review article therapeutic potential of curcumin for the...

Review ArticleTherapeutic Potential of Curcumin for the Treatment ofBrain Tumors

Neil V Klinger1 and Sandeep Mittal123

1Department of Neurosurgery Wayne State University Detroit MI USA2Department of Oncology Wayne State University Detroit MI USA3Karmanos Cancer Institute Wayne State University Detroit MI USA

Correspondence should be addressed to Sandeep Mittal smittalmedwayneedu

Received 23 July 2016 Accepted 7 September 2016

Academic Editor Mohamed Essa

Copyright copy 2016 N V Klinger and S Mittal 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

Brainmalignancies currently carry a poor prognosis despite the currentmultimodal standard of care that includes surgical resectionand adjuvant chemotherapy and radiation As new therapies are desperately needed naturally occurring chemical compounds havebeen studied for their potential chemotherapeutic benefits and low toxicity profile Curcumin found in the rhizome of turmeric hasextensive therapeutic promise via its antioxidant anti-inflammatory and antiproliferative properties Preclinical in vitro and in vivodata have shown it to be an effective treatment for brain tumors including glioblastoma multiforme These effects are potentiatedby curcuminrsquos ability to induce G2M cell cycle arrest activation of apoptotic pathways induction of autophagy disruption ofmolecular signaling inhibition of invasion and metastasis and by increasing the efficacy of existing chemotherapeutics Furtherclinical data suggest that it has low toxicity in humans even at large doses Curcumin is a promising nutraceutical compound thatshould be evaluated in clinical trials for the treatment of human brain tumors

1 Introduction

Primary central nervous system tumors have an incidenceof 2786 per 100000 [1] Glioblastoma (GBM) is the mostcommon malignant primary CNS tumor with an annualincidence of 319 per 100000 GBM accounts for 154 of allprimary brain tumors and 456 of primary malignant braintumors [1 2] The current standard of care for GBM consistsof surgical resection followed by the Stupp regimen (adjuvantchemotherapy and radiation) and it has been used in practicefor over a decade without substantial improvements Thisaggressive multimodal treatment prolongs median overallsurvival to 15 months [3ndash5] Other therapies approved foruse in GBM include alternating electrical fields produced byOptuneTherapy (Novocure Inc) further prolongingmediansurvival to 20 months [6] With such poor prognoses addi-tional therapeutics are needed to improve survival and qualityof life for patients with malignant gliomas Complementarymedicine and nutraceuticals are of particular interest andhave been studied extensively as anticancer agents because

they are usually associated with low toxicity profiles Thisallows them to be safely used at high doses or added toexisting chemotherapy regimens as adjuvant treatment

Curcumin is found in rhizome of turmeric (Curcumalonga) which is a member of the ginger family (Figure 1)[7] Its traditional uses long known by Ayurvedic medicinefrom India and traditional Chinesemedicine include treatinginfections liver and skin disorders dressing wounds burnsand decreasing inflammation [7] In fact powderedCurcumalonga has been used in Asian medicine cosmetics and fabricdying for more than 2000 years [8] Curcumin possessesmultiple beneficial chemical properties including antiox-idant anti-inflammatory and chemotherapeutic potentialboth against cultured cells and in treatment studies usinganimal models Current data suggests that curcumin maybe useful in a wide spectrum of human disorders includingAlzheimerrsquos disease Parkinsonrsquos disease diabetes cardio-vascular disease arthritis and various neoplasms includingbrain tumors [9 10]

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 9324085 14 pageshttpdxdoiorg10115520169324085

2 Oxidative Medicine and Cellular Longevity

Curcuma longa Curcumin

Enol form

Keto form

Demethoxycurcumin

Bisdemethoxycurcumin

OH

OH

HO

O

O

O

CH3CH3

OH

O

HO

O

O

O

CH3CH3

OH

O

HO

O

O

CH3

OH

O

HO

O

(a) (b)

Figure 1 (a) Curcuma longa from Koehlerrsquos Medicinal Plants 1887 (b) From top to bottom curcumin in its enol form curcumin in its ketoform demethoxycurcumin and bisdemethoxycurcumin

2 Mechanism and Preclinical Data

Curcuminrsquos effects on glioma cells in vitro and in vivo havebeen well studied Curcumin has many molecular targets(Figure 2) and therefore diverse and complex mechanisms ofactionThe antitumoral effects of curcumin are thought to actthrough many different signaling pathways such as cellularproliferation [11ndash13] apoptosis [11 12 14] autophagy [15ndash17]angiogenesis [18ndash20] immunomodulation [21] invasion [1422 23] and metastasis [24ndash26] These pathways have beenreviewed comprehensively elsewhere [27ndash31] In addition toits effectiveness as an antineoplastic curcumin has beenfound to be protective against reactive oxygen species (ROS)A study by Rathore et al [32] examined the effects of curcumaoil on a transient ischemiamodel in Sprague-Dawley ratsThemiddle cerebral artery was occluded using a nylon filamentfor twohours followed by a 24-hour reflowperiod Treatmentwith curcuma oil reduced the size of infarcted cerebral tissueimproved neurologic function and reduced oxidative stresscaused during the reperfusion period The authors reportedthat these protective effects were obtained by inhibition ofROS reducing peroxynitrite levels and caspase-3 activity andpreventing destabilization of the mitochondrial membranepotential [32] In an in vitro model of ischemia-reperfusionusing rat cortical neurons curcumin was found to protectneurons from death caused by oxygen and glucose depri-vation The authors of this study suggested that curcuminactivates an antioxidant protein thioredoxin in the Nrf2pathway [33] In addition curcumin may inhibit cellularglyoxalases leading to decreased ATP and glutathione which

can impact cellular metabolism and may account for some ofits anti-inflammatory and antitumor effects [34]

21 Curcumin Induces G2MCell Cycle Arrest There is a bevyof data to suggest that curcumin is able to induce G2Mcell cycle arrest and apoptosis More recent work has triedto explain how this cell cycle arrest can occur Wu et alpublished a study in 2013 [35] that suggests that this mightbe due to increased DAPK1 expression The authors treatedthe U251 GBM cell line with curcumin and found a dose-dependent increase in DAPK1 mRNA by real-time RT-PCRand verified a corresponding increase in protein expressionby western blot analysis Further they used siRNA (si-DAPK1-1 and si-DAPK1-2) transfection to suppress DAPK1and found that curcuminhad an attenuated ability to suppressSTAT3 and NF-120581B phosphorylation They also showed thattheir knockdown of DAPK1 inhibited curcumin-mediatedcaspase-3 activation and led to decreased apoptosis (330apoptotic cells versus 583 in their control) [35] Thesefindings suggest that DAPK1 plays an important role incurcumin-mediated cell death Other studies in U251 GBMcells show that p53 expression is upregulated by curcumintreatment as were CDKi p21Waf1Cip1 (p21) and ING4mdasha tumor suppressor gene that has been found to be sup-pressed in gliomas [36 37] Curcumin owes part of itsantiproliferative effects to suppression of cyclin D1 and toinduction of p21 In a study that treated U87 GBM cells withcurcumin transcription factor Egr-1 was found to activatetranscription of p21 independent of p53 activation Egr-1expression was reportedly induced by curcumin via ERK

Oxidative Medicine and Cellular Longevity 3

Initiation

Nrf2SHHGLI1PTCH1NotchERCC-1c-Myc

SurvivalCaspaseBcl-2Bcl-xLBAXBAKSurvivinNF-120581BRASERKEGR-1JNK

MetastasisICAM-1SnailTwistTIMP

Invasion

MMPAP-1MAPKuPACXCR-4

Angiogenesis

VEGFAHIF1ACD31CD105FGF

ResistanceABCG2MRPs

Inflammation

IL-6IL-8TNF120572COX-2

S

M Proliferation

Cyclin B1 D1Wnt120573-cateninPI3KAKTmTORhTERTHDACsJAKSTAT-3p53CDKCDKICdc25c 27SACWeeCHK1EGFR

G1G2

Figure 2 Cancer pathway targets affected by curcumin When the listed targets have multiple contributions to tumorigenesis (eg NF-120581B)they are only placed under one category Figure modifiedlowast from Davis et al 2003 [44] lowastAs permitted by Creative Commons Attribution-NonCommercial-Share Alike 30 license and BJCOPEN initiative ABCG2 ATP-binding cassette subfamilyGmember 2 AKT protein kinaseB AP-1 activator protein 1 BAK Bcl-2 homologous antagonistkiller BAX Bcl-2-like protein 4 Bcl-2 B-cell lymphoma 2 Bcl-xL B-celllymphoma-extra large caspase cysteine-aspartic protease CD105 endoglin CD31 platelet endothelial cell adhesion molecule (PECAM-1)CDC cell division cycle CDK cyclin-dependent kinase CDKI cyclin-dependent kinase inhibitor CHK1 checkpoint kinase 1 c-Myc v-Mycavianmyelocytomatosis viral oncogene homolog COX-2 prostaglandin-endoperoxide synthase 2 CXCR-4 C-X-C chemokine receptor type4 EGFR epidermal growth factor receptor EGR-1 early growth response protein 1 ERCC-1 excision repair cross-complementation group1 ERK extracellular signal-regulated kinases FGF fibroblast growth factor GLI1 GLI family zinc finger 1 HDAC histone deacetylasesHIF1A hypoxia inducible factor 1 alpha subunit hTERT telomerase reverse transcriptase ICAM-1 intercellular adhesion molecule 1 ILinterleukin JAK Janus kinase JNK c-Jun N-terminal kinase MAPK mitogen-activated protein kinases MMP matrix metalloproteinasesMRPmultidrug resistance proteinmTORmechanistic target of rapamycin NF-120581B nuclear factor kappa-light-chain-enhancer of activated Bcells Nrf2 nuclear factor (erythroid-derived 2) like 2 PI3K phosphatidylinositol-45-bisphosphate 3-kinase PTCH1 patched 1 SAC spindleassembly checkpoint SHH sonic hedgehog Snail zinc finger protein SNAI1 STAT-3 signal transducer and activator of transcription 3 TIMPtissue inhibitors of metalloproteinases TNF tumor necrosis factor uPA urokinase VEGF vascular endothelial growth factor

and JNK [13] An in vitro study using U87 human gliomacell line showed that 5ndash10 120583M curcumin could inhibit pro-liferation and that treated cells were arrested in G2M stageby increased expression of DUSP-2 and inhibition of ERKand JNK phosphorylation Interestingly trapping cells in theG2M phase appears to enhance their sensitivity to radiation[38 39] Curcuminrsquos radiosensitizing effects have also beenexamined in neuroblastoma (SK-N-MC) cells Pretreatingcells with 100 nM curcumin suppressed radiation inducedNF-120581B enhanced radiation induced caspase activation andinhibited antiapoptotic molecules [40]

22 Curcumin Activates Apoptotic Pathways An in vitrostudy using human GBM (A172 KNS60 U251MG(KO))and medulloblastoma (ONS76) cell lines showed that whilecurcumin was able to inhibit growth of these cell linesonly KNS60 and ONS76 were arrested at G2M These

findings suggest that the mechanism for growth inhibitionis not exclusively due to cell cycle arrest They also found asignificant increase in caspase 37 activity curcumin inducedDNA damage and apoptosis triggered by overexpressionof BAX and downregulating Bcl2 and survivin as wellas inhibition of telomerase and downregulation of hTERT[41] An in vitro study using 8401 GBM cell line foundthat curcumin decreased cell proliferation reduced mito-chondrial membrane potential induced DNA fragmenta-tion induced apoptosis via a caspase-dependent pathway(caspase-3 caspase-8 and caspase-9) and inhibited NF-120581Btranscription factor activity [42] In U87MG GBM cell linecurcumin can induce apoptosis by suppressing antiapoptoticsignals by promoting activation of caspase-8 and throughan increased BAXBcl-2 ratio [43] Solubilized curcumin(667 120583M in PBS 3 DMSO) can increase caspase 37 activityin both mouse (B16F10 melanoma GL261 glioma and N18


neuroblastoma) and human (HOG oligodendroglioma andA549 lung cancer) cell lines and it decreased tumor cellviability as measured by MTT assay Further LDH releasein these experiments was not increased suggesting apoptoticcell death [19]The authors of this study also report that cyclinD1 NF-120581B AKT ERK and Bcl-xL were suppressed whenB16F10 cells were treated with curcumin [19] In an in vivoarm of this experiment the authors injected 10000 B16F10mouse melanoma cells in the brain of C57BL6 mice Theythen received either daily tail vein injections of 200120583L of theirsolubilized curcumin (estimated final plasma concentrationof 35 120583M in PBS 015 DMSO) or a control injection (PBS015 DMSO) for 18 days Additionally this experiment wasrepeated with intracerebral delivery of the curcumin solutionvia a stainless steel cannula While all of the control animalsdeveloped intracranial tumors only one of the 5 treated micedeveloped detectable tumor [19]

23 Curcumin Induces Autophagy Autophagy is a cellularprocess for disassembling unnecessary or dysfunctional cel-lular components and is essential formaintaining energy dur-ing states of nutritional stress and during programmed celldeath It also appears to have an important role in regulationof glioma-initiating cells which are poorly differentiated andshare features of neural stem cells An in vitro study publishedin 2012 showed that curcumin can induce differentiation andhalt growth of glioma-initiating cells (SU-2 and SU-3) fromsurgically resected human GBM by activating autophagyIn the same study glioma-initiating cells were implantedintracranially in athymic nude mice and randomized to atreatment group consisting of intraperitoneal (IP) injectionof curcumin (300mgkg) every 3 days or control group(119899 = 14 each) Those mice who received treatment hadincreased survival (study halted after 120 days) versus non-treated animals [16] In a separate study curcumin activatedthe ERK12 pathway and inhibited the AKTmTORp70S6Kpathway resulting in autophagy both in vitro and in vivousinga subcutaneous xenograftmodel in nudemice with U87 cellsThe authors report that curcumin induced G2M cell cyclearrest in addition to autophagy in U87 and U373 GBM cells[17]

24 Curcumin Disrupts Molecular Signaling The NF-120581Bpathway is upregulated in GBM and inhibitors of NF-120581Bexhibit relatively low toxicity to normal tissues A preclin-ical study of NF-120581B inhibitors found that NF-120581B activitycorrelated with percentage cell viability in C6 and U138GBM lines [45] The authors report that inhibition of NF-120581B leads to mitochondrial dysfunction with arrest in theG2M phase of the cell cycle Interestingly NF-120581B is foundto be overstimulated in cisplatin-resistant C6 cells and NF-120581B inhibitors were able to overcome cisplatin resistance [45]Similarly progranulin has been found to be overexpressedin many GBM cell lines (U87 GBM8904 and S1R1) andtumor samples [46] Progranulin overexpression contributesto tumorigenesis and treatment resistance by upregulatingDNA repair and stemness genes using the transcription factorAP-1 Curcumin is an AP-1 inhibitor and it was found todownregulate progranulin promoter activity and expression

[46] Other studies have shown that curcumin can reduceGBM cell survival through inhibition of AP-1 and NF-120581Bby preventing constitutive activation of JNK and AKT [47]An in vitro study examined the role of glucose-6-phosphatetranslocase (G6PT) in U87 GBM cell signal transduction Inthis experiment suppression of gene expression was accom-plished using siRNAs and led to apoptosis and necrosisCurcumin (35 120583M) also inhibited G6PT gene expressiongt90 However the authors also report transfection with anexpression vector for G6PT rescued cells from curcumin-mediated cell death This suggests that G6PT may be anovel chemotherapeutic target and that G6PT overexpressionmay lead to treatment resistance [48] In a separate set ofexperiments murine glioma cell lines (Tu-2449 Tu-9648and Tu-251) with constitutively expressed STAT3 treated withcurcumin showed a dose-dependent decrease in the activityof phosphorylated JAK1 and JAK2 and led to downstreaminactivation of STAT3 In an in vivo arm of this study C6B3F1mice were fed a diet rich in fat and cholesterol with or withoutfortification with curcumin for 7 days Subsequently theyreceived intracranial implantation of either Tu-2449 or Tu-9648 glioma cells and maintained their diet Fifteen percentof Tu-2449 implantedmice who received curcumin-enricheddiets had tumor-free long-term survival versus 0 of thecontrol dieted animals Curcumin fed Tu-9648 implantedmice experienced a 38 increase in tumor-free long-termsurvival [49]

The sonic hedgehog (SHH) signaling pathways are impor-tant in the carcinogenesis of medulloblastoma It is a majorregulator of cell proliferation and death Curcumin hasbeen shown to downregulate SHH leading to decreaseddownstream targets GLI1 and PTCH1 and cytotoxicity in celllines MED-4 MED-5 and DAOY [50] Targeting SHH andGLI1 with curcumin treatment has also been done in gliomacells (U87 and T98G) Similar to medulloblastoma mRNAand protein levels of SHH and GLI1 were downregulatedwith curcumin treatment IP injection of curcumin in U87-implanted nude mice also reduced tumor volume prolongedsurvival and decreased GLI1 expression [51] In the medul-loblastoma cell line DAOY curcumin has been shown toinhibit Wnt120573-catenin signaling and suppress proliferationwith IC50 of 35 120583M after 48 hours [52] Mechanistically cur-cuminmay decrease histone deacetylase 4 expression leadingto increased tubulin acetylation and mitotic catastrophe inaddition to its effects on G2M cell cycle arrest in DAOYmedulloblastoma cells [53]

25 Curcumin Decreases Invasion and Metastasis Abnormalexpression of matrix metalloproteinases (MMPs) mem-brane-associated or secreted enzymes used to digest extra-cellular matrix proteins is one method by which gliomacells are able to invade normal brain tissue Data has shownthat curcumin is able to suppress expression of MMP-1MMP-3 MMP-9 and MMP-14 in GBM cell lines U87MGand U373MG via the common upstream AP-1 and MAPkinases [22 23 54] Urokinase-type plasminogen activator(uPA) is a serine protease that starts a degradative cas-cade by converting extracellular plasminogen to plasminand eventually degrades extracellular matrix collagen and


activates other MMPs to aid in invasion [55] Curcumin canprevent nuclear translocation of RelANF-120581B which preventsupregulation of uPA [55] Curcumin has also been found todramatically reduce MMP-9 in murine glioma cell lines Tu-2449 Tu-9648 and Tu-251 [49] An important contributorto tumors propensity to invade and metastasize is angio-genesis Cell lines derived from surgically resected pituitaryadenomas treated with curcumin have decreased HIF1A andVEGFA both of which are involved in tumoral angiogenesis[56]

26 Curcumin Increases the Efficacy of Existing Chemother-apeutics Data also exists to suggest that curcumin actssynergistically with chemotherapeutics already approved forthe treatment of brain tumors A preclinical study examinedthe efficacy of curcumin for the treatment of GBM invitro and in vivo [57] Cell lines U138MG U87 U373 andC6 were treated with curcumin and found to have IC50values of 29 19 21 and 25 120583M respectively whereas IC50for astrocytes was 135120583M Chemotherapy synergism wassubsequently tested using U138 and C6 cell lines Curcuminalone resulted in 55 and 75 viability respectively Whencisplatin was added in combination with 25 120583M curcuminthe viability dropped to 30 and 10 for U138 and C6cell lines respectively When doxorubicin was added incombination with 25120583M curcumin viability was reportedto be 36 and 46 Mechanistically the authors reportedthat curcumin decreased activation of PI3KAKT and NF-120581B pathways decreased expression of Bcl-xL and causedmitochondrial dysfunction and apoptosis The authors alsoimplanted Wistar rats with C6 GBM cells intracranially andtreated them with 50mgkgday curcumin via IP injectionwithin days 10ndash20 after implantation Sixty-four percent ofcurcumin treated animals developed tumors as compared to100 of the DMSO treated controls Of the treated animalswho developed tumors average tumor volume was 73 lessthan that of the controls [57] Curcumin in combinationwith temozolomide (TMZ) appears to have additive cytotoxicbenefit in GBM cells [15] Further both drugs appear tocause G2M arrest by activating proteins such as Wee Cdc2CHK1 and Cdc25c Decreased phosphorylation of cyclin B1and cyclin D1 was also observed [15] The authors foundthat treatment with either TMZ or curcumin appears toinduce autophagy that was dependent on ERK12 prior toapoptosis Curcumin was also found to inhibit STAT3 NF-120581B and PI3KAKT [15] A study by Ramachandran et al [58]investigated potentiation of etoposide (ETP) and TMZ bycurcumin and a trade preparation of turmeric called TumericForce (TF) in human U87 GBM and D283 medulloblas-toma cell lines U87 IC50 values for ETP TMZ curcuminand TF were 65 gt2000 373 and 308120583gmL respectivelyFor D283 cells those IC50 values were 019 147 287 and16 120583gmL Combination index values in U87 glioma cellsfor ETP + curcumin TMZ + curcumin and ETP + TMZ+ curcumin were 055 207 and 039 120583gmL respectivelyThe combination index values with TF instead of curcuminwere 038 057 and 005 120583gmL [58] Curcumin has also beenstudied for efficacy in combination with paclitaxel (PTX) forthe treatment of GBM LN18 and U138MG cell lines treated

with 20120583M curcumin and 10 nM PTX were found to havea combination index of 01 and 009 respectively indicatinga synergistic effect This combination activated caspase-3caspase-8 and calpain increased BAX and reduced Bcl-2 initiating apoptosis Combination therapy also decreasedthe ability of LN18 and U138MG cells to invade matrigel[59] In addition to acting synergistically curcumin mayprevent chemotherapy resistance A study reported in 2008on Sprague-Dawley rats showed curcumin can inhibit aprotein linked with multidrug resistance in the luminalmembrane of capillaries at the blood-brain barrier- (BBB-)ATP-binding cassette transporter ABCG2 [60] A separateintriguing method by which GBM may resist hydrophobictherapeutic agents is by accumulating lipid droplets thatsequester these drugs Curcumin is hydrophobic and hasbeen shown to concentrate near the cell membrane and incytoplasmic droplets of U251N humanGBM cells [61] Zhanget al sought to overcome this mechanism of resistance invitro using pyrrolidine-2 a cytoplasmic phospholipase A2120572inhibitor in combination with curcumin When the cellswere pretreated with pyrrolidine-2 24 hours before curcuminadministration cell viability was found to approach 0 [61]

27 Curcuminoids and Curcumin Derivatives Demethoxy-curcumin (C2) and bisdemethoxycurcumin (C3) (Figure 1)are two curcuminoids often found in small percentages ofcurcumin extractions An in silico study published in 2009[62] examined the docking of curcuminoids with the Bcl-2 apoptotic proteins (Protein Data Bank accession numbers1G5M and 1GJH) The authors calculated free energies andinhibition constants for these molecules and found thatC2 binds more favorably than curcumin (Δ119866 minus697 versusminus453 kcalmol 119870119894 056 versus 221 nm) In vitro treatment ofU87 GBM cells showed marked decrease in Bcl-2 expressionwith all three compounds after 48 hours and that C2 showedsignificant progression of percent apoptosis compared tocurcumin or C3 An in vitro binding assay utilizing circulardichroism spectroscopy showed that C2 like the natural Bcl-2 inhibitor Bak caused a conformational change differentfrom curcumin or C3 [62] These findings suggest thatC2 induces Bcl-2 mediated apoptosis more effectively thancurcumin or C3 A study published by Huang et al [63]also examined the effects of C2 They showed that C2 hadIC50 of 227120583M in GBM 8401 cells and that apoptosiswas induced by decreasing the mitochondrial membranepotential and caspase-dependent pathways similar to otherstudies of curcumin [63] Other curcumin analogs have beendeveloped in an attempt to improve upon the compoundrsquostherapeutic promise For example lead compounds identifiedby Campos et al show comparable IC50 values against GBM(U87MG) and neuroblastoma (SK-N-SH and SK-N-FI) celllines [64]

3 Delivery Mechanisms

The therapeutic benefits of curcumin are limited by its poorabsorption rapid metabolism and poor water solubility [65]Curcumin is broken down by multiple enzymatic pathways


including glucuronidation sulfation alcohol dehydrogenaseand p450 system leading to rapid metabolism and excretion[66] However its lack of toxicity allows for administrationof large doses Twenty-four subjects with mean age of 34were provided capsules with 05ndash12 g of curcumin and serumanalysis was conducted prior to testing at 1 2 and 4 hoursafter dosing Peak serum concentration was lt2120583M even at10- and 12-gram doses [67 68] These clinical data also showthat doses up to 12 grams per day do not provoke serious sideeffects though trouble with tablet bulk diarrhea and yellowstool were noted [67 68] Piperine an inhibitor of hepaticand intestinal glucuronidation has long been suggested tobe administered as an adjuvant to prevent the degradation ofmedications including curcumin [69ndash71] Ten subjects withmean age of 60 years participated in a randomized crossovertrial to compare the effects of oral curcumin (2 g) alone orwith the addition of piperine (20mg) A two-week washoutperiod was used before the crossover They found that whenadministered with piperine peak serum concentrations ofcurcumin increased 30-fold and the relative bioavailabilitywas 2000The119881119863 for curcumin administered with piperinewas 203 Lkg No adverse events were reported in this study[69]

Though current literature contains mixed data curcumindistribution to the brain might be hindered by limited BBBpermeability [65 72] Certain nanoparticle formulationssuch as poly(lactic-co-glycolic acid) have been shown toincrease distribution to brain tissue [65] The half-life ofcurcumin-loaded poly(lactic-co-glycolic acid) in brain tis-sues from Sprague-Dawley rats for this study was reportedto increase from 9 minutes to 15 minutes When brainregions were examined separately the compoundrsquos half-life was found to be significantly extended in the cerebralcortex (20 versus 2 minutes) and hippocampus (17 versus8 minutes) but not in the cerebellum brainstem striatumor other brain regions [65] Curcumin has also been loadedinto poly(butyl)cyanoacrylate (PBCA) nanoparticles usingapolipoprotein E3 to increase transport across the BBB [73]This delivery system was found to induce apoptosis in SH-SY5Y neuroblastoma cells more efficaciously than curcuminsolution or curcumin loaded in the PBCA carrier withoutApoE3 [73] Nanostructured lipid carriers (tripalmitin-oleicacid) loaded with curcumin had IC50 of approximately20120583gmL against A172 GBM cells compared to IC50 of80 120583gmL with curcumin alone Further the authors showedthat curcumin delivered with the lipid carriers to subcuta-neous flank tumor bearing nude mice decreased tumor vol-ume by 82 [74] Polymeric micelles have also been studiedfor curcumin delivery Amphiphilic block copolymers formmicelles when placed in aqueous solutions These vesiclesor polymersomes can be made of one or more differenthigh-molecular weight amphiphilic block copolymers suchas oleic acid and PEG 400 as a diblock nanostructure Thiscombination has been shown effective in delivering curcuminand reducing tumor burden in mouse models [75 76]Monomethoxy PEG has a higher molecular weight of 2 kDaversus 400Da and has also been tested in attempt to obtaina better thermodynamic profile [77] When tested in vitrowith the U87 human glioblastoma cell line monomethoxy

PEG-oleate conjugation product showed IC50 values of 24120583Mversus IC50 of 48 120583M for free curcumin [77] Intranasaldelivery of therapeutics to the brain represents a noninvasiveway to bypass the BBB Exosome encapsulated curcuminhas been administered intranasally to C57BL6j mice in anattempt to treat inflammation induced by administrationof lipopolysaccharide (LPS) [78] It was found that theseexosomes were taken up by brainmicroglia within 15minutesand inhibited LPS-induced inflammation [78] Other lipidcarriers have also been designed for intranasal curcumindelivery to the central nervous system Testing in Wistarrats showed that maximum concentration was reached afterapproximately 3 hours and delivery to brain tissues wasgreater with the lipid carrier than the plain drug suspension(86 and 54 ngg resp) [79]

Dendrosome carriers comprised of esterified oleoylchloride and polyethylene glycol 400 have recently beenpublished as effective means of delivery curcumin [75 76]In vitro data treating U87MG GBM cells with curcumindendrosomal curcumin and empty dendrosome found thatdendrosomal curcumin had superior efficacy at 24 48 and72 hours As with many other studies the authors foundincreased caspase activity when these cells were treated withcurcumin Interestingly they also examined pluripotencytranscription factors (OCT4A OCT4BI SOX-2 and Nanog)and found that treating U87 cells with dendrosomal cur-cumin led to significant decreases in these factors Duringcellular differentiation miR-145 expression suppresses thesepluripotent genes The authors reported that dendroso-mal curcumin was able to exert its effects by inciting anapproximately 35-fold elevation of miR-145 [75] Treatmentof A431 (epidermoid carcinoma) and WEHI-164 (mousefibrosarcoma) cell lines with dendrosomal curcumin resultedin IC50 values of 143 and 75 120583M at 48 hours respectivelycompared to 37 120583M for curcumin alone against WEKI-164cells [76] WEHI-164 cells were injected subcutaneously inthe flank in an in vivo experiment using BALBcmice and theresults showed that treatment with dendrosomal curcuminled to significant reductions in tumor burden compared tocurcumin treated animals or control [76] Dendrosomal cur-cumin has also shown efficacy in the treatment of metastaticbreast cancer cells (4T1) in vitro and in vivo with 11 ofanimals having metastases at necropsy compared to 89of control The authors also reported that treatment withdendrosomal curcumin led to downregulation of VEGFCOX-2 and MMP expression [80]

Curcumin has also been conjugated as a poly(glycerol-sebacate-curcumin) polymer similar to carmustine polymersused for local treatment with gliomas [81] In vitro studiesshow IC50 values in response to this polymer of 232120583gmLwith U87 cells and 202120583gmL with T98 cells [81] Poly-caprolactone implants have been studied as another deliverymethod for test agents with poor bioavailability An in vitroassay with 9 L rat glioma cells reported that curcumin-loaded poly(120576-caprolactone)-poly(ethylene glycol)-poly(120576-caprolactone) nanofibers caused dose-dependent growthinhibition [82] Gupta et al reported a preclinical study[83] in August-Copenhagen Irish rats who received fourpolycaprolactone implants that were loaded with 40mg of


curcumin Analysis of liver brain and plasma by high-performance liquid chromatography (HPLC) with fluo-rescence spectroscopy showed an increase in curcuminlevels versus animals receiving sham implant and a dietsupplemented with 1000 ppm curcumin [83] They alsodemonstrated that these implants can reduce benzo[a]pyreneinduced lung DNA adducts by 62 in Sprague-Dawley rats[83]

Curcumin microparticles in a poly(DL-lactide-co-gly-colide) polymer has been formulated in an attempt toimprove delivery of the drug and sustain its release Theinvestigators reported that a single subcutaneous injectionwas able to sustain release in the blood and body tissuesof BALBc mice for 4 weeks Levels of curcumin in thelungs and brain show 10ndash30-fold greater distribution thanthe blood Further animals implanted with MDA-MB-231human breast adenocarcinoma cells were effectively treatedwith these microparticles (49 decreased tumor volume ver-sus empty microparticle) whereas repeated systemic injec-tions of curcumin alone were no different than the vehicletreatment [84] Curcumin nanoparticles (NanoCurc) [2185] have also been used as a method to overcome the deliveryand bioavailability barriers of curcumin These particlesunlike free curcumin are able to disperse in an aqueousenvironment [21] Studies using xenograft models of humanpancreatic cancer in athymicmice show that NanoCurc canlead to approximately 50 reduction in tumor volume Thisinhibition was enhanced with the addition of gemcitabineThe authors reported that these effectswere observed throughdecreased NF-120581B activation MMP-9 and cyclin D1 [85]These nanoparticles have also been shown to suppress in vitrogrowth by MTS cell proliferation assay of embryonal tumorlines (DAOY and D283Med) U87 GBM cells and glioblas-toma neurosphere lines (JHH-GBM14 and HSR-GBM1) in adose-dependent manner [86] The authors suggested that inthis experiment the effects could be due to a combination ofG2M arrest and apoptotic induction [86]

Additional benefits of using delivery systems include theability to deliver multiple compounds simultaneously Forexample Dilnawaz and Sahoo used magnetic nanoparticles(MNP) to deliver both curcumin and TMZ to monolayerand spheroid T-98G GBM cultures In monolayer culturesIC50 values (120583gmL) for TMZ curcumin TMZ and curcuminwere 11 66 and 08 without MNP delivery and 02 06 and01 withMNPdeliveryThese same values in spheroid cultureswere 23 28 and 10withoutMNP and 10 11 and 52 withMNPdelivery Combination index analysis showed that the drugcombination functioned synergistically in both cultures [87]Another study using magnetic core nanocapsules reportedthe ability to deliver drugs with differing hydrophobicity [88]They were able to accommodate doxorubicin (hydrophilic)and curcumin (hydrophobic) in the same particles for deliv-ery to RG2 rat glioma cells [88]

Curcumin has also been coupled to an antibody as adelivery vehicle Langone et al [89] demonstrated that cur-cumin coupled to Muc18 a melanoma specific antibodyincreased its efficacy against B16F10 melanoma The in vitroIC50 valuewas reduced from22120583Mto 009120583Min cells treatedwith the curcumin-antibody adduct versus curcumin alone

In addition C57BL6 mice implanted with 1000 B16F10cells in their right forebrain showed a 10-fold decrease intumor burden when treated with and curcumin-antibodyadduct [89] The authors reported that this effect wasachieved by suppressing NF-120581B [89] In 2014 Langone etal published another study that used an antibody deliverysystem for curcumin In this experiment a GBM-specificCD68 antibody was used to target GL261 (mouse) T98G(human) and U87MG (human) GBM cells [18] GL261 cellswere treated in vitro with 50120583M of curcumin for 24 hoursand western blot analysis showed suppression of NF-120581BIn addition curcumin was found to inhibit AKT-1 (neuralsurvival and antiapoptotic) Bcl-xL (antiapoptotic) cyclin D1(cell cycle promoter) and VEGF (promoting angiogenesis)[18] Curcumin alone yielded IC50 15 120583M whereas treatmentwith the curcumin-antibody adduct had IC50 of 0125 120583MIC50 values for U87MG and T98G cells were 25 and 8120583Mfor curcumin alone and 0400 and 0225120583M respectively fortreatment with the CD68 antibody-linked curcumin GL261cells were also implanted in the right forebrain of C57BL6mice These mice were treated with intracranial infusionsof 16 pmol CD68 antibody-linked curcumin followed by tailvein infusion of curcumin and resulted in a reduction ofintracranial tumor burden [18]

4 ToxicitySafety

Natural products are of interest as anticancer agents becausethey have been associated with low toxicity profiles Thisallows them to be safely used at high doses or added toexisting regimens Indeed curcumin has been administeredto human subjects at large doses without major side effects[67ndash69] However some data exists that serves to cautionagainst its use Despite being an antioxidant curcumin maylead to a temporary increase in ROS and a decrease incell viability by depletion of glutathione [90] Curcuminmight cause DNA base damage and fragmentation throughcytochrome p450 enzyme generation of a curcumin radicaland lead to apoptotic cell death in healthy as well as tumoraltissues [91] Interestingly this damage was attenuated whencurcumin was present at larger concentrations [92] SimilarDNA damage findings have been noted during in vivo studies[93 94] Curcumin may inhibit the tumor suppressor p53function in colon cancer cells and contribute to tumorige-nesis [95] Administration of curcumin with camptothecinor cyclophosphamide may inhibit their effectiveness thuscareful study of curcumin is warranted prior to its additionto an existing chemotherapy [96]

5 Clinical Data

There are over one hundred clinical trials examining thepotential therapeutic effects of curcumin (Table 1 httpsclinicaltrialsgov) Many of these trials examine the efficacyof curcumin for the treatment of gastrointestinal diseases(eg Cohnrsquos disease ulcerative colitis and inflammatorybowel disease) endocrine disorders (eg diabetes mellitus)neoplasms (breast gastrointestinal cervical lymphoma andpancreatic) immune system diseases (eg atopy multiple


Table 1 Active clinical trials assessing therapeutic benefit of curcumin

Trial Status Site Disease Measure Trial IDlowast

Vascular

Curcumin or placebo Ongoing Lawson Health ResearchInstitute CA AAA Serum creatinine NCT01225094

Curcumin or placebo Ongoing University of ColoradoBoulder USA Vascular aging

Arterial stiffness arterialpulse-wave velocity NOdilation

NCT01968564

Curcumin or placebo Ongoing UPEI CA Vascular stiffnessArterial stiffness bytonometry IL-6 CRPCK

NCT02281981

NeurologicpsychiatricCurcumin with orwithout yoga Recruiting VA Los Angeles USA AD Biomarkers for MCI NCT01811381

Curcumin Recruiting SHSC CA Adolescent bipolardisorder

Mood by CDRS-Rbiomarkers

NCT01928043

Curcumin with othersupplements or placebo Ongoing HCL France Fibromyalgia QOL by GIQLI NCT01469936

Curcumin or placebo Ongoing UCLA USA MCI normal aging Cognitive changes byneuropsych assessment

NCT01383161

Curcumin or placebowith omega-3 fatty acid Invitation only TUMS Iran Migraine HA endothelial factors

inflammationNCT02532023

Curcumin or placebowith IFN-1205731A Ongoing Merck Serono Italy Multiple sclerosis Proportion of subjects

with active T2 lesionsNCT01514370

Curcumin or placebo Recruiting Beersheva MentalHealth Center Israel Schizophrenia Psychotic symptoms

(PANSS)NCT02298985

Curcumin Recruiting VA Los Angeles USA Schizophrenia MCCB NCT02104752

Curcumin or placebo Not yetrecruiting Yale USA Schizophrenia

schizoaffective MCCB NCT02476708

GastrointestinalCurcumin or placebowith thiopurines Recruiting CHU France Crohnrsquos disease Rutgeerts endoscopic

scoreNCT02255370

Curcumin with tripletherapy or triple therapyalone

Not yetrecruiting

Rabin Medical CenterIsrael

Helicobacter pyloriinfection

Eradication by ureabreath test

NCT02018328

Curcumin with seleniumand green tea or placebo Recruiting Meir Medical Center

IsraelIrritable bowelsyndrome QOL by questionnaires NCT01167673

Curcumin or placebo Not yetrecruiting NCI USA MAG andor GIM

Changes in IL-1120573 safetytolerability histologicgrade

NCT02782949

Curcumin or placebo Not yetrecruiting

Schneider ChildrenrsquosMedical Center Israel

Pediatric ulcerativecolitis

Disease activity byPUCAI

NCT02277223

Curcumin or placebowith 5-ASA Recruiting Asian Institute of

Gastroenterology India Ulcerative colitis Time to clinical andendoscopic remission

NCT02683733


Gastroenterology IndiaUlcerative colitis inremission

Percentage of patients inremission

NCT02683759

OncologicCurcumin or placebo Recruiting Emory University USA Breast cancer NF-120581B by ELISA NCT01740323Curcumin at twodifferent doses Recruiting OSU USA Breast cancer obesity Adherence tolerability

safetyNCT01975363

Curcumin or HPR Plusor placebo Recruiting University of Rochester

USANoninflammatorybreast cancer

Mean radiationdermatitis severity

NCT02556632

Curcumin with standardtreatment Recruiting UZ Leuven Belgium Endometrial

carcinomaPeripheral bloodinflammatory markers

NCT02017353


Table 1 Continued


Curcumin Recruiting Baylor ResearchInstitute USA Squamous CIN3 Safety feasibility overall

and pathologic responseNCT02554344

Curcumin and piperine Recruiting Mayo USA Cancer with inflamedureteral stent

AE max tolerable doseoptimal dose

NCT02598726

Curcumin withcholecalciferol Recruiting Case CCC USA CLL or SLL stages

0-II

Overall response rate byNCI-WG (CLL) orCheson (SLL)

NCT02100423

Curcumin Recruiting University HospitalSalzburg Austria

Locally advanced ormetastatic cancer

Safety max tolerabledose tumor response

NCT02138955

Curcumin or placebo Recruiting UPR Puerto Rico FAPTolerability and efficacyby polyp number andsize

NCT00927485

Curcumin or placebo Ongoing NCI USA FAP Laboratory biomarkeranalysis

NCT00641147

Curcumin withanthocyanin extract Recruiting The Hospital Galliera

Italy Colorectal adenoma 120573-Catenin NFk120573 Ki-67p53 by IHCNCT01948661

Curcumin with 5-FU Recruiting Baylor ResearchInstitute USA

Metastatic coloncancer resistant to5-FU

Safety toxicity responsebiomarkers

NCT02724202

Curcumin withFOLFOX or FOLFOXalone

Ongoing University of LeicesterUK

Metastatic colorectalcancer

Tolerable long-termdose safety

NCT01490996

Curcumin withAvastinFOLFIRI

Not yetrecruiting

Gachon University GilMedical Center Korea

Metastatic colorectalcancer PFS NCT02439385

Curcumin withirinotecan Recruiting UNC Lineberger USA Metastatic colorectal

cancerMax tolerated dosepharmacokinetics

NCT01859858

Curcumin or placebowith capecitabine andradiation

Ongoing MD Anderson USA Rectal cancer Pathologic completeresponse rate

NCT00745134

Curcumin or placebowith docetaxel Recruiting Centre Jean Perrin

FranceMetastatic prostatecancer

Time to progressionPSA response

NCT02095717

Curcumin or placebo Recruiting UT Southwestern USA Prostate cancer PSA recurrence freesurvival

NCT02064673

Curcumin or placebowith RT Recruiting SBUMS Iran Prostate cancer Proctitis and cystitis by

CTCAE PSANCT02724618

Curcumin withgemcitabine metforminand paclitaxel

Recruiting City of Hope MedicalCenter USA

Metastatic pancreaticcancer

Feasibility compliancetoxicity survival

NCT02336087

Curcumin withEGFR-TKI Recruiting Lady Davis Institute CA Nonresectable mutant

EGFR NSCLC

Feasibility adherenceAE QOL (FACT-L)CRP

NCT02321293

Other

Curcumin or placebo Recruiting University of ColoradoDenver USA ADPKD

Changes in FMD-BAand aortic pulse-wavevelocity

NCT02494141

Curcumin mouthwash Recruiting Aurora BayCare MedicalCenter USA

Chemotherapyinduced mucositis

AE toxicity painhealing time

NCT02300727

Curcumin or placebo Recruiting Lawson Health ResearchInstitute CA CKD Albuminuria eGFR

IL-18NCT02369549

Curcumin or placebo Recruiting NNFTI Iran DMII Triglyceride and CRPlevels

NCT02529969

Curcumin or placebo Recruiting NNFTI Iran DMII Fasting blood sugarantioxidant capacity

NCT02529982

Curcumin with othernutraceuticals or placebo

Not yetrecruiting IRCCS Neuromed Italy NAFLD ALT AST GGT NCT02369536


Table 1 Continued


Curcumin in Orabase Ongoing SVSIDS India Oral submucousfibrosis

Reduction of lesionnumber of bands NCT02645656

Curcumin Recruiting University of ArizonaUSA Rheumatoid arthritis AE pharmacokinetics

ESR CRP NCT02543931

lowastSource httpswwwclinicaltrialsgov A search performed using the keyword ldquocurcuminrdquo revealed 129 studies Only active studies (48) were included in thetable Clinical trials that were complete (58) were withdrawn (8) were terminated (3) or have unknown status (12) were excludedCA Canada CCC Comprehensive Cancer Center CHU Clermont-Ferrand University Hospital HCL Hospices Civiles de Lyon NCI National CancerInstitute NNFTI National Nutrition and Food Technology Institute OSU Ohio State University SBUMS Shahid Beheshti University of Medical SciencesSHSC Sunnybrook Health Sciences Centre SVSIDS Sri Venkata Sai Institute of Dental Sciences TUMS Tehran University of Medical Sciences UCLAUniversity of California Los Angeles UK United Kingdom UNC University of North Carolina UPEI University of Prince Edward Island UPR University ofPuerto Rico UT University of Texas USA United States of America5-ASA 5-Aminosalicylic Acid 5-FU 5-Fluorouracil AAA Abdominal Aortic AneurysmAD Alzheimerrsquos disease ADPKD Autosomal Dominant Polycystic Kidney Disease AE adverse events ALT Alanine Aminotransferase AST AspartateAminotransferase CDRS-R Childrenrsquos Depression Rating Scale-Revise CIN Cervical Intraepithelial Neoplasia CK Creatine Kinase CKD Chronic KidneyDisease CLL Chronic Lymphocytic Leukemia CRP C-Reactive Protein DMII Diabetes Mellitus Type 2 EGFR epidermal growth factor receptor eGFREstimated Glomerular Filtration Rate ESR Erythrocyte Sedimentation Rate FAP Familial Adenomatous Polyposis FMD-BA Brachial Artery Flow-MediatedDilation FOLFOX Folinic Acid 5-Fluorouracil Oxaliplatin GGT Gamma-Glutamyl Transferase GIM Gastric IntestinalMetaplasia GIQLI GastrointestinalQuality of Life Index HA headache IHC Immunohistochemistry IL Interleukin MAG Multifocal Atrophic Gastritis MCCB MATRICS ConsensusCognitive Battery MCI Mild Cognitive Impairment NCI-WG National Cancer Institute-Working Group NAFLD Nonalcoholic Fatty Liver Disease NF-120581B nuclear factor kappa-light-chain-enhancer of activated B cells NO Nitric Oxide NSCLC Nonsmall Cell Lung Cancer PANSS Positive and NegativeSyndrome Scale PFS Progression Free Survival PSA prostate-specific antigen PUCAI Pediatric Ulcerative Colitis Activity Index QOL quality of life RTRadiotherapy SLL Small Lymphocytic Lymphoma TKI Tyrosine Kinase Inhibitor VA Veterans Affairs

sclerosis and rheumatoid arthritis) and psychiatric disorders(eg Alzheimerrsquos disease schizophrenia cognitive impair-ment and depression) To date no clinical data exist on treat-ment of brain tumors with curcumin despite the vast amountof promising preclinical data A study completed inMay 2013(NCT01712542) examined the bioavailability of curcumin inpatients with GBM but results from this study have not yetbeen made available Other human bioavailability data arediscussed in ldquoDelivery Mechanismsrdquo

6 Conclusion

The use of curcumin for the treatment of CNS tumors needsto be investigated Preclinical data support its use in vitroand in vivo In addition there have been several limitedstudies demonstrating the safety of administration of oralcurcumin in humans Initial efficacy studies might focus onpatients that have progressed on the current standard of careAs discussed previously curcumin may also enhance thecytotoxic capabilities of other chemotherapeutics Data alsoexists to suggest that curcumin might affect tumoral stemcell-like populations [16 46 97]These stem cell-like featuresare found in nestin and CD133 positive cells are associatedwith higher grade and poor prognosis [46 98 99] Addingcurcumin to other chemotherapeutic regimens may aid inslowing or halting growth of these progenitor cells and thustheir tumors Since the administration of curcumin appearsrelatively safe it could be added to current standard of careregimens in early or advanced diseaseThe greatest barrier tothe use of curcumin as a therapeutic is its poor distributionto affected tissues The use of delivery vehicles or curcuminderivatives may increase the efficacy of curcumin further byimproving distribution slowing degradation and improvingtarget specific affinity Since individuals afflicted with braintumors have such poor prognoses there is a dire need to

identify new therapeutic agents As in the case with GBM itis unfortunate that large clinical trials have been undertakenwithout identifying improvements to the standard of care thatwas formulated over 10 years ago [100ndash104] Clinical trialsshould be undertaken to corroborate the benefits of curcuminseen in preclinical studies and improve the prognoses ofindividuals with brain tumors

Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper

References

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[2] S-PWeathers andM R Gilbert ldquoAdvances in treating glioblas-tomardquo F1000Prime Reports vol 6 article 46 2014

[3] R Stupp M E Hegi W P Mason et al ldquoEffects of radio-therapy with concomitant and adjuvant temozolomide versusradiotherapy alone on survival in glioblastoma in a randomisedphase III study 5-year analysis of the EORTC-NCIC trialrdquoTheLancet Oncology vol 10 no 5 pp 459ndash466 2009

[4] R Stupp W P Mason M J Van Den Bent et al ldquoRadiotherapyplus concomitant and adjuvant temozolomide for glioblas-tomardquo The New England Journal of Medicine vol 352 no 10pp 987ndash996 2005

[5] D R Johnson H E Leeper and J H Uhm ldquoGlioblastomasurvival in the United States improved after food and drugadministration approval of bevacizumab a population-basedanalysisrdquo Cancer vol 119 no 19 pp 3489ndash3495 2013

[6] R Stupp S Taillibert A A Kanner et al ldquoMaintenance therapywith tumor-treating fields plus temozolomide vs temozolomide


alone for glioblastoma a randomized clinical trialrdquoThe Journalof the American Medical Association vol 314 no 23 pp 2535ndash2543 2015

[7] B B Aggarwal Y-J Surh and S Shishodia The MolecularTargets andTherapeutic Uses of Curcumin inHealth andDiseaseSpringer 2007

[8] H P T Ammon and M A Wahl ldquoPharmacology of Curcumalongardquo Planta Medica vol 57 no 1 pp 1ndash7 1991

[9] W-H Lee C-Y Loo M Bebawy F Luk R S Mason and RRohanizadeh ldquoCurcumin and its derivatives their applicationin neuropharmacology and neuroscience in the 21st centuryrdquoCurrent Neuropharmacology vol 11 no 4 pp 338ndash378 2013

[10] A Goel A B Kunnumakkara and B B Aggarwal ldquoCurcuminas lsquoCurecuminrsquo from kitchen to clinicrdquo Biochemical Pharmacol-ogy vol 75 no 4 pp 787ndash809 2008

[11] C Schaaf B Shan M Buchfelder et al ldquoCurcumin acts as anti-tumorigenic and hormone-suppressive agent in murine andhuman pituitary tumour cells in vitro and in vivordquo Endocrine-Related Cancer vol 16 no 4 pp 1339ndash1350 2009

[12] MMiller S Chen JWoodliff and S Kansra ldquoCurcumin (difer-uloylmethane) inhibits cell proliferation induces apoptosis anddecreases hormone levels and secretion in pituitary tumor cellsrdquoEndocrinology vol 149 no 8 pp 4158ndash4167 2008

[13] B H Choi C G Kim Y-S Bae Y Lim Y H Lee and SY Shin ldquop21Waf1Cip1 expression by curcumin in U-87MGhuman glioma cells role of early growth response-1 expressionrdquoCancer Research vol 68 no 5 pp 1369ndash1377 2008

[14] 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

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[16] W Zhuang L Long B Zheng et al ldquoCurcumin promotesdifferentiation of glioma-initiating cells by inducing autophagyrdquoCancer Science vol 103 no 4 pp 684ndash690 2012

[17] H Aoki Y Takada S Kondo R Sawaya B B Aggarwal andY Kondo ldquoEvidence that curcumin suppresses the growth ofmalignant gliomas in vitro and in vivo through induction ofautophagy role of Akt and extracellular signal-regulated kinasesignaling pathwaysrdquoMolecular Pharmacology vol 72 no 1 pp29ndash39 2007

[18] P Langone P R Debata J D R Inigo et al ldquoCoupling to aglioblastoma-directed antibody potentiates antitumor activityof curcuminrdquo International Journal of Cancer vol 135 no 3 pp710ndash719 2014

[19] S Purkayastha A Berliner S S Fernando et al ldquoCurcuminblocks brain tumor formationrdquo Brain Research vol 1266 pp130ndash138 2009

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[24] S S Bhandarkar and J L Arbiser ldquoCurcumin as an inhibitor ofangiogenesisrdquo inTheMolecular Targets and Therapeutic Uses ofCurcumin in Health and Disease pp 185ndash195 Springer 2007

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[26] B E Bachmeier A G Nerlich C M Iancu et al ldquoThe chemo-preventive polyphenol curcumin prevents hematogenous breastcancer metastases in immunodeficient micerdquo Cellular Physiol-ogy and Biochemistry vol 19 no 1ndash4 pp 137ndash152 2007

[27] J Ravindran S Prasad and B B Aggarwal ldquoCurcumin andcancer cells how many ways can curry kill tumor cells selec-tivelyrdquoThe AAPS Journal vol 11 no 3 pp 495ndash510 2009

[28] G Sa and T Das ldquoAnti cancer effects of curcumin cycle of lifeand deathrdquo Cell Division vol 3 no 1 article 14 2008

[29] N Hasima and B B Aggarwal ldquoCancer-linked targets modu-lated by curcuminrdquo International Journal of Biochemistry andMolecular Biology vol 3 no 4 pp 328ndash351 2012

[30] P Anand C Sundaram S Jhurani A B Kunnumakkara andB B Aggarwal ldquoCurcumin and cancer an lsquoold-agersquo disease withan lsquoage-oldrsquo solutionrdquo Cancer Letters vol 267 no 1 pp 133ndash1642008

[31] H Hatcher R Planalp J Cho F M Torti and S V TortildquoCurcumin from ancient medicine to current clinical trialsrdquoCellular andMolecular Life Sciences vol 65 no 11 pp 1631ndash16522008

[32] P Rathore P Dohare S Varma et al ldquoCurcuma oil reducesearly accumulation of oxidative product and is anti-apoptogenicin transient focal ischemia in rat brainrdquo NeurochemicalResearch vol 33 no 9 pp 1672ndash1682 2008

[33] J-XWu L-Y Zhang Y-L Chen S-S Yu Y Zhao and J ZhaoldquoCurcumin pretreatment and post-treatment both improve theantioxidative ability of neurons with oxygen-glucose depriva-tionrdquo Neural Regeneration Research vol 10 no 3 pp 481ndash4892015

[34] T Santel G Pflug N Y A Hemdan et al ldquoCurcumin inhibitsglyoxalase 1mdasha possible link to its anti-inflammatory and anti-tumor activityrdquo PLoS ONE vol 3 no 10 Article ID e3508 2008

[35] B Wu H Yao S Wang and R Xu ldquoDAPK1 modulates acurcumin-induced G2M arrest and apoptosis by regulatingSTAT3 NF-120581B and caspase-3 activationrdquo Biochemical andBiophysical Research Communications vol 434 no 1 pp 75ndash802013

[36] E Liu J Wu W Cao et al ldquoCurcumin induces G2M cellcycle arrest in a p53-dependent manner and upregulates ING4expression in human gliomardquo Journal of Neuro-Oncology vol85 no 3 pp 263ndash270 2007

[37] I Garkavtsev S V Kozin O Chernova et al ldquoThe candi-date tumour suppressor protein ING4 regulates brain tumourgrowth and angiogenesisrdquo Nature vol 428 no 6980 pp 328ndash332 2004


[38] Y Qian J Ma X Guo et al ldquoCurcumin enhances the radiosen-sitivity ofU87 cells by inducingDUSP-2 up-regulationrdquoCellularPhysiology and Biochemistry vol 35 no 4 pp 1381ndash1393 2015

[39] B Pauwels A Wouters M Peeters J B Vermorken and FLardon ldquoRole of cell cycle perturbations in the combinationtherapy of chemotherapeutic agents and radiationrdquo FutureOncology vol 6 no 9 pp 1485ndash1496 2010

[40] N Aravindan R Madhusoodhanan S Ahmad D Johnsonand T S Herman ldquoCurcumin inhibits NF120581B mediated radio-protection and modulate apoptosis related genes in humanneuroblastoma cellsrdquo Cancer Biology and Therapy vol 7 no 4pp 569ndash576 2008

[41] A K Khaw M P Hande G Kalthur and M P HandeldquoCurcumin inhibits telomerase and induces telomere shorten-ing and apoptosis in brain tumour cellsrdquo Journal of CellularBiochemistry vol 114 no 6 pp 1257ndash1270 2013

[42] T-Y Huang T-H Tsai C-W Hsu and Y-C Hsu ldquoCur-cuminoids suppress the growth and induce apoptosis throughcaspase-3-dependent pathways in glioblastoma multiforme(GBM) 8401 cellsrdquo Journal of Agricultural and Food Chemistryvol 58 no 19 pp 10639ndash10645 2010

[43] S Karmakar N L Banik and S K Ray ldquoCurcumin sup-pressed anti-apoptotic signals and activated cysteine proteasesfor apoptosis in human malignant glioblastoma U87MG cellsrdquoNeurochemical Research vol 32 no 12 pp 2103ndash2113 2007

[44] DW Davis D J McConkey J L Abbruzzese and R S HerbstldquoSurrogate markers in antiangiogenesis clinical trialsrdquo BritishJournal of Cancer vol 89 no 1 pp 8ndash14 2003

[45] A Zanotto-Filho E Braganhol R Schroder et al ldquoNF120581Binhibitors induce cell death in glioblastomasrdquo BiochemicalPharmacology vol 81 no 3 pp 412ndash424 2011

[46] I Bandey S-H Chiou A-P Huang J-C Tsai and P-H TuldquoProgranulin promotes Temozolomide resistance of glioblas-toma by orchestrating DNA repair and tumor stemnessrdquoOnco-gene vol 34 no 14 pp 1853ndash1864 2015

[47] K M Dhandapani V B Mahesh and D W Brann ldquoCurcuminsuppresses growth and chemoresistance of human glioblastomacells via AP-1 and NF120581B transcription factorsrdquo Journal ofNeurochemistry vol 102 no 2 pp 522ndash538 2007

[48] A Belkaid I B Copland D Massillon and B Annabi ldquoSilenc-ing of the human microsomal glucose-6-phosphate translocaseinduces glioma cell death potential new anticancer target forcurcuminrdquo FEBS Letters vol 580 no 15 pp 3746ndash3752 2006

[49] J Weissenberger M Priester C Bernreuther et al ldquoDietarycurcumin attenuates glioma growth in a syngeneic mousemodel by inhibition of the JAK1 2STAT3 signaling pathwayrdquoClinical Cancer Research vol 16 no 23 pp 5781ndash5795 2010

[50] 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

[51] W-Z Du Y Feng X-F Wang et al ldquoCurcumin suppressesmalignant glioma cells growth and induces apoptosis by inhi-bition of SHHGLI1 signaling pathway in vitro and vivordquo CNSNeuroscience ampTherapeutics vol 19 no 12 pp 926ndash936 2013

[52] M He Y Li L Zhang et al ldquoCurcumin suppresses cell pro-liferation through inhibition of the Wnt120573-catenin signalingpathway in medulloblastomardquo Oncology Reports vol 32 no 1pp 173ndash180 2014

[53] S J Lee C Krauthauser V Maduskuie P T Fawcett J MOlson and S A Rajasekaran ldquoCurcumin-induced HDAC

inhibition and attenuation of medulloblastoma growth in vitroand in vivordquo BMC Cancer vol 11 article 114 2011

[54] N A AThani B Sallis R Nuttall et al ldquoInduction of apoptosisand reduction of MMP gene expression in the U373 cell lineby polyphenolics in Aronia melanocarpa and by curcuminrdquoOncology Reports vol 28 no 4 pp 1435ndash1442 2012

[55] K Tsunoda G Kitange T Anda et al ldquoExpression of the con-stitutively activated RelANF-120581B in human astrocytic tumorsand the in vitro implication in the regulation of urokinase-typeplasminogen activator migration and invasionrdquo Brain TumorPathology vol 22 no 2 pp 79ndash87 2005

[56] B Shan C Schaaf A Schmidt et al ldquoCurcumin suppressesHIF1A synthesis and VEGFA release in pituitary adenomasrdquoJournal of Endocrinology vol 214 no 3 pp 389ndash398 2012

[57] A Zanotto-Filho E Braganhol M I Edelweiss et al ldquoThecurry spice curcumin selectively inhibits cancer cells growth invitro and in preclinical model of glioblastomardquo The Journal ofNutritional Biochemistry vol 23 no 6 pp 591ndash601 2012

[58] C Ramachandran S M Nair E Escalon and S J MelnickldquoPotentiation of etoposide and temozolomide cytotoxicity bycurcumin and turmeric force in brain tumor cell linesrdquoJournal of Complementary and Integrative Medicine vol 9 no1 article 20 2012

[59] M M Hossain N L Banik and S K Ray ldquoSynergistic anti-cancer mechanisms of curcumin and paclitaxel for growthinhibition of human brain tumor stem cells and LN18 andU138MG cellsrdquo Neurochemistry International vol 61 no 7 pp1102ndash1113 2012

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[61] I Zhang Y Cui A Amiri Y Ding R E Campbell and DMaysinger ldquoPharmacological inhibition of lipid droplet forma-tion enhances the effectiveness of curcumin in glioblastomardquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol100 pp 66ndash76 2016

[62] P M Luthra R Kumar and A Prakash ldquoDemethoxycurcumininduces Bcl-2 mediated G2M arrest and apoptosis in humanglioma U87 cellsrdquo Biochemical and Biophysical Research Com-munications vol 384 no 4 pp 420ndash425 2009

[63] T-Y Huang C-W Hsu W-C Chang M-Y Wang J-F Wuand Y-C Hsu ldquoDemethoxycurcumin retards cell growth andinduces apoptosis in human brain malignant glioma GBM8401 cellsrdquo Evidence-Based Complementary and AlternativeMedicine vol 2012 Article ID 396573 11 pages 2012

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[66] B S Patil G K Jayaprakasha K N Chidambara Murthyand A Vikram ldquoBioactive compounds historical perspectivesopportunities and challengesrdquo Journal of Agricultural and FoodChemistry vol 57 no 18 pp 8142ndash8160 2009

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[68] A-L Chen C-H Hsu J-K Lin et al ldquoPhase I clinical trial ofcurcumin a chemopreventive agent in patients with high-riskor pre-malignant lesionsrdquoAnticancer Research vol 21 no 4 pp2895ndash2900 2001

[69] 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

[70] C K Atal R K Dubey and J Singh ldquoBiochemical basisof enhanced drug bioavailability by piperine evidence thatpiperine is a potent inhibitor of drug metabolismrdquo Journal ofPharmacology and ExperimentalTherapeutics vol 232 no 1 pp258ndash262 1985

[71] C K Atal U Zutshi and P G Rao ldquoScientific evidence on therole of Ayurvedic herbals on bioavailability of drugsrdquo Journal ofEthnopharmacology vol 4 no 2 pp 229ndash232 1981

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

[73] R S Mulik J Monkkonen R O Juvonen K R Mahadik andA R Paradkar ldquoApoE3 mediated polymeric nanoparticlescontaining curcumin apoptosis induced in vitro anticanceractivity against neuroblastoma cellsrdquo International Journal ofPharmaceutics vol 437 no 1-2 pp 29ndash41 2012

[74] YChen L PanM JiangD Li andL Jin ldquoNanostructured lipidcarriers enhance the bioavailability and brain cancer inhibitoryefficacy of curcumin both in vitro and in vivordquo Drug Deliveryvol 23 no 4 pp 1383ndash1392 2016

[75] M TMirgani B IsacchiM Sadeghizadeh et al ldquoDendrosomalcurcumin nanoformulation downregulates pluripotency genesvia miR-145 activation in U87MG glioblastoma cellsrdquo Interna-tional Journal of Nanomedicine vol 9 no 1 pp 403ndash417 2014

[76] E Babaei M Sadeghizadeh Z M Hassan M A H Feizi FNajafi and S M Hashemi ldquoDendrosomal curcumin signifi-cantly suppresses cancer cell proliferation in vitro and in vivordquoInternational Immunopharmacology vol 12 no 1 pp 226ndash2342012

[77] V Erfani-Moghadam A Nomani M Zamani Y YazdaniF Najafi and M Sadeghizadeh ldquoA novel diblock copolymerof (monomethoxy poly [ethylene glycol]-oleate) with a smallhydrophobic fraction to make stable micellespolymersomesfor curcumin delivery to cancer cellsrdquo International Journal ofNanomedicine vol 9 no 1 pp 5541ndash5554 2014

[78] X Zhuang X Xiang W Grizzle et al ldquoTreatment of braininflammatory diseases by delivering exosome encapsulatedanti-inflammatory drugs from the nasal region to the brainrdquoMolecular Therapy vol 19 no 10 pp 1769ndash1779 2011

[79] R G Madane and H S Mahajan ldquoCurcumin-loaded nanos-tructured lipid carriers (NLCs) for nasal administration designcharacterization and in vivo studyrdquo Drug Delivery vol 23 no4 pp 1326ndash1334 2016

[80] B Farhangi A M Alizadeh H Khodayari et al ldquoProtectiveeffects of dendrosomal curcumin on an animalmetastatic breasttumorrdquoEuropean Journal of Pharmacology vol 758 pp 188ndash1962015

[81] Z-J Sun B Sun R-B Tao X Xie X-L Lu and D-L Dong ldquoApoly(glycerol-sebacate-curcumin) polymer with potential usefor brain gliomasrdquo Journal of BiomedicalMaterials Research PartA vol 101 no 1 pp 253ndash260 2013

[82] G Guo S Fu L Zhou et al ldquoPreparation of curcumin loadedpoly(120576-caprolactone)-poly(ethylene glycol)-poly(120576-caprolacto-ne) nanofibers and their in vitro antitumor activity againstGlioma 9L cellsrdquo Nanoscale vol 3 no 9 pp 3825ndash3832 2011

[83] R C Gupta S S Bansal F Aqil et al ldquoControlled-releasesystemic deliverymdasha new concept in cancer chemopreventionrdquoCarcinogenesis vol 33 no 8 pp 1608ndash1615 2012

[84] K Shahani S K Swaminathan D Freeman A Blum L Maand J Panyam ldquoInjectable sustained release microparticles ofcurcumin a new concept for cancer chemopreventionrdquo CancerResearch vol 70 no 11 pp 4443ndash4452 2010

[85] S Bisht M Mizuma G Feldmann et al ldquoSystemic admin-istration of polymeric nanoparticle-encapsulated curcumin(NanoCurc) blocks tumor growth and metastases in preclinicalmodels of pancreatic cancerrdquo Molecular Cancer Therapeuticsvol 9 no 8 pp 2255ndash2264 2010

[86] K J Lim S Bisht E E Bar A Maitra and C G EberhartldquoA polymeric nanoparticle formulation of curcumin inhibitsgrowth clonogenicity and stem-like fraction inmalignant braintumorsrdquo Cancer Biology amp Therapy vol 11 no 5 pp 464ndash4732011

[87] F Dilnawaz and S K Sahoo ldquoEnhanced accumulation of cur-cumin and temozolomide loaded magnetic nanoparticlesexecutes profound cytotoxic effect in glioblastoma spheroidmodelrdquo European Journal of Pharmaceutics and Biopharmaceu-tics vol 85 no 3 pp 452ndash462 2013

[88] J-H Fang Y-H Lai T-L Chiu Y-Y Chen S-H Hu and S-YChen ldquoMagnetic corendashshell nanocapsules with dual-targetingcapabilities and co-delivery of multiple drugs to treat braingliomasrdquoAdvanced Healthcare Materials vol 3 no 8 pp 1250ndash1260 2014

[89] P Langone P R Debata S Dolai et al ldquoCoupling to a cancercell-specific antibody potentiates tumoricidal properties ofcurcuminrdquo International Journal of Cancer vol 131 no 4 ppE569ndashE578 2012

[90] E-M Strasser B Wessner N Manhart and E Roth ldquoTherelationship between the anti-inflammatory effects of curcuminand cellular glutathione content in myelomonocytic cellsrdquoBiochemical Pharmacology vol 70 no 4 pp 552ndash559 2005

[91] M Yoshino M Haneda M Naruse et al ldquoProoxidant activityof curcumin copper-dependent formation of 8-hydroxy-21015840-deoxyguanosine in DNA and induction of apoptotic cell deathrdquoToxicology in Vitro vol 18 no 6 pp 783ndash789 2004

[92] K Sakano and S Kawanishi ldquoMetal-mediated DNA damageinduced by curcumin in the presence of human cytochromeP450 isozymesrdquo Archives of Biochemistry and Biophysics vol405 no 2 pp 223ndash230 2002

[93] J Nair S Strand N Frank et al ldquoApoptosis and age-dependantinduction of nuclear and mitochondrial etheno-DNA adductsin Long-Evans Cinnamon (LEC) rats enhanced DNA damageby dietary curcumin upon copper accumulationrdquo Carcinogene-sis vol 26 no 7 pp 1307ndash1315 2005

[94] N Frank J Knauft F Amelung J Nair H Wesch and HBartsch ldquoNo prevention of liver and kidney tumors in Long-Evans Cinnamon rats by dietary curcumin but inhibition atother sites and of metastasesrdquoMutation ResearchFundamentalandMolecularMechanisms ofMutagenesis vol 523-524 pp 127ndash135 2003

[95] P J Moos K Edes J E Mullally and F A Fitzpatrick ldquoCur-cumin impairs tumor suppressor p53 function in colon cancercellsrdquo Carcinogenesis vol 25 no 9 pp 1611ndash1617 2004


[96] S Somasundaram N A Edmund D T Moore G W SmallY Y Shi and R Z Orlowski ldquoDietary curcumin inhibitschemotherapy-induced apoptosis in models of human breastcancerrdquo Cancer Research vol 62 no 13 pp 3868ndash3875 2002

[97] D Fong A Yeh R Naftalovich T H Choi and M M ChanldquoCurcumin inhibits the side population (SP) phenotype of therat C6 glioma cell line towards targeting of cancer stem cellswith phytochemicalsrdquo Cancer Letters vol 293 no 1 pp 65ndash722010

[98] R Galli E Binda U Orfanelli et al ldquoIsolation and characteri-zation of tumorigenic stem-like neural precursors from humanglioblastomardquo Cancer Research vol 64 no 19 pp 7011ndash70212004

[99] M Zhang T Song L Yang et al ldquoNestin and CD133 valuablestem cell-specific markers for determining clinical outcome ofglioma patientsrdquo Journal of Experimental amp Clinical CancerResearch vol 27 no 1 article 85 1 page 2008

[100] MRGilbert J J DignamT S Armstrong et al ldquoA randomizedtrial of bevacizumab for newly diagnosed glioblastomardquo TheNew England Journal of Medicine vol 370 no 8 pp 699ndash7082014

[101] M R Gilbert M Wang K D Aldape et al ldquoDose-densetemozolomide for newly diagnosed glioblastoma a randomizedphase III clinical trialrdquo Journal of Clinical Oncology vol 31 no32 pp 4085ndash4091 2013

[102] O L Chinot W Wick W Mason et al ldquoBevacizumab plusradiotherapyndashtemozolomide for newly diagnosed glioblas-tomardquoThe New England Journal of Medicine vol 370 no 8 pp709ndash722 2014

[103] M Westphal O Heese J P Steinbach et al ldquoA randomisedopen label phase III trial with nimotuzumab an anti-epidermalgrowth factor receptor monoclonal antibody in the treatmentof newly diagnosed adult glioblastomardquo European Journal ofCancer vol 51 no 4 pp 522ndash532 2015

[104] R Stupp M E Hegi T Gorlia et al ldquoCilengitide combinedwith standard treatment for patients with newly diagnosedglioblastoma with methylated MGMT promoter (CENTRICEORTC 26071-22072 study) a multicentre randomised open-label phase 3 trialrdquoTheLancetOncology vol 15 no 10 pp 1100ndash1108 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


Curcuma longa Curcumin

Enol form

Keto form

Demethoxycurcumin

Bisdemethoxycurcumin

OH

OH

HO

O

O

O

CH3CH3

OH

O

HO

O

O

O

CH3CH3

OH

O

HO

O

O

CH3

OH

O

HO

O

(a) (b)

Figure 1 (a) Curcuma longa from Koehlerrsquos Medicinal Plants 1887 (b) From top to bottom curcumin in its enol form curcumin in its ketoform demethoxycurcumin and bisdemethoxycurcumin

2 Mechanism and Preclinical Data

Curcuminrsquos effects on glioma cells in vitro and in vivo havebeen well studied Curcumin has many molecular targets(Figure 2) and therefore diverse and complex mechanisms ofactionThe antitumoral effects of curcumin are thought to actthrough many different signaling pathways such as cellularproliferation [11ndash13] apoptosis [11 12 14] autophagy [15ndash17]angiogenesis [18ndash20] immunomodulation [21] invasion [1422 23] and metastasis [24ndash26] These pathways have beenreviewed comprehensively elsewhere [27ndash31] In addition toits effectiveness as an antineoplastic curcumin has beenfound to be protective against reactive oxygen species (ROS)A study by Rathore et al [32] examined the effects of curcumaoil on a transient ischemiamodel in Sprague-Dawley ratsThemiddle cerebral artery was occluded using a nylon filamentfor twohours followed by a 24-hour reflowperiod Treatmentwith curcuma oil reduced the size of infarcted cerebral tissueimproved neurologic function and reduced oxidative stresscaused during the reperfusion period The authors reportedthat these protective effects were obtained by inhibition ofROS reducing peroxynitrite levels and caspase-3 activity andpreventing destabilization of the mitochondrial membranepotential [32] In an in vitro model of ischemia-reperfusionusing rat cortical neurons curcumin was found to protectneurons from death caused by oxygen and glucose depri-vation The authors of this study suggested that curcuminactivates an antioxidant protein thioredoxin in the Nrf2pathway [33] In addition curcumin may inhibit cellularglyoxalases leading to decreased ATP and glutathione which

can impact cellular metabolism and may account for some ofits anti-inflammatory and antitumor effects [34]

21 Curcumin Induces G2MCell Cycle Arrest There is a bevyof data to suggest that curcumin is able to induce G2Mcell cycle arrest and apoptosis More recent work has triedto explain how this cell cycle arrest can occur Wu et alpublished a study in 2013 [35] that suggests that this mightbe due to increased DAPK1 expression The authors treatedthe U251 GBM cell line with curcumin and found a dose-dependent increase in DAPK1 mRNA by real-time RT-PCRand verified a corresponding increase in protein expressionby western blot analysis Further they used siRNA (si-DAPK1-1 and si-DAPK1-2) transfection to suppress DAPK1and found that curcuminhad an attenuated ability to suppressSTAT3 and NF-120581B phosphorylation They also showed thattheir knockdown of DAPK1 inhibited curcumin-mediatedcaspase-3 activation and led to decreased apoptosis (330apoptotic cells versus 583 in their control) [35] Thesefindings suggest that DAPK1 plays an important role incurcumin-mediated cell death Other studies in U251 GBMcells show that p53 expression is upregulated by curcumintreatment as were CDKi p21Waf1Cip1 (p21) and ING4mdasha tumor suppressor gene that has been found to be sup-pressed in gliomas [36 37] Curcumin owes part of itsantiproliferative effects to suppression of cyclin D1 and toinduction of p21 In a study that treated U87 GBM cells withcurcumin transcription factor Egr-1 was found to activatetranscription of p21 independent of p53 activation Egr-1expression was reportedly induced by curcumin via ERK


Initiation




Invasion


Angiogenesis


ResistanceABCG2MRPs

Inflammation


S

M Proliferation


G1G2































4 ToxicitySafety


5 Clinical Data





Vascular




NCT01968564


NCT02281981




NCT01928043



NCT01383161






(PANSS)NCT02298985





scoreNCT02255370


Not yetrecruiting




NCT02018328





NCT02782949





NCT02277223



NCT02683733




NCT02683759


safetyNCT01975363




NCT02556632



NCT02017353


Table 1 Continued






NCT02598726


0-II


NCT02100423




NCT02138955


NCT00927485


NCT00641147






NCT02724202





NCT01490996


Not yetrecruiting





NCT01859858



NCT00745134




NCT02095717


NCT02064673







NCT02336087


EGFR NSCLC


NCT02321293

Other



NCT02494141




NCT02300727


IL-18NCT02369549


NCT02529969


NCT02529982




Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Initiation




Invasion


Angiogenesis


ResistanceABCG2MRPs

Inflammation


S

M Proliferation


G1G2































4 ToxicitySafety


5 Clinical Data





Vascular




NCT01968564


NCT02281981




NCT01928043



NCT01383161






(PANSS)NCT02298985





scoreNCT02255370


Not yetrecruiting




NCT02018328





NCT02782949





NCT02277223



NCT02683733




NCT02683759


safetyNCT01975363




NCT02556632



NCT02017353


Table 1 Continued






NCT02598726


0-II


NCT02100423




NCT02138955


NCT00927485


NCT00641147






NCT02724202





NCT01490996


Not yetrecruiting





NCT01859858



NCT00745134




NCT02095717


NCT02064673







NCT02336087


EGFR NSCLC


NCT02321293

Other



NCT02494141




NCT02300727


IL-18NCT02369549


NCT02529969


NCT02529982




Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































4 ToxicitySafety


5 Clinical Data





Vascular




NCT01968564


NCT02281981




NCT01928043



NCT01383161






(PANSS)NCT02298985





scoreNCT02255370


Not yetrecruiting




NCT02018328





NCT02782949





NCT02277223



NCT02683733




NCT02683759


safetyNCT01975363




NCT02556632



NCT02017353


Table 1 Continued






NCT02598726


0-II


NCT02100423




NCT02138955


NCT00927485


NCT00641147






NCT02724202





NCT01490996


Not yetrecruiting





NCT01859858



NCT00745134




NCT02095717


NCT02064673







NCT02336087


EGFR NSCLC


NCT02321293

Other



NCT02494141




NCT02300727


IL-18NCT02369549


NCT02529969


NCT02529982




Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Vascular




NCT01968564


NCT02281981




NCT01928043



NCT01383161






(PANSS)NCT02298985





scoreNCT02255370


Not yetrecruiting




NCT02018328





NCT02782949





NCT02277223



NCT02683733




NCT02683759


safetyNCT01975363




NCT02556632



NCT02017353


Table 1 Continued






NCT02598726


0-II


NCT02100423




NCT02138955


NCT00927485


NCT00641147






NCT02724202





NCT01490996


Not yetrecruiting





NCT01859858



NCT00745134




NCT02095717


NCT02064673







NCT02336087


EGFR NSCLC


NCT02321293

Other



NCT02494141




NCT02300727


IL-18NCT02369549


NCT02529969


NCT02529982




Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued






NCT02598726


0-II


NCT02100423




NCT02138955


NCT00927485


NCT00641147






NCT02724202





NCT01490996


Not yetrecruiting





NCT01859858



NCT00745134




NCT02095717


NCT02064673







NCT02336087


EGFR NSCLC


NCT02321293

Other



NCT02494141




NCT02300727


IL-18NCT02369549


NCT02529969


NCT02529982




Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued





ESR CRP NCT02543931



6 Conclusion



Competing Interests


References





















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article therapeutic potential of curcumin for the...

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