control of CYP450 activity is the mainissue in cancer prevention through increasing the degree ofcellular safety A study in rat model showed that curcumininhibits the alkylation reaction catalyzed by CYP1A1 1A2[68] In another interesting study it was reported that CYPplays a vital role in the formation of aflatoxine-DNA adductand this intermediate product is suppressed or inhibited bycurcumin treatment [69] Curcumin has shown its effect inhampering CYP1A1 activity in DMBA-treated cells and alsoinhibited the metabolic activation of DMBA and decreasedthe DMBA-induced cytotoxicity [70]

In the Phase II reactions conjugation with a smallhydrophilic endogenous substance increases the hydrophilic-ity and facilitates the emission However the activationof Phase II enzymes such as Glutathione S Transferase inthe treatment and suppression of cancer is critical and isa significant strategy Several earlier studies reported thatturmeric and its constituents play a significant role in theprevention of cancer via the activation of GST genes

An important finding showed that turmericcurcuminenhances the activity of Phase II enzyme GST [71ndash76]Curcumin also elevates the protein as well as mRNA expres-sions of GSTs and NQO1 in mouse tissues suggesting arole of curcumin in transcriptional regulation of phase IIenzymes [77] Moreover curcumin induces GST expressionby signalling through the nuclear erythroid-derived 2-related


Turmericcurcumin

Bloodtissue Observed in liver

Inductionof apoptosis

(bcl2 and bax)

Activation of tumorsuppressor gene

(p53 PTEN and Rb)and PPAR

Suppression ofVEGF

Akt and PI3K

Downregulationof AR and ER

HER-2 and EFGR)

Activation ofphase-II gene

(GST and NAT)

Inactivationof phase-I

gene (CYP-450)

Detoxification of toxicparticle to water

soluble molecules

Inactivation ofreactivespecies

Excreted viaurine

Prevention of cancer formation

Downregulationof oncogene

(c-myc c-fos

Figure 2 Turmericcurcumin shows an important role in cancer prevention via induction of apoptosis activation of tumour suppressor geneand phase II gene and inactivation of oncogene hormonal receptor gene and angiogenesis and phase-I gene

factor 2 (NRF-2) and NF-120581B via an antioxidant responseelement [78]

25 Androgen DegradationDown Regulation by CurcuminThe androgen receptor (AR) is a ligand activated steroidhormone receptor that plays a vital and significant rolein developing the function of normal prostrate as well asin prostate cancer development and progression [79 80]Change in the function or overexpression of AR has beenobserved in cancer [81] The treatment basis on allopath likehormone therapywas considered as a potential treatment butits limitationdisadvantage as prostate cancer cells becomeprogressive and may lead to metastasis [82] The regulationof AR activities is a critical step in the control or suppressionof tumor development and progression An important studyof curcumin on androgen dependent LNCaP prostate cancercell line and an androgen independent PC-3 prostate cancercell showed that AR protein level is downregulated [83]Earlier studies had shown that curcumin downregulates the

transactivation and expression of AR and AR-related cofac-tors [84]The constituent has a potential therapeutic effect onprostate cancer cells through the downregulation of AR andAR-related cofactors AP-1 NF and CBP [84] Another studyreported that curcumin acts as an inducer of apoptosis inboth androgen-dependent and hormone refractory prostatecancer cells [85] Curcumin blocks the activation of androgenand IL-6 on prostate-specific antigen expression in humanprostatic carcinoma cells [86]

26 Effect of Curcumin on PI3 KAkt Pathways PI3KAktsignalling pathway is important and critical in mediating cellsurvival proliferation migration and angiogenesis PI3 Kcatalyzes the production of the lipid secondary messengerphosphatidylinositol-345-triphosphate including the ser-inethreonine kinase Akt [87 88] Mutation andor lossof PTEN function plays an important role in the acti-vation of PI3 K and is associated with the growth andprogression of various types of cancers [89 90] ActivatedPI3 K shows a role in the conversion of phosphatidylinositol


into PtdIns(34)P2 (PIP2) and PtdIns(345)P3 (PIP3) Phos-phatidylinositol dependent kinases 12 (PDKs 12) play a keyrole in the phosphorylation of Akt at residues Thr308 andSer473 [91ndash93] Activated Akt plays a role in promoting cellsurvival by suppressing apoptosis via subsequent modulationof a wide range of target molecules [94ndash97] PTEN a tumorsuppressor gene is a multifunctional phosphatase whosemajor substrate is phosphatidylinositol-345-trisphosphate(PIP3) [98] Phosphatase activity of PTENplays an importanteffect in dephosphorylation of PIP3 By this way PTENnegatively regulates the phosphoinositide-3-kinase (PI3 K)-PKBAkt pathway and prevents the tumor development ortumor suppression The inhibition of the PI3 KAkt andactivation of PTEN pathway is a good strategy in the pre-vention of cancer An important study showed that curcumininhibits the phosphorylation of Akt mTOR and their down-stream substrates and this inhibitory effect acts downstreamof phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase1 [99]

27 Effect of Curcumin on Cycloxygenase Enzyme COX is aninducible enzyme in the conversion of arachidonic acid toprostaglandins (PGs) There are two types of cycloxygenaseCOX1 plays a vital role in physiological functions and COX2is upregulated or overexpressed in various types of cancers[100ndash102] It was previously stated that curcumin inhibitsthe critical stage of tumor initiation and promotion stages[103 104] and COX inhibition [105] Curcumin also inhibitsthe COX2 expression on colon cancer cell lines [106] Earlierstudies reported that curcumin plays an important rolein the downregulation of the expression of COX-2 andfinally prevents or suppresses the cancer progression [107]Moreover curcumin plays a significant role in the cancerprevention via controlling the activities of various genes inthe initiation promotion and progression stage of tumordevelopment and progression (Figure 3)

28 NF-120581B and Curcumin in Cancer Prevention NF-120581Bfamily of transcription factors shows an important role inimmune inflammatory response and also stimulates thedevelopment and progression of cancer In this regard animportant study demonstrated that curcumin showed as ananticancer antioxidant and anti-inflammatory effect via thedownregulation of the transcription factors NF-120581B AP-1 andEgr-1 [108] and repression of the genes for cell adhesionmolecules (chemokines TNF Cox-2 andMMP-9) [109 110]Another study showed that curcumin is a pharmacologicallysafe agent and has been involved in the suppression of NF-120581Bactivation and NF-120581B gene products [111]

An important study in pancreatic cancer cells reportedthat curcumin showed a vital role in the suppression ofNF-120581Bactivation by inhibiting I120581B kinase ultimately induces I120581B120572phosphorylation and inhibits the NF-120581B downstream geneexpression [112]

Several findings showed that curcumin suppresses theexpression of a variety of NF-120581B regulated gene productsinvolved in cancer development and progression such as

cyclin D1 VEGF COX-2 c-myc Bcl-2 ICAM-1 andMMP-9[110 113ndash115]

Numerous studies has shown that curcumin is a potentinhibitor of NF-120581B activation [63 109 111 116ndash119]

29 Effect of Curcumin on Oncogene Alteration or muta-tion of protooncogene is key factors in the developmentand progression of various types of tumours An activatedoncogene has been noticed in various types of cancer[120ndash122] Safe route of inactivation of an oncogene is aprime interest in the prevention of tumor Several earlierinvestigations reported that curcumin shows a significanteffect in cancer prevention via the inactivation of oncogeneCurcumin downregulated N-Myc [123] in various cancertypes and decreased the expression of proto-oncogenes suchas ras and fos in tumorous skin [124] A report on theeffect of curcumin in hepatocellular carcinoma revealed thatcurcumin blocked transactivation of the c-Met promoterthrough AP-1 [125] Another finding on curcumin effectin the downregulation of oncogene showed that curcumininduced the antiproliferative antimigratory and apoptoticeffects via the downregulation of various genes includingc-Myc N-Myc cyclin D1 and antiapoptotic factors Bcl-2and Bcl-xL [126] Several other studies showed the effectof curcumin in the inhibition or downregulation of variousoncogenes such as EGFR HER-2 PI3 KAkt and MAPKpathway [127ndash131] Curcumin is involved in the induction ofapoptosis through downregulating the expression of c-mycBcl-2 and mutant-type p53 and upregulating the expressionof Fas [132]

210 Effect of Curcumin on Signal Transducer and Activator ofTranscription 3 (STAT3) The Signal Transducer and Activa-tor of Transcription 3 (STAT3) protein is one of the importantmembers of the STAT family of transcription factors [133]STA3 plays a role in the cancer development and progressionand overexpression or high level of STAT3 has been observedin various types of cancers [134 135] Curcumin inhibitsconstitutive STAT3 phosphorylation [136] Other resultsalso show that the curcumin significantly suppressed Stat3phosphorylation in bronchoepithelial cells and lung cancerderived cells indicative of Stat3 pathway suppression andfinally inhibits the proliferative capacity of bronchoepithelialcells and lung cancer cells [137]

211 Effect of Curcumin in Peroxisome Proliferator-ActivatedReceptors (PPARs) PPARs belong to the super family ofnuclear receptors containing three genes that give differentsubtypes such as PPAR-120572 PPAR-120575 and PPAR-120574 [138] Cur-cumin showed a role in the upregulation of PPAR-120574 [139] andinterrupted with PDGF and EGF signaling stimulated geneexpression of PPAR120574 and thereby plays a role in the inhibi-tion of cell proliferation of activated HSCs [140] A study ofcurcumin effects on colon cancer cells confirmed that growthinhibition and stimulation of the transactivating activity ofperoxisomeproliferator-activated receptor c (PPAR-c) whichappears to mediate the suppression of gene expression of


Curcumin

Activation of tumorsuppressor gene (P53 and PTEN)

Initiation Promotion Progression

Inactivation of VEFG

AKT and PI3K

Induction of apoptosis(bcl2 and bax)


Figure 3 Curcumin shows an important role in the prevention of cancer through the inhibition of initiation promotion and progressionsteps via modulation of molecular cascades

cyclin D1 and the epidermal growth factor receptor (EGFR)[141]

212 Effect of Curcumin on Matrix Metalloproteinases-9(MMP-9) Matrix metalloproteinases (MMPs) have beenconsidered as one of the important vital molecules assistingtumor cells during metastasis [142ndash145] MMP9 memberof the matrix metalloproteinases (MMPs) shows a majorrole in the breakdown of extracellular matrix in normalphysiological processes including embryonic developmentreproduction and tissue remodeling as well as in diseaseprocesses such as tumor metastasis [146] Altered expressionof MMP-9 has been observed in various types of tumorsHowever curcumin shows a vital role in the inhibition ofMMP-9 activities and finally plays a role in the managementof cancer A study showed that curcumin inhibits TPA-induced MMP-9 expression and cell invasion through sup-pressing NF-120581B and AP-1 activation [147]

Another study showed that curcumin significantly inhib-ited the MMP-9 enzymatic activity and protein expressionthat was induced by PMA [148] An important study hasshown in a human breast cancer xenograft model thatadministration of curcumin noticeably decreased metastasisto lung and suppressed the expression of NF-120581B MMP-9COX-2 VEGF and intercellular adhesion molecule-1 [149]Earlier results suggest that curcumin plays a role in regulatingcell metastasis by inhibiting MMP-2 and MMP-9 in breastcancer cell line [150] Curcumin showed inhibition of phorbolester-induced upregulation of cyclooxygenase-2 and matrixmetalloproteinase-9 inMCF10A human breast epithelial cellsstudy [151]

3 Clinical Trials Based Study of Curcumin

Several valuable clinical trials have been performed usingturmeric and its constituents to check their efficacy andsafety Curcumin shows the chemopreventive effect in varioustypes of tumor via modulation of biological processes Animportant study based on twenty-five patients with severaldifferent premalignant or high-risk lesions suggested thatoral curcumin may have chemopreventive effects on theprogression of these lesions [152] Another uncontrolledstudy based on advanced colorectal cancer refractory tostandard treatments glutathione S transferase has showna 59 reduction in the activity with the oral curcuminextract dose of 440mg daily and five patients maintainedradiologically stable disease over the 2- to 4-month studyperiod [153] Another study in chronic smokers was per-formed to check the antimutagenic effects of turmeric andit was found that that turmeric significantly reduced theurinary excretion of mutagens in smokers with doses of15 gmsday for 30 days whereas in the control group (non-smokers) there was no change in the urinary excretionof mutagens after 30 days [154] An important study wasperformed in 39 subjects (thirteen with dental caries twenty-one with head and neck cancer and five healthy volunteers)and saliva was collected in 50mL tubes before and afterone hour when subjects chewed two curcumin chaplets Itwas found that curcumin treatment led to a reduction inIKK120573 kinase activity in the salivary cells of head and necksquamous cell carcinoma [155] A study was performed toevaluate the safety and feasibility of combination therapyusing curcumin with gemcitabine-based chemotherapy ontwenty-one patients and showed 8 gms oral curcumin dailywith gemcitabine-based chemotherapy was safe and feasible


in patients with pancreatic cancer [156] Another importantstudy was performed on patients with colorectal cancer andpatients were ingested curcumin capsules with a dose of(36 g 18 and 45 g daily) for 7 days This finding suggeststhat a daily dose of 36 grams curcumin is pharmacologicallyeffective in the colorectum with negligible distribution ofcurcumin outside the gut [157]

4 Toxicity of Curcumin

Turmeric and its constituents play a vital role in the man-agement of various diseases including cancer Toxicity andlethal dose level of curcumin are important before usingin health management Several studies were performed tocheck the safe dose of curcumin in animal model studiesNo significant toxicity was observed of turmeric and itsconstituent curcumin at various doses An important study inwhich animals were fed curcumin with a dose of 18 gmskgand 08mgkg in rat and monkey respectively for 90 daysshowed no adverse effects [158] An important study inwhich animals were fed curcumin with a dose of 18 gmskgand 08mgkg in rat and monkey respectively for 90 daysshowed no adverse effects [158] Curcumin is remarkablywell tolerated but its bioavailability is poor It does notshow to be toxic to humans [159] even at high doses Earlierstudies concluded that combination therapy using 8 g oralcurcumin daily with gemcitabine-based chemotherapy wassafe and feasible in patients with pancreatic cancer [156] andother study concluded that oral curcumin is well toleratedand despite its limited absorption showed biological activity[160] An important study based on advanced pancreaticcancer patients showed that 5 patients out of 17 patientsreceiving curcumin with dose 8 gmsday with gemcitabineshowed intractable abdominal pain after a few days to 2weeksof curcumin intake [161]

A study reported that hepatotoxicity was seen in mice fedwith whole turmeric (02 1 5) or ethanolic turmericextract (ETE 005 025) for 14 days [162] Earlier reportbased on curcumin has shown that curcumin doses rangingfrom 045 to 36 gmsday for 1 to 4 months showed nauseaand diarrhea and also caused an increase in serum alkalinephosphatase and lactate dehydrogenase contents [163]

5 Role of AnalogueDerivatives of Curcumin

Some drugs due to their hydrophobic nature show poorbioavailability and a very low quantity of drugs go to thetarget tissues and show less activity Low bioavailability ofcurcumin due to its low aqueous solubility has been a majorobstacle for its clinical development as a therapeutic drug[164]

However increasing the absorption of drugs for betteractivity is the main research of interest in this vista Ana-logues or derivatives of drugs show higher absorption andbetter activity without any adverse complications Nanoparti-cleencapsulation systems give better efficacy and bioavaibil-ity of drugs and also provide the best option in the healthmanagementwithout any untoward effects Severalmedicinal

plants and their constituents play a significant role in diseasemanagement via modulation of various biological activitiesBut medicinal plants and their constituents show somelimitation in the term of efficacy due to the low absorptioncapacity Therefore in clinical trials of oral administration ofcurcumin to human cancer patients the systemic availabilityof curcumin was found to be negligible because of poorabsorption of the compound [153 157]

Clinical trials based studies showed that various types ofderivatives such as FLLL 11 and FLLL 12 RL 90 RL91 andGO-YO30 play a significant role as therapeutic drugs

Earlier investigators showed that GO-Y030 curcuminanalogue inhibited colorectal carcinoma cell growth in vitroand in a mouse model [165] and this analogue also inhibitsSTAT3 activity and cell growth in the breast and pancreaticcarcinomas [166]The inhibition of STAT3 via GO-Y030 alsoplays an important role in downregulation of the expressionof STAT3-regulated genes in colorectal cancer stem cellssuch as Cyclin D1 [167] surviving [168] Bcl-2 and Bcl-XL [167 169] An important study showed that GO-Y030reduced the STAT3 downstream target gene expression andinduced apoptosis in colon cancer stem cells [170]

Another important study reported that analogues such asGO-Y030 and GO-Y078 showed 7- to 12-fold more potentgrowth suppression ofmyeloma cells and showed 6- to 15-foldstronger inhibition of NF-120581B PI3 KAKT JAKSTAT3 andIRF4 pathways than curcumin [171] In MDA-MB-231 cellsGOYO30 has a reported IC50 of 12 120583M [172] significantlyless than curcumin

An important study has compared the inhibitory effi-cacy of analogues of curcumin such as GO-Y030 FLLL-11 and FLLL-12 in colorectal cancer cell lines includingHCT116 HT-29 and SW480 and found that GOY030 FLLL-11 and FLLL-12 showed more potent inhibition of cell via-bilityproliferation in all HCT116 HT-29 and SW480 humancolorectal carcinoma as compared to curcumin [166]

Earlier investigators reported that analogues such asFLLL11 and FLLL12 showed more potency than curcuminat inhibiting cell viability cell migration and colony for-mation in soft agar than curcumin and theses analoguesinduced apoptosis in human breast and prostate cancer cellsFLLL11 and FLLL12 analogues of curcumin also synergizewith doxorubicin to suppress the growth of MDA-MB-231breast cancer cells [173] Earlier investigators showed thatD6 compound promotes apoptosis in melanoma cells via themitochondrial intrinsic pathway [174]The analogues such as26-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and26-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91) mod-ulated the expression of cell signaling proteins specificallyin SKBr3 cells protein levels of Her-2 Akt and NF120581B weredecreased whereas activity of stress kinases JNK12 and P38MAPK were increased [175]

A recent study showed that RL66 decreased the phospho-rylation of Akt on Ser-473 in a time-dependentmanner RL66decreased Akt phosphorylation after 6 h in MDA-MB-231cells whereas the phosphorylation of Akt was only decreasedafter 36 h in MDA-MB-468 cells [176] Other studies alsoreported that RL66 had superior cytotoxicity compared toother analogs of curcumin such as 35-bis(flurobenzylidene)


piperidin-4-one (EF24) [177] 5-bis(4-hydroxy-3-methoxy-benzylidnen)-N-methyl-4-piperidone [178] (PAC) and GO-Y030 [172] in MDA-MB-231 cells

6 Bioavailability of Curcumin

Curcumin shows a vital role in health management throughthe modulation of various biological activities includingregulation of molecular pathways Therefore in spite of itspotential effects in health benefits of curcumin are limiteddue to its poor solubility low absorption from the gutrapid metabolism and rapid systemic elimination [179]Enhancement of absorption solubility and slowing downthe rapid metabolism of curcumin are a main interest ofresearch in medical sciences In this vista various studiesbased on animal model and clinical trials have provedthat new formulation of curcumin based on nanoparticlesliposomes and other new formulations shows a valuable rolein health management due to high absorption solubility andslowing down the rapidmetabolism compared to normal cur-cumin However new formulation of curcumin shows bettertherapeutic role in health management due to increased orenhanced bioavailability

Curcumin revealed poor bioavailability has been wellrecognized by earlier finding [164] and a study reportedthat 10mgkg of curcumin given intravenously to rats yielda maximum serum level of 036 plusmn 005 120583gmL whereas500mgkg of curcumin administered orally only yielded a006 plusmn 001 120583gmL maximum serum level [180]

Furthermore curcumin was given orally to rats at adose of 2 gkg a maximum serum concentration of 135 plusmn023 120583gmLwas observed at time 083 hours while in humansthe dose of 2 g of curcumin resulted in either undetectable orvery low (0006 plusmn 0005 120583gmL at 1 h) serum levels [181]

Therefore new formulation based on adjuvants nanopar-ticles liposomes micelles and phospholipid complexes iscurrently evaluatedused to increase the bioavailability andbiological activity of curcumin[182ndash186] An important studyformulated innovative preparation such as THERACUR-MIN and confirmed that its oral bioavailability is approxi-mately 30-times higher than curcumin powder in both ratsand humans and results also show that THERACURMINenhanced gastrointestinal absorption as a result of colloidaldispersion [187] Another study was performed to evalu-ate the safety and pharmacokinetics of newly developednanoparticle curcumin with increased water solubility suchas THERACURMIN and it was concluded that THERACUR-MIN can safely increase plasma curcumin levels in a dose-dependent manner at least up to 210 mg without saturatingthe absorption system [188] A study also reported thatcurcumin loaded cellulose nanoparticles (cellulose-CUR)formulation showed the highest cellular uptake and causedmaximum ultrastructural changes related to apoptosis inprostate cancer cells [169] and other study concluded that SF-derived curcumin nanoparticles show higher efficacy againstbreast cancer cells and also have the potential to treat in vivobreast tumors [189]

A study was performed to evaluate the liposomal cur-cuminrsquos potential against cancer models of mesenchymal

(OS) and epithelial origin and it was observed that 2-Hydroxypropyl-120574-cyclodextrincurcumin-liposome compl-ex shows promising anticancer potential both in vitro and invivo against KHOS OS cell line and MCF-7 breast cancer cellline [190]

A study based on in vivo pharmacokinetics showed thatcurcumin entrapped nanoparticles demonstrate at least 9-fold increase in oral bioavailability as compared to curcuminadministered with piperine as absorption enhancer [191]and study based on human colorectal cancer cell lines suchas LoVo and Colo205 cells showed that in vitro treatmentwith liposomal curcumin induced a dose-dependent growthinhibition and apoptosis [192] An important study showedthat encapsulating the curcumin into the hydrogel nanopar-ticles yielded a homogenous curcumin dispersion in aqueoussolution as compared to the free form of curcumin [193]and earlier finding observed that after oral administrationof CUR-PLGA-NPs the relative bioavailability was 56-foldincreased and also showed longer half-life compared withthat of native curcumin Increased oral bioavailability of CURmay be linked with improved water solubility higher releaserate in the intestinal juice enhanced absorption by improvedpermeability inhibition of P-glycoprotein- (P-gp-) mediatedefflux and increased residence time in the intestinal cavity[194] An important study has discussed in detail regardingthe most recent development in bioavailability absorptionand metabolism of curcumin in detail [195]

7 Conclusions

Cancer is a deadly disease for both men and women andalso a major health problem worldwide The present mode oftreatment based on chemotherapy and radiotherapy is veryexpensive and also exhibits serious side effects in humanbeings Keeping in view the significance of herbs this reviewis written to show the role of curcumin in the prevention ofvarious types of cancer through the activation or inactivationof various genetic pathways These reported features com-binedwith the absence of side effects and being inexpensive aswell as easy to access turmeric and its constituent curcuminmay be proved very effective therapeutics in themanagementof cancers

Conflict of Interests

The authors have no conflict of interests to disclose

References

[1] A Rahmani M Alzohairy A Y Babiker M A Rizvi and G HElkarimahmad ldquoClinicopathological significance of PTEN andbcl2 expressions in oral squamous cell carcinomardquo InternationalJournal of Clinical and Experimental Pathology vol 5 no 9 pp965ndash971 2012

[2] A Rahmani M Alzohairy H Khadri A K Mandal andM ARizvi ldquoExpressional evaluation of vascular endothelial growthfactor (VEGF) protein in urinary bladder carcinoma patientsexposed to cigarette smokerdquo International Journal of Clinicaland Experimental Pathology vol 5 no 3 pp 195ndash202 2012


[3] J Teng Z-Y Wang D F Jarrard and D E Bjorling ldquoRolesof estrogen receptor 120572 and 120573 in modulating urothelial cellproliferationrdquo Endocrine-Related Cancer vol 15 no 1 pp 351ndash364 2008

[4] Dar-ul-Iman Healing ldquoFood of the Prophet (Sallallaho AlayhiWasallam)rdquo 2000 httpchishtiorgfoods of the prophethtm

[5] M I Al-Bukhari Sahi Al-Bukhari The Collection of AuthenticSayings of Prophet Mohammad (peace be upon him) Division 71on Medicine Hilal Yayinlari Ankara Turkey 2nd edition 1976

[6] A H Rahmani S M Aly H Ali A Y Babiker S Srikarand A A Khan ldquoTherapeutic effects of date fruits (Phoenixdactylifera) in the prevention of diseases viamodulation of anti-inflammatory antioxidant and anti-tumour activityrdquo Interna-tional Journal of Clinical and Experimental Medicine vol 7 pp483ndash491 2014

[7] A H Rahmani A S Albutti and S M Aly ldquoTherapeutics roleof olive fruitsoil in the prevention of diseases via modulationof anti-oxidant anti-tumour and genetic activityrdquo InternationalJournal of Clinical and Experimental Medicine vol 7 pp 799ndash808 2014

[8] A H Rahmani M A Alzohairy M A Khan and S M AlyldquoTherapeutic implications of black seed and its constituentthymoquinone in the prevention of cancer through inactivationand activation of molecular pathwaysrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2014 Article ID 72465813 pages 2014

[9] I Chattopadhyay K Biswas U Bandyopadhyay and RK Banerjee ldquoTurmeric and curcuminBiological actions andmedicinal applicationsrdquo Current Science vol 87 pp 44ndash502004

[10] J Milobedeska V Kostanecki and V Lampe ldquoStructure ofcurcuminrdquo Berichte der Deutschen Chemischen Gesellschaft vol43 pp 2163ndash2170 1910

[11] V Lampe and JMilobedeska ldquoStudien uber curcuminrdquoBerichteder Deutschen Chemischen Gesellschaft vol 46 pp 2235ndash22401913

[12] M Sharma R Manoharlal N Puri and R Prasad ldquoAntifungalcurcumin induces reactive oxygen species and triggers an earlyapoptosis but prevents hyphae development by targeting theglobal repressor TUP1 in Candida albicansrdquo Bioscience Reportsvol 30 no 6 pp 391ndash404 2010

[13] O A K Khalil O M M de Faria Oliveira J C R Vellosa et alldquoCurcumin antifungal and antioxidant activities are increasedin the presence of ascorbic acidrdquo Food Chemistry vol 133 no 3pp 1001ndash1005 2012

[14] S Prasad S C Gupta A K Tyagi and B B AggarwalldquoCurcumin a component of golden spice from bedside tobench and backrdquo Biotechnology Advances 2014

[15] M Kanai ldquoTherapeutic applications of curcumin for patientswith pancreatic cancerrdquoWorld Journal of Gastroenterology vol20 pp 9384ndash9391 2014

[16] A Rahmani M Alzohairy A K Mandal and M A RizvildquoExpressional evaluation of androgen receptor in transitionalcell carcinoma of urinary bladder patientsrdquo British Journal ofMedicine and Medical Research vol 1 pp 233ndash238 2011

[17] A Y Babiker A H Rahmani M S Abdalaziz et al ldquoExpres-sional analysis of p16 and cytokeratin19 protein in the genesis oforal squamous cell carcinoma patientsrdquo International Journal ofClinical and Experimental Medicine vol 7 pp 1524ndash1530 2014

[18] S-S Han S-T Chung D A Robertson D Ranjan and SBondada ldquoCurcumin causes the growth arrest and apoptosis of

B cell lymphoma by downregulation of egr-1 C-myc Bcl-X(l)NF-120581B and p53rdquoClinical Immunology vol 93 no 2 pp 152ndash1611999

[19] M-J Park E-H Kim I-C Park et al ldquoCurcumin inhibitscell cycle progression of immortalized human umbilical veinendothelial (ECV304) cells by up-regulating cyclin-dependentkinase inhibitor p21WAF1CIP1 p27KIP1 and p53rdquo Interna-tional Journal of Oncology vol 21 no 2 pp 379ndash383 2002

[20] G Sa and T Das ldquoAnti cancer effects of curcumin cycle of lifeand deathrdquo Cell Division vol 3 article 14 2008

[21] S Shankar and R K Srivastava ldquoInvolvement of Bcl-2 familymembers phosphatidylinositol 31015840-kinaseAKT and mitochon-drial p53 in curcumin (diferulolylmethane)- induced apoptosisin prostate cancerrdquo International Journal of Oncology vol 30no 4 pp 905ndash918 2007

[22] S Ali A Ahmad A Aboukameel et al ldquoIncreased Ras GTPaseactivity is regulated by miRNAs that can be attenuated by CDFtreatment in pancreatic cancer cellsrdquoCancer Letters vol 319 no2 pp 173ndash181 2012

[23] S Ali A Ahmad S Banerjee et al ldquoGemcitabine sensitivitycan be induced in pancreatic cancer cells through modulationof miR-200 and miR-21 expression by curcumin or its analogueCDFrdquo Cancer Research vol 70 no 9 pp 3606ndash3617 2010

[24] B Bao S Ali S Banerjee et al ldquoCurcumin analogue CDFinhibits pancreatic tumor growth by switching on suppres-sor microRNAs and attenuating EZH2 expressionrdquo CancerResearch vol 72 no 1 pp 335ndash345 2012

[25] B Bao S Ali D Kong et al ldquoAnti-tumor activity of a novelcompound-CDF is mediated by regulating miR-21 miR-200and pten in pancreatic cancerrdquo PLoS ONE vol 6 no 3 ArticleID e17850 2011

[26] R A Weinberg ldquoThe retinoblastoma protein and cell cyclecontrolrdquo Cell vol 81 pp 323ndash330 1995

[27] C Broceno SWilkie and SMittnacht ldquoRB activation defect intumor cell linesrdquoProceedings of theNational Academy of Sciencesof the United States of America vol 99 no 22 pp 14200ndash142052002

[28] J S Foster D C Henley A Bukovsky P Seth and JWimalasena ldquoMultifaceted regulation of cell cycle progressionby estrogen regulation of Cdk inhibitors and Cdc25A inde-pendent of cyclin D1-Cdk4 functionrdquo Molecular and CellularBiology vol 21 no 3 pp 794ndash810 2001

[29] R L Sutherland and E A Musgrove ldquoCyclins and breastcancerrdquo Journal of Mammary Gland Biology and Neoplasia vol9 no 1 pp 95ndash104 2004

[30] R K Srivastava Q Chen I Siddiqui K Sarva and S ShankarldquoLinkage of curcumin-induced cell cycle arrest and apoptosis bycyclin-dependent kinase inhibitor p21WAF1CIP1rdquo Cell Cyclevol 6 no 23 pp 2953ndash2961 2007

[31] AMukhopadhyay S Banerjee L J Stafford C XiaM Liu andB B Aggarwal ldquoCurcumin-induced suppression of cell prolif-eration correlates with down-regulation of cyclin D1 expressionand CDK4-mediated retinoblastoma protein phosphorylationrdquoOncogene vol 21 no 57 pp 8852ndash8861 2002

[32] K Hollowood and J C Macartney ldquoReduced apoptotic celldeath in follicular lymphomardquoThe Journal of Pathology vol 163no 4 pp 337ndash342 1991

[33] L Sachs and J Lotem ldquoControl of programmed cell death innormal and leukemic cells new implications for therapyrdquoBloodvol 82 no 1 pp 15ndash21 1993


[34] E Tourkina P Gooz J C Oates A Ludwicka-Bradley RM Silver and S Hoffman ldquoCurcumin-induced apoptosis inscleroderma lung fibroblasts Role of protein kinase C120576rdquo TheAmerican Journal of Respiratory Cell andMolecular Biology vol31 no 1 pp 28ndash35 2004

[35] J Yu X Zhou XHeMDai andQ Zhang ldquoCurcumin inducesapoptosis involving BaxBcl-2 in humanhepatoma SMMC-7721cellsrdquo Asian Pacific Journal of Cancer Prevention vol 12 no 8pp 1925ndash1929 2011

[36] C Ramachandran and W You ldquoDifferential sensitivity ofhuman mammary epithelial and breast carcinoma cell lines tocurcuminrdquo Breast Cancer Research and Treatment vol 54 no3 pp 269ndash278 1999

[37] ZM ShaoM IDawson X S Li et al ldquop53 independentG0G1arrest and apoptosis induced by a novel retinoid in humanbreast cancer cellsrdquo Oncogene vol 11 pp 493ndash504 1995

[38] T Choudhuri S Pal M L Agwarwal T Das and G SaldquoCurcumin induces apoptosis in human breast cancer cellsthrough p53-dependent Bax inductionrdquo FEBS Letters vol 512no 1ndash3 pp 334ndash340 2002

[39] J H Bae J-W Park and T K Kwon ldquoRuthenium red inhibitorof mitochondrial Ca2+ uniporter inhibits curcumin-inducedapoptosis via the prevention of intracellular Ca2+ depletion andcytochrome c releaserdquo Biochemical and Biophysical ResearchCommunications vol 303 no 4 pp 1073ndash1079 2003

[40] S Mukherjee U Ghosh N P Bhattacharyya R K Bhat-tacharya S Dey and M Roy ldquoCurcumin-induced apoptosisin human leukemia cell HL-60 is associated with inhibition oftelomerase activityrdquo Molecular and Cellular Biochemistry vol297 no 1-2 pp 31ndash39 2007

[41] A R Hussain M Al-Rasheed P S Manogaran et al ldquoCur-cumin induces apoptosis via inhibition of PI31015840-kinaseAKTpathway in acute T cell leukemiasrdquo Apoptosis vol 11 no 2 pp245ndash254 2006

[42] M Tomita H Kawakami J N Uchihara et al ldquoCurcumin(diferuloylmethane) inhibits constitutive active NF-kappaBleading to suppression of cell growth of human T-cell leukemiavirus type I-infected T-cell lines and primary adult T-cellleukemia cellsrdquo International Journal of Cancer vol 118 pp 765ndash772 2006

[43] H-W Chen and H-C Huang ldquoEffect of curcumin on cell cycleprogression and apoptosis in vascular smooth muscle cellsrdquoBritish Journal of Pharmacology vol 124 no 6 pp 1029ndash10401998

[44] B Agarwal P Swaroop P Protiva S V Raj H Shirin and P RHolt ldquoCox-2 is needed but not sufficient for apoptosis inducedby Cox-2 selective inhibitors in colon cancer cellsrdquo Apoptosisvol 8 no 6 pp 649ndash654 2003

[45] M A Azuine and S V Bhide ldquoChemopreventive effect ofturmeric against stomach and skin tumors induced by chemicalcarcinogens in Swiss micerdquo Nutrition and Cancer vol 17 no 1pp 77ndash83 1992

[46] C Ramachandran H B Fonseca P Jhabvala E A Escalon andS J Melnick ldquoCurcumin inhibits telomerase activity throughhuman telomerase reverse transcritpase inMCF-7 breast cancercell linerdquo Cancer Letters vol 184 no 1 pp 1ndash6 2002

[47] T Dorai Y-C Cao B Dorai R Buttyan and A E KatzldquoTherapeutic potential of curcumin in human prostate cancerIII Curcumin inhibits proliferation induces apoptosis andinhibits angiogenesis of LNCaP prostate cancer cells in vivordquoProstate vol 47 no 4 pp 293ndash303 2001

[48] L Moragoda R Jaszewski and A P N Majumdar ldquoCurcumininduced modulation of cell cycle and apoptosis in gastric andcolon cancer cellsrdquo Anticancer Research vol 21 no 2 pp 873ndash878 2001

[49] R Hanif L Qiao S J Shiff and B Rigas ldquoCurcumin a naturalplant phenolic food additive inhibits cell proliferation andinduces cell cycle changes in colon adenocarcinoma cell linesby a prostaglandin-independent pathwayrdquo Journal of Laboratoryand Clinical Medicine vol 130 no 6 pp 576ndash584 1997

[50] M J van Erk E Teuling Y C M Staal et al ldquoTime- and dose-dependent effects of curcumin on gene expression in humancolon cancer cellsrdquo Journal of Carcinogenesis vol 3 article 82004

[51] P Sindhwani J A Hampton M Baig R Keck and S SelmanldquoCurcumin a food spice with cytotoxic activity against urinarybladder cancerrdquo Journal of the American College of Surgeons vol191 pp 94ndash95 2000

[52] A M Kamat G Sethi and B B Aggarwal ldquoCurcumin poten-tiates the apoptotic effects of chemotherapeutic agents andcytokines through down-regulation of nuclear factor-120581B andnuclear factor-120581B-regulated gene products in IFN-120572-sensitiveand IFN-120572-resistant human bladder cancer cellsrdquo MolecularCancer Therapeutics vol 6 no 3 pp 1022ndash1030 2007

[53] P Sindhwani J A Hampton M M Baig R Keck and S HSelman ldquoCurcumin prevents intravesical tumor implantation oftheMBT-2 tumor cell line in C3Hmicerdquo Journal of Urology vol166 no 4 pp 1498ndash1501 2001

[54] C Park G Y Kim G D Kim B T Choi Y-M Parkand Y H Choi ldquoInduction of G2M arrest and inhibitionof cyclooxygenase-2 activity by curcumin in human bladdercancer T24 cellsrdquoOncology Reports vol 15 no 5 pp 1225ndash12312006

[55] S D Catz and J L Johnson ldquoTranscriptional regulation of bcl-2 by nuclear factor 120581B and its significance in prostate cancerrdquoOncogene vol 20 no 50 pp 7342ndash7351 2001

[56] J L Herrmann F Briones Jr S Brisbay C J Logothetis andT J McDonnell ldquoProstate carcinoma cell death resulting frominhibition of proteasome activity is independent of functionalBcl-2 and p53rdquo Oncogene vol 17 no 22 pp 2889ndash2899 1998

[57] S Liekens E De Clercq and J Neyts ldquoAngiogenesis regulatorsand clinical applicationsrdquo Biochemical Pharmacology vol 61no 3 pp 253ndash270 2001

[58] J Folkman ldquoTumor angiogenesis theraperutic implicationsrdquoThe New England Journal of Medicine vol 285 pp 1182ndash11861971

[59] S Shishodia M M Chaturvedi and B B Aggarwal ldquoRole ofcurcumin in cancer therapyrdquo Current Problems in Cancer vol31 no 4 pp 243ndash305 2007

[60] H-P Gerber V Dixit and N Ferrara ldquoVascular endothelialgrowth factor induces expression of the antiapoptotic proteinsBcl-2 and A1 in vascular endothelial cellsrdquo The Journal ofBiological Chemistry vol 273 no 21 pp 13313ndash13316 1998

[61] A B Kunnumakkara S Guha S Krishnan P Diagaradjane JGelovani andB B Aggarwal ldquoCurcumin potentiates antitumoractivity of gemcitabine in an orthotopic model of pancreaticcancer through suppression of proliferation angiogenesis andinhibition of nuclear factor-120581B-regulated gene productsrdquo Can-cer Research vol 67 no 8 pp 3853ndash3861 2007

[62] A K Singh G S Sidhu T Deepa and R K MaheshwarildquoCurcumin inhibits the proliferation and cell cycle progressionof human umbilical vein endothelial cellrdquo Cancer Letters vol107 no 1 pp 109ndash115 1996


[63] R Mohan J Sivak P Ashton et al ldquoCurcuminoids inhibit theangiogenic response stimulated by fibroblast growth factor-2including expression of matrix metalloproteinase gelatinase BrdquoThe Journal of Biological Chemistry vol 275 no 14 pp 10405ndash10412 2000

[64] C C Chua R C Hamdy and B H L Chua ldquoMechanism oftransforming growth factor-1205731-induced expression of vascularendothelial growth factor in murine osteoblastic MC3T3-E1cellsrdquo Biochimica et Biophysica ActamdashMolecular Cell Researchvol 1497 no 1 pp 69ndash76 2000

[65] G Chadalapaka I Jutooru S Chintharlapalli et al ldquoCurcumindecreases specificity protein expression in bladder cancer cellsrdquoCancer Research vol 68 no 13 pp 5345ndash5354 2008

[66] S Singh and B B Aggarwal ldquoActivation of transcriptionfactorNF120581B is suppressed by curcumin (diferuloylmethane)rdquo Journalof Biological Chemistry vol 270 pp 24995ndash25000 1995

[67] Z J Sun G Chen W Zhang et al ldquoCurcumin duallyinhibits both mammalian target of rapamycin and nuclearfactor-120581B pathways througha crossed phosphatidylinositol 3-kinaseAktI120581B kinase complex signaling axis in adenoid cysticcarcinomardquoMolecular Pharmacology vol 79 pp 106ndash118 2011

[68] R Thapliyal and G B Maru ldquoInhibition of cytochrome P450isozymes by curcumins in vitro and in vivordquo Food and ChemicalToxicology vol 39 no 6 pp 541ndash547 2001

[69] P F Firozi V S Aboobaker and R K Bhattacharya ldquoActionof curcumin on the cytochrome P450-system catalyzing theactivation of aflatoxin B1rdquo Chemico-Biological Interactions vol100 no 1 pp 41ndash51 1996

[70] H P Ciolino P J Daschner T T YWang andG C Yeh ldquoEffectof curcumin on the aryl hydrocarbon receptor and cytochromeP450 1A1 inMCF-7 human breast carcinoma cellsrdquo BiochemicalPharmacology vol 56 no 2 pp 197ndash206 1998

[71] S V Singh X Hu S K Srivastava et al ldquoMechanism ofinhibition of benzo[a]pyrene-induced forestomach cancer inmice by dietary curcuminrdquo Carcinogenesis vol 19 no 8 pp1357ndash1360 1998

[72] RThapliyal S SDeshpande andG BMaru ldquoMechanism(s) ofturmeric-mediated protective effects against benzo(a)pyrene-derived DNA adductsrdquo Cancer Letters vol 175 no 1 pp 79ndash882002

[73] R A Sharma C R Ireson R D Verschoyle et al ldquoEffectsof dietary curcumin on glutathione S-transferase andmalondialdehyde-DNA adducts in rat liver and colon mucosarelationship with drug levelsrdquo Clinical Cancer Research vol 7no 5 pp 1452ndash1458 2001

[74] T Nishinaka Y Ichijo M Ito et al ldquoCurcumin activates humanglutathione S-transferase P1 expression through antioxidantresponse elementrdquo Toxicology Letters vol 170 no 3 pp 238ndash247 2007

[75] J T Piper S S Singhal M S Salameh R T Torman YC Awasthi and S Awasthi ldquoMechanisms of anticarcinogenicproperties of curcumin the effect of curcumin on glutathionelinked detoxification enzymes in rat liverrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 4 pp 445ndash456 1998

[76] S P Valentine M J Le Nedelec A R Menzies M J ScandlynM G Goodin and R J Rosengren ldquoCurcuminmodulates drugmetabolizing enzymes in the female Swiss Webster mouserdquo LifeSciences vol 78 no 20 pp 2391ndash2398 2006

[77] R Garg S Gupta and G B Maru ldquoDietary curcuminmodulates transcriptional regulators of phase I and phase II

enzymes in benzo[a]pyrene-treated mice mechanism of itsanti-initiating actionrdquo Carcinogenesis vol 29 no 5 pp 1022ndash1032 2008

[78] J Park and C N Conteas ldquoAnti-carcinogenic properties of cur-cumin on colorectal cancerrdquo World Journal of GastrointestinalOncology vol 2 pp 169ndash176 2010

[79] W Gao C E Bohl and J T Dalton ldquoChemistry and structuralbiology of androgen receptorrdquo Chemical Reviews vol 105 no 9pp 3352ndash3370 2005

[80] C A Heinlein and C Chang ldquoAndrogen receptor in prostatecancerrdquo Endocrine Reviews vol 25 no 2 pp 276ndash308 2004

[81] A H Rahmani M Alzohairy A Y Y Babiker A A KhanS M Aly and M A Rizvi ldquoImplication of androgen receptorin urinary bladder cancer a critical mini reviewrdquo InternationalJournal of Molecular Epidemiology and Genetics vol 4 pp 150ndash155 2013

[82] B J Feldman and D Feldman ldquoThe development of androgen-independent prostate cancerrdquoNature Reviews Cancer vol 1 no1 pp 34ndash45 2001

[83] H Guo Y-M Xu Z-Q Ye J-H Yu and X-Y Hu ldquoCurcumininduces cell cycle arrest and apoptosis of prostate cancer cells byregulating the expression of I120581B120572 c-Jun and androgen receptorrdquoPharmazie vol 68 no 6 pp 431ndash434 2013

[84] K Nakamura Y Yasunaga T Segawa et al ldquoCurcumin down-regulates AR gene expression and activation in prostate cancercell linesrdquo International Journal of Oncology vol 21 no 4 pp825ndash830 2002

[85] T Dorai N Gehani and A Katz ldquoTherapeutic potential of cur-cumin in human prostate cancermdashI Curcumin induces apop-tosis in both androgen-dependent and androgen-independentprostate cancer cellsrdquo Prostate Cancer and Prostatic Diseasesvol 3 no 2 pp 84ndash93 2000

[86] K-H Tsui T-H Feng C-M Lin P-L Chang andH-H JuangldquoCurcumin blocks the activation of androgen and interlukin-6 on prostate-specific antigen expression in human prostaticcarcinoma cellsrdquo Journal of Andrology vol 29 no 6 pp 661ndash668 2008

[87] B Li W Xu C Luo D Gozal and R Liu ldquoVEGF-inducedactivation of the PI3-KAkt pathway reduces mutant SOD1-mediated motor neuron cell deathrdquo Molecular Brain Researchvol 111 no 1-2 pp 155ndash164 2003

[88] E R Isenovic Y Meng A Divald N Milivojevic and J RSowers ldquoRole of phosphatidylinositol 3-kinaseAkt pathwayin angiotensin II and insulin-like growth factor-1 modulationof nitric oxide synthase in vascular smooth muscle cellsrdquoEndocrine vol 19 no 3 pp 287ndash291 2002

[89] A J Philp I G Campbell C Leet et al ldquoThe phosphatidylinos-itol 31015840-kinase p85120572 gene is an oncogene in human ovarian andcolon tumorsrdquo Cancer Research vol 61 no 20 pp 7426ndash74292001

[90] H K Roy B F Olusola D L Clemens et al ldquoAKT proto-oncogene overexpression is an early event during sporadiccolon carcinogenesisrdquoCarcinogenesis vol 23 no 1 pp 201ndash2052002

[91] D D Sarbassov D A Guertin S M Ali and D M SabatinildquoPhosphorylation and regulation of AktPKB by the rictor-mTOR complexrdquo Science vol 307 no 5712 pp 1098ndash1101 2005

[92] C Belham S Wu and J Avruch ldquoIntracellular signallingPDK1mdasha kinase atthe hub of thingsrdquo Current Biology vol 9 pp93ndash96 1999


[93] S I Yu G Shen O K Tin J-H Kim and A-N T KongldquoCurcumin inhibits Aktmammalian target of rapamycin sig-naling through protein phosphatase-dependent mechanismrdquoMolecular Cancer Therapeutics vol 7 no 9 pp 2609ndash26202008

[94] M H Cardone N Roy H R Stennicke et al ldquoRegulation ofcell death protease caspase-9 by phosphorylationrdquo Science vol282 no 5392 pp 1318ndash1321 1998

[95] M Pap and G M Cooper ldquoRole of glycogen synthase kinase-3in the phosphatidylinositol 3- kinaseAkt cell survival pathwayrdquoThe Journal of Biological Chemistry vol 273 no 32 pp 19929ndash19932 1998

[96] C Rommel B A Clarke S Zimmermann et al ldquoDifferentia-tion stage-specific inhibition of the Raf-MEK-ERK pathway byAktrdquo Science vol 286 no 5445 pp 1738ndash1741 1999

[97] S Pugazhenthit A Nesterova C Sable et al ldquoAktproteinkinase B up-regulates Bcl-2 expression through cAMP-responseelement-binding proteinrdquo The Journal of Biological Chemistryvol 275 no 15 pp 10761ndash10766 2000

[98] T Maehama and J E Dixon ldquoThe tumor suppressorPTENMMAC1 dephosphorylates the lipid second messengerphosphatidylinositol 345-trisphosphaterdquo The Journal ofBiological Chemistry vol 273 no 22 pp 13375ndash13378 1998

[99] S Yu G Shen T O Khor J-H Kim and A-N T KongldquoCurcumin inhibits Aktmammalian target of rapamycin sig-naling through protein phosphatase-dependent mechanismrdquoMolecular Cancer Therapeutics vol 7 no 9 pp 2609ndash26202008

[100] R A Gupta and R N DuBois ldquoColorectal cancer and thecyclooxygenase pathwayrdquo Nature Reviews Cancer vol 1 pp 11ndash21 2001

[101] A Koki N K Khan B M Woerner et al ldquoCyclooxygenase-2 in human pathological diseaserdquo Advances in ExperimentalMedicine and Biology vol 507 pp 177ndash184 2002

[102] A G Asting H CarenM Andersson C Lonnroth K Lagerst-edt and K Lundholm ldquoCOX-2 gene expression in colon cancertissue related to regulating factors and promoter methylationstatusrdquo BMC Cancer vol 11 article 238 2011

[103] M-T Huang W Ma Y-P Lu et al ldquoEffects of curcumindemethoxycurcumin bisdemethoxycurcumin andtetrahydrocurcumin on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotionrdquo Carcinogenesis vol 16 no10 pp 2493ndash2497 1995

[104] C V Rao A Rivenson B Simi and B S Reddy ldquoChemopre-vention of colon carcinogenesis by dietary curcumin a naturallyoccurring plant phenolic compoundrdquo Cancer Research vol 55no 2 pp 259ndash266 1995

[105] M-T Huang T Lysz T Ferraro T F Abidi J D Laskinand A H Conney ldquoInhibitory effects of curcumin on invitro lipoxygenase and cyclooxygenase activities in mouseepidermisrdquo Cancer Research vol 51 no 3 pp 813ndash819 1991

[106] A Goel C R Boland andD P Chauhan ldquoSpecific inhibition ofcyclooxygenase-2 (COX-2) expression by dietary curcumin inHT-29 human colon cancer cellsrdquo Cancer Letters vol 172 no 2pp 111ndash118 2001

[107] B B Aggarwal A Kumar and A C Bharti ldquoAnticancer poten-tial of curcumin preclinical and clinical studiesrdquo AnticancerResearch vol 23 no 1A pp 363ndash398 2003

[108] S-S Han Y-S Keum H-J Seo and Y-J Surh ldquoCurcuminsuppresses activation of NF-120581B and AP-1 induced by phorbolester in cultured human promyelocytic leukemia cellsrdquo Journal

of Biochemistry and Molecular Biology vol 35 no 3 pp 337ndash342 2002

[109] C Jobin C A Bradham M P Russo et al ldquoCurcuminblocks cytokine-mediated NF-120581B activation and proinflamma-tory gene expression by inhibiting inhibitory factor I-120581B kinaseactivityrdquo The Journal of Immunology vol 163 no 6 pp 3474ndash3483 1999

[110] S Singh and B B Aggarwal ldquoActivation of transcription factorNF-120581B is suppressed by curcumin (diferuloylmethane)rdquo TheJournal of Biological Chemistry vol 270 pp 24995ndash25000 2005

[111] S M Plummer K A Holloway M M Manson et al ldquoInhi-bition of cyclo-oxygenase 2 expression in colon cells by thechemopreventive agent curcumin involves inhibition of NF-120581Bactivation via the NIKIKK signalling complexrdquo Oncogene vol18 no 44 pp 6013ndash6020 1999

[112] M S Lan Li B B Aggarwal S Shishodia J Abbruzzese and RKurzrock ldquoNuclear factor-120581B and I120581B are constitutively activein human pancreatic cells and their down-regulation by cur-cumin (Diferuloylmethane) is associated with the suppressionof proliferation and the induction of apoptosisrdquoCancer vol 101no 10 pp 2351ndash2362 2004

[113] A B Kunnumakkara P Diagaradjane P Anand et al ldquoCur-cumin sensitizes human colorectal cancer to capecitabine bymodulation of cyclin D1 COX-2 MMP-9 VEGF and CXCR4expression in an orthotopic mouse modelrdquo International Jour-nal of Cancer vol 125 no 9 pp 2187ndash2197 2009

[114] S T Tharakan T Inamoto B Sung B B Aggarwal andA M Kamat ldquoCurcumin potentiates the antitumor effectsof gemcitabine in an orthotopic model of human bladdercancer through suppression of proliferative and angiogenicbiomarkersrdquo Biochemical Pharmacology vol 79 no 2 pp 218ndash228 2010

[115] R Wilken M S Veena M B Wang and E S SrivatsanldquoCurcumin a review of anti-cancer properties and therapeuticactivity in head and neck squamous cell carcinomardquoMolecularCancer vol 10 article 12 2011

[116] A Kumar S Dhawan N J Hardegen and B B AggarwalldquoCurcumin (diferuloylmethane) inhibition of tumor necrosisfactor (TNF)- mediated adhesion of monocytes to endothelialcells by suppression of cell surface expression of adhesionmolecules and of nuclear factor-120581B activationrdquo BiochemicalPharmacology vol 55 no 6 pp 775ndash783 1998

[117] M-H Pan S-Y Lin-Shiau and J-K Lin ldquoComparative studieson the suppression of nitric oxide synthase by curcumin andits hydrogenated metabolites through down-regulation of I120581Bkinase and NF120581B activation in macrophagesrdquo BiochemicalPharmacology vol 60 no 11 pp 1665ndash1676 2000

[118] F Zhang N K Altorki J R Mestre K Subbaramaiahand A J Dannenberg ldquoCurcumin inhibits cyclooxygenase-2transcription in bile acid- and phorbol ester-treated humangastrointestinal epithelial cellsrdquo Carcinogenesis vol 20 no 3pp 445ndash451 1999

[119] M K Jang D H Sohn and J-H Ryu ldquoA curcuminoid andsesquiterpenes as inhibitors of macrophage TNF-120572 release fromCurcuma zedoariardquo Planta Medica vol 67 no 6 pp 550ndash5522001

[120] D J Slamon W Godolphin L A Jones et al ldquoStudies ofthe HER-2neu proto-oncogene in human breast and ovariancancerrdquo Science vol 244 no 4905 pp 707ndash712 1989

[121] K Sato M Moriyama S Mori et al ldquoAn immunohistologicevaluation of c-erbB-2 gene product in patients with urinarybladder carcinomardquo Cancer vol 70 pp 2493ndash2499 1992


[122] J Avruch D Zhou and N Bardeesy ldquoYAP oncogene overex-pression supercharges colon cancer proliferationrdquo Cell Cyclevol 11 no 6 pp 1090ndash1096 2012

[123] M H Elamin Z Shinwari S-F Hendrayani et al ldquoCurcumininhibits the sonic hedgehog signaling pathway and triggersapoptosis in medulloblastoma cellsrdquo Molecular Carcinogenesisvol 49 no 3 pp 302ndash314 2010

[124] P Limtrakul S Anuchapreeda S Lipigorngoson and F WDunn ldquoInhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcuminrdquo BMCCancer vol 1 article 1 2001

[125] D-W Seol Q Chen and R Zarnegar ldquoTranscriptional activa-tion of the hepatocyte growth factor receptor (c-met) gene byits ligand (hepatocyte growth factor) is mediated through AP-1rdquo Oncogene vol 19 no 9 pp 1132ndash1137 2000

[126] M L Y Bangaru S Chen JWoodliff and SKansra ldquoCurcumin(diferuloylmethane) induces apoptosis and blocks migration ofhumanmedulloblastoma cellsrdquoAnticancer Research vol 30 no2 pp 499ndash504 2010

[127] A Chen J Xu and A C Johnson ldquoCurcumin inhibits humancolon cancer cell growth by suppressing gene expression ofepidermal growth factor receptor through reducing the activityof the transcription factor Egr-1rdquo Oncogene vol 25 no 2 pp278ndash287 2006

[128] L Korutla J Y Cheung J Mendelsohn and R Kumar ldquoInhi-bition of ligand-induced activation of epidermal growth factorreceptor tyrosine phosphorylation by curcuminrdquo Carcinogene-sis vol 16 no 8 pp 1741ndash1745 1995

[129] T Dorai N Gehani and A Katz ldquoTherapeutic potential ofcurcumin in human prostate cancer II Curcumin inhibitstyrosine kinase activity of epidermal growth factor receptor anddepletes the proteinrdquo Molecular Urology vol 4 no 1 pp 1ndash62000

[130] R-L Hong W H Spohn and M-C Hung ldquoCurcumininhibits tyrosine kinase activity of p185(neu) and also depletesp185(neu1)rdquoClinical Cancer Research vol 5 no 7 pp 1884ndash18911999

[131] L Camacho-Barquero I Villegas J M Sanchez-Calvo et alldquoCurcumin a Curcuma longa constituent acts on MAPK p38pathway modulating COX-2 and iNOS expression in chronicexperimental colitisrdquo International Immunopharmacology vol7 no 3 pp 333ndash342 2007

[132] Y Wu Y Chen J Xu and L Lu ldquoAnticancer activities ofcurcumin on human Burkittrsquos lymphomardquo Zhonghua Zhong LiuZa Zhi vol 24 no 4 pp 348ndash352 2002

[133] N Diaz S Minton C Cox et al ldquoActivation of Stat3 in primarytumors from high-risk breast cancer patients is associated withelevated levels of activated Src and survivin expressionrdquoClinicalCancer Research vol 12 no 1 pp 20ndash28 2006

[134] D Germain and D A Frank ldquoTargeting the cytoplasmicand nuclear functions of signal transducers and activators oftranscription 3 for cancer therapyrdquoClinical Cancer Research vol13 no 19 pp 5665ndash5669 2007

[135] L Lin S Deangelis E Foust et al ldquoA novel small moleculeinhibits STAT3 phosphorylation and DNA binding activity andexhibits potent growth suppressive activity in human cancercellsrdquoMolecular Cancer vol 9 article 217 2010

[136] W Glienke L Maute J Wicht and L Bergmann ldquoCurcumininhibits constitutive STAT3 phosphorylation in human pancre-atic cancer cell lines and downregulation of survivinBIRC5gene expressionrdquo Cancer Investigation vol 28 no 2 pp 166ndash171 2010

[137] M G Alexandrow L J Song S Altiok J Gray E B Haura andN B Kumar ldquoCurcumin a novel Stat3 pathway inhibitor forchemoprevention of lung cancerrdquo European Journal of CancerPrevention vol 21 no 5 pp 407ndash412 2012

[138] A Jacob RWuM Zhou and PWang ldquoMechanismof the anti-inflammatory effect of curcumin PPAR-120574 activationrdquo PPARResearch vol 2007 Article ID 89369 5 pages 2007

[139] J Xu Y Fu andAChen ldquoActivation of peroxisomeproliferator-activated receptor-120574 contributes to the inhibitory effects ofcurcumin on rat hepatic stellate cell growthrdquo The AmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 285 no 1 pp G20ndashG30 2003

[140] Y Zhou S Zheng J Lin Q-J Zhang and A Chen ldquoTheinterruption of the PDGF and EGF signaling pathways bycurcumin stimulates gene expression of PPAR120574 in rat activatedhepatic stellate cell in vitrordquo Laboratory Investigation vol 87 no5 pp 488ndash498 2007

[141] A Chen and J Xu ldquoActivation of PPAR120574 by curcumin inhibitsMoser cell growth andmediates suppression of gene expressionof cyclin D1 and EGFRrdquo American Journal of PhysiologyGastrointestinal and Liver Physiology vol 288 no 3 pp G447ndashG456 2005

[142] M D Sternlicht and Z Werb ldquoHow matrix metalloproteinasesregulate cell behaviorrdquoAnnual Review ofCell andDevelopmentalBiology vol 17 pp 463ndash516 2001

[143] M Egeblad and Z Werb ldquoNew functions for the matrix met-alloproteinases in cancer progressionrdquo Nature Reviews Cancervol 2 no 3 pp 161ndash174 2002

[144] C C Lynch and L M Matrisian ldquoMatrix metalloproteinases intumor-host cell communicationrdquo Differentiation vol 70 no 9-10 pp 561ndash573 2002

[145] B Fingleton ldquoMatrix metalloproteinases roles in cancer andmetastasisrdquo Frontiers in Bioscience vol 11 no 1 pp 479ndash4912006

[146] R Fridman M Toth D Pena and S Mobashery ldquoActivationof progelatinase B (MMP-9) by gelatinase A (MMP-2)rdquo CancerResearch vol 55 no 12 pp 2548ndash2555 1995

[147] S K Kim Y W Kim H J Youn and S H Jung ldquoCurcuminsuppresses MMP-9 expression via inhibition of PKCaMAPKsand NF-BAP-1 activationrdquo Cancer Research vol 72 2012

[148] M-S Woo S-H Jung S-Y Kim et al ldquoCurcumin suppressesphorbol ester-induced matrix metalloproteinase-9 expressionby inhibiting the PKC to MAPK signaling pathways in humanastroglioma cellsrdquo Biochemical and Biophysical Research Com-munications vol 335 no 4 pp 1017ndash1025 2005

[149] B B Aggarwal S Shishodia Y Takada et al ldquoCurcuminsuppresses the paclitaxel-induced nuclear factor-120581B pathway inbreast cancer cells and inhibits lung metastasis of human breastcancer in nude micerdquo Clinical Cancer Research vol 11 no 20pp 7490ndash7498 2005

[150] Z KHassan andMHDaghestani ldquoCurcumin effect onMMPsand TIMPs genes in a breast cancer cell linerdquo Asian PacificJournal of Cancer Prevention vol 13 no 7 pp 3259ndash3264 2012

[151] K W Lee J-H Kim H J Lee and Y-J SurhldquoCurcumin inhibits phorbol ester-induced up-regulationof cyclooxygenase-2 and matrix metalloproteinase-9 byblocking ERK12 phosphorylation and NF-120581B transcriptionalactivity in MCF10A human breast epithelial cellsrdquo Antioxidantsand Redox Signaling vol 7 no 11-12 pp 1612ndash1620 2005

[152] A-L Chen C-H Hsu J-K Lin et al ldquoPhase I clinical trial ofcurcumin a chemopreventive agent in patients with high-risk


or pre-malignant lesionsrdquo Anticancer Research vol 21 no 4Bpp 2895ndash2900 2001

[153] R A Sharma H R McLelland K A Hill et al ldquoPharmacody-namic and pharmacokinetic study of oral Curcuma extract inpatients with colorectal cancerrdquo Clinical Cancer Research vol 7no 7 pp 1894ndash1900 2001

[154] K Polasa T C Raghuram T P Krishna and K KrishnaswamyldquoEffect of turmeric on urinary mutagens in smokersrdquoMutagen-esis vol 7 no 2 pp 107ndash109 1992

[155] S G Kim M S Veena S K Basak et al ldquoCurcumin treatmentsuppresses IKK120573 kinase activity of salivary cells of patients withhead and neck cancer a pilot studyrdquo Clinical Cancer Researchvol 17 no 18 pp 5953ndash5961 2011

[156] M Kanai K Yoshimura M Asada et al ldquoA phase IIIstudy of gemcitabine-based chemotherapy plus curcumin forpatients with gemcitabine-resistant pancreatic cancerrdquo CancerChemotherapy and Pharmacology vol 68 no 1 pp 157ndash1642011

[157] G Garcea D P Berry D J L Jones et al ldquoConsumptionof the putative chemopreventive agent curcumin by cancerpatients assessment of curcumin levels in the colorectum andtheir pharmacodynamic consequencesrdquo Cancer EpidemiologyBiomarkers amp Prevention vol 14 no 1 pp 120ndash125 2005

[158] M Majeed V Badmaev U Shivakumar and R RajendranCurcuminoids Antioxidant Phytonutrients Nutriscience Pis-cataway NJ USA 1995

[159] K B Soni and R Kuttan ldquoEffect of oral curcumin adminis-tration on serum peroxides and cholesterol levels in humanvolunteersrdquo Indian Journal of Physiology and Pharmacology vol36 no 4 pp 273ndash275 1992

[160] N Dhillon B B Aggarwal R A Newman et al ldquoPhase IItrial of curcumin in patients with advanced pancreatic cancerrdquoClinical Cancer Research vol 14 no 14 pp 4491ndash4499 2008

[161] R Epelbaum M Schaffer B Vizel V Badmaev and G Bar-Sela ldquoCurcumin and gemcitabine in patients with advancedpancreatic cancerrdquoNutrition and Cancer vol 62 no 8 pp 1137ndash1141 2010

[162] S V Kandarkar S S Sawant A D Ingle S S Deshpandeand G B Maru ldquoSubchronic oral hepatotoxicity of turmericin micemdashhistopathological and ultrastructural studiesrdquo IndianJournal of Experimental Biology vol 36 no 7 pp 675ndash679 1998

[163] R A Sharma S A Euden S L Platton et al ldquoPhase I clinicaltrial of oral curcumin biomarkers of systemic activity andcompliancerdquo Clinical Cancer Research vol 10 no 20 pp 6847ndash6854 2004

[164] PAnandA BKunnumakkara RANewman andB BAggar-wal ldquoBioavailability of curcumin problems and promisesrdquoMolecular Pharmaceutics vol 4 no 6 pp 807ndash818 2007

[165] H Shibata H Yamakoshi A Sato et al ldquoNewly synthesizedcurcumin analog has improved potential to prevent colorectalcarcinogenesis in vivordquo Cancer Science vol 100 no 5 pp 956ndash960 2009

[166] L Cen B Hutzen S Ball et al ldquoNew structural analogues ofcurcumin exhibit potent growth suppressive activity in humancolorectal carcinoma cellsrdquo BMCCancer vol 9 article 99 2009

[167] J Bromberg M Wrzeszczynska G Devgan et al ldquoStat3 as anoncogenerdquo Cell vol 98 pp 295ndash303 1999

[168] T Gritsko A Williams J Turkson et al ldquoPersistent activationof Stat3 signaling induces survivin gene expression and confersresistance to apoptosis in human breast cancer cellsrdquo ClinicalCancer Research vol 12 no 1 pp 11ndash19 2006

[169] M M Yallapu M R Dobberpuhl D M Maher M Jaggiand S C Chauhan ldquoDesign of curcumin loaded cellulosenanoparticles for prostate cancerrdquo Current Drug Metabolismvol 13 no 1 pp 120ndash128 2012

[170] L Lin Y Liu H Li et al ldquoTargeting colon cancer stem cellsusing a new curcumin analogue GO-Y030rdquo British Journal ofCancer vol 105 no 2 pp 212ndash220 2011

[171] C Kudo H Yamakoshi A Sato et al ldquoNovel curcuminanalogs GO-Y030 and GO-Y078 are multitargeted agents withenhanced abilities for multiple myelomardquo Anticancer Researchvol 31 no 11 pp 3719ndash3726 2011

[172] B Hutzen L Friedman M Sobo et al ldquoCurcumin analogueGO-Y030 inhibits STAT3 activity and cell growth in breast andpancreatic carcinomasrdquo International Journal of Oncology vol35 no 4 pp 867ndash872 2009

[173] L Lin BHutzen S Ball et al ldquoNew curcumin analogues exhibitenhanced growth-suppressive activity and inhibit AKT and sig-nal transducer and activator of transcription 3 phosphorylationin breast and prostate cancer cellsrdquo Cancer Science vol 100 no9 pp 1719ndash1727 2009

[174] M Pisano G Pagnan M A Dettori et al ldquoEnhanced anti-tumor activity of a new curcumin-related compound againstmelanoma and neuroblastoma cellsrdquo Molecular Cancer vol 9article 137 2010

[175] T J Somers-Edgar S Taurin L Larsen A Chandramouli MA Nelson and R J Rosengren ldquoMechanisms for the activityof heterocyclic cyclohexanone curcumin derivatives in estrogenreceptor negative human breast cancer cell linesrdquo InvestigationalNew Drugs vol 29 no 1 pp 87ndash97 2011

[176] B Yadav S Taurin L Larsen and R J Rosengren ldquoRL66 asecond-generation curcumin analog has potent in vivo and invitro anticancer activity in ER-negative breast cancer modelsrdquoInternational Journal of Oncology vol 41 no 5 pp 1723ndash17322012

[177] A L Kasinski Y Du S L Thomas et al ldquoInhibition ofI120581B kinase-nuclear factor-120581B signaling pathway by 35-bis(2-flurobenzylidene)piperidin-4-one (EF24) a novel monoketoneanalog of curcuminrdquo Molecular Pharmacology vol 74 no 3pp 654ndash661 2008

[178] E M Al-Hujaily A G Mohamed I Al-Sharif et al ldquoPACa novel curcumin analogue has anti-breast cancer propertieswith higher efficiency on ER-negative cellsrdquo Breast CancerResearch and Treatment vol 128 no 1 pp 97ndash107 2011

[179] B Wahlstr G Blennow and B Wahlstrom ldquoA study on the fateof curcumin in the ratrdquoActa pharmacologica et toxicologica vol43 pp 86ndash92 1978

[180] K-Y Yang L-C Lin T-Y Tseng S-C Wang and T-H TsaildquoOral bioavailability of curcumin in rat and the herbal analysisfrom Curcuma longa by LC-MSMSrdquo Journal of Chromatog-raphy B Analytical Technologies in the Biomedical and LifeSciences vol 853 no 1-2 pp 183ndash189 2007

[181] G Shoba D Joy T Joseph M Majeed R Rajendran and P SS R Srinivas ldquoInfluence of piperine on the pharmacokineticsof curcumin in animals and human volunteersrdquo Planta Medicavol 64 no 4 pp 353ndash356 1998

[182] S Bisht and A Maitra ldquoSystemic delivery of curcumin 21stcentury solutions for an ancient conundrumrdquo Current DrugDiscovery Technologies vol 6 pp 192ndash199 2009

[183] J Shaikh D D Ankola V Beniwal D Singh M N V RaviKumar and J Pharm ldquoNanoparticle encapsulation improvesoral bioavailability of curcumin by at least 9-fold when com-pared to curcumin administered with piperine as absorption


enhancerrdquo European Journal of Pharmaceutical Sciences vol 37pp 223ndash230 2009

[184] M Takahashi S Uechi K Takara Y Askin K Wada and JAgric ldquoEvaluation of an oral carrier system in rats bioavail-ability and antioxidant properties of liposome-encapsulatedcurcuminrdquo Journal of Agricultural and Food Chemistry vol 57pp 9141ndash9146 2009

[185] S Onoue H Takanashi Y Kawabata et al ldquoFormulation designand photochemical studies on nanocrystal solid dispersionof curcumin with improved oral bioavailabilityrdquo Journal ofPharmaceutical Sciences vol 99 pp 1871ndash1881 2009

[186] B Antony B Merina V Iyer N Judy K Lennertz and S JoyalldquoA pilot cross-over study to evaluate human oral bioavailabilityof BCM-95 CG (Biocurcumax) a novel bioenhanced prepara-tion of curcuminrdquo Indian Journal of Pharmaceutical Sciencesvol 70 no 4 pp 445ndash449 2008

[187] H Sasaki Y Sunagawa K Takahashi et al ldquoInnovative prepa-ration of curcumin for improved oral bioavailabilityrdquo Biologicaland Pharmaceutical Bulletin vol 34 no 5 pp 660ndash665 2011

[188] M Kanai A Imaizumi Y Otsuka et al ldquoDose-escalation andpharmacokinetic study of nanoparticle curcumin a poten-tial anticancer agent with improved bioavailability in healthyhuman volunteersrdquo Cancer Chemotherapy and Pharmacologyvol 69 no 1 pp 65ndash70 2012

[189] V Gupta A Aseh C N Rıos B B Aggarwal and A B MathurldquoFabrication and characterization of silk fibroin-derived cur-cumin nanoparticles for cancer therapyrdquo International Journalof Nanomedicine vol 4 pp 115ndash122 2009

[190] S S Dhule P Penfornis T Frazier et al ldquoCurcumin-loaded120574-cyclodextrin liposomal nanoparticles as delivery vehicles forosteosarcomardquo Nanomedicine vol 8 no 4 pp 440ndash451 2012

[191] J Shaikh D D Ankola V Beniwal D Singh and M N V RKumar ldquoNanoparticle encapsulation improves oral bioavailabil-ity of curcumin by at least 9-fold when compared to curcuminadministered with piperine as absorption enhancerrdquo EuropeanJournal of Pharmaceutical Sciences vol 37 no 3-4 pp 223ndash2302009

[192] L Li B Ahmed K Mehta and R Kurzrock ldquoLiposomalcurcumin with and without oxaliplatin effects on cell growthapoptosis and angiogenesis in colorectal cancerrdquo MolecularCancer Therapeutics vol 6 no 4 pp 1276ndash1282 2007

[193] D Guzman-Villanueva I M El-Sherbiny D Herrera-Ruiz andH D C Smyth ldquoDesign and in vitro evaluation of a new nano-microparticulate system for enhanced aqueous-phase solubilityof curcuminrdquo BioMed Research International vol 2013 ArticleID 724763 9 pages 2013

[194] X Xie Q Tao Y Zou et al ldquoPLGA nanoparticles improve theoral bioavailability of curcumin in rats characterizations andmechanismsrdquo Journal of Agricultural and Food Chemistry vol59 no 17 pp 9280ndash9289 2011

[195] S Prasad A K Tyagi and B B Aggarwal ldquoRecent develop-ments in delivery bioavailability absorption and metabolismof curcumin the golden pigment from golden spicerdquo CancerResearch and Treatment vol 46 pp 2ndash18 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Liver cancer

Breast cancer

Arthritis Cataract

Diabetes

Lung cancer

Turmericcurcumin

Pancreas cancer

Bladder cancer

Oral cancerColorectal cancer

Stomach cancer

Cardiovasculardisease

Figure 1 Turmericcurcumin shows pivotal role in the prevention of diseases including cancer

as being antiprotozoal and antioxidant and this uniquenessmight have a significant effect on several types of diseasesanticipation [12 13] Important reviews based on curcuminprovide an overview of the history chemistry analogs andmechanism of action of curcumin [14] and another studydiscussed in detail the therapeutic implications of curcuminin patients with pancreatic cancer [15]

2 Curcumin Modulator ofMolecular Pathways

Tumorigenesis and tumor progression are thought to be asa result of some changes in the different types of geneticpathways [16 17] Curcumin chief constituents of turmericshows a vital role in cancer prevention and treatmentthrough modulation of various biological activities includingmolecular cascades However understanding the turmericrsquosmechanism of action in the activation or inactivation ofgenetic pathways will provide significant information todevelop therapeutic approaches to manage various types ofcancers

21 Effect of Curcumin on Tumor Suppressor Genes Tumorsuppressor genes play a vital and significant role in theinhibition of cancer formation and its progression Whenan alteration or mutation occurs in a gene then tumorsuppressor gene lost its ability to perform normal functionTumor suppressor gene p53 is the guardian of all genesand regulates the various cellular and molecular pathwaysand prevents cancer formation Numerous in vivo and invitro reports showed that turmeric and its constituents havea significant role in cancer prevention or inhibition Animportant study showed that curcumin down-regulates theexpression of p53 as well as the survival genes egr-1 c-myc and bcl-XL in B cells [18] Another report has alsoindicated that curcumin inhibits cell cycle progression ofimmortalized human umbilical vein endothelial cells viaupregulating the CDK inhibitors p21WAF1CIP1 p27KIP1

and p53 [19] Further studies reported that curcumin mainlyacts in p53-dependent manner and also showed that wild p53was highly susceptible to curcumin toxicity [20]

Another tumor suppressor gene phosphatase and tensinhomolog deleted on chromosome ten (PTEN) has a role inthe progression of the cell cycle and apoptosis The alterationor mutation of PTEN gene has been noticed in several typesof cancers A study of the curcumin has shown that PTENincreases the curcumin-induced apoptosis whereas inactivePTEN decreasesinhibits the curcumin-induced apoptosis[21] A study showed that difluorinated curcumin (CDF) anontoxic analog modulates the expression of miR-21 andPTEN in pancreatic cancer [22ndash25]

The retinoblastoma is a type of tumour suppressor geneand shows an important role in the control of cell cyclepRb the protein coded for by the RB1 gene shows animportant role in cell cycle regulation promoting G1S arrestand growth restriction via inhibition of the E2F transcriptionfactors [26] It is inactivated through hyperphosphorylationcatalyzed by the cyclin D-cyclin-dependent kinase 4 (cyclinD-cdk4) and cyclin E-cdk2 complexes [27ndash29] Variousmedicinal plants and their constituents show a vital role in theregulation of Rb genes via regulation of phophorylation Inthis vista curcumin chief constituents of turmeric also showsan important role in modulation of Rb gene via reductionin hyperphosphorylation An important study based onprostate cancer cells has revealed that curcumin induced theexpression of cyclin-dependent kinase (CDK) inhibitors p16p21 and p27 and inhibited the expression of cyclin E andcyclin D1 and hyperphosphorylation of retinoblastoma (Rb)protein [30] and another study has shown that suppression ofcyclin D1 by curcumin led to inhibition of CDK4-mediatedphosphorylation of retinoblastoma protein [31]

22 Effect of Curcumin on Apoptotic Genes Apoptosis is oneof the prerequisites to maintain the normal and healthy inter-nal milieu Any alteration or change in the normal process ofapoptosis may increase cell survival and support the tumor











Turmericcurcumin



(bcl2 and bax)



Suppression ofVEGF

Akt and PI3K


HER-2 and EFGR)


(GST and NAT)


gene (CYP-450)


soluble molecules


Excreted viaurine



(c-myc c-fos


















Curcumin




AKT and PI3K


































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Turmericcurcumin



(bcl2 and bax)



Suppression ofVEGF

Akt and PI3K


HER-2 and EFGR)


(GST and NAT)


gene (CYP-450)


soluble molecules


Excreted viaurine



(c-myc c-fos


















Curcumin




AKT and PI3K


































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Turmericcurcumin



(bcl2 and bax)



Suppression ofVEGF

Akt and PI3K


HER-2 and EFGR)


(GST and NAT)


gene (CYP-450)


soluble molecules


Excreted viaurine



(c-myc c-fos


















Curcumin




AKT and PI3K


































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Curcumin




AKT and PI3K


































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Curcumin




AKT and PI3K


































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























7 Conclusions




References





















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Curcumin: A Potential Candidate in Prevention ...curcumin [ ]. Another report in human breast cancer cell line showed that CD induces G-G arrest and apoptosis via regulation

Documents