Curcumin, a component of turmeric: from farm to pharmacyCurcumin, a component of turmeric: From farm Subash C. GuptaGorkem Kismali Bharat B. Aggarwal* Cytokine Research Laboratory, Department of Experimental Therapeutics,The University of Texas MD Anderson Cancer Center, Houston, TX,USA Curcumin, an active polyphenol of the golden spice turmeric, chronic diseases. Multiple studies have indicated the safety is a highly pleiotropic molecule with the potential to modulate and efficacy of curcumin in numerous animals including the biological activity of a number of signaling molecules. Tra- rodents, monkeys, horses, rabbits, and cats and have pro- ditionally, this polyphenol has been used in Asian countries to vided a solid basis for evaluating its safety and efficacy in treat such human ailments as acne, psoriasis, dermatitis, and humans. To date, more than 65 human clinical trials of curcu- rash. Recent studies have indicated that curcumin can target min, which included more than 1000 patients, have been com- newly identified signaling pathways including those associ- pleted, and as many as 35 clinical trials are underway.
ated with microRNA, cancer stem cells, and autophagy. Exten- Curcumin is now used as a supplement in several countries including the United States, India, Japan, Korea, Thailand, delineated the molecular basis for the pharmaceutical uses of China, Turkey, South Africa, Nepal, and Pakistan. In this this polyphenol against cancer, pulmonary diseases, neurolog- review, we provide evidence for the pharmaceutical uses of ical diseases, liver diseases, metabolic diseases, autoimmune curcumin for various diseases. V C 2013 BioFactors, 00(00):000– Keywords: autophagy; cancer stem cells; curcumin; microRNA potential therapeutics for most chronic diseases because oftheir safety, affordability, long-term use, and ability to target Since ancient times, natural agents derived from fruits, vegeta- multiple cell signaling pathways . Curcumin is one such bles, spices, legumes, and cereals have been preferred as agent that was described about two centuries ago as the Abbreviations: ACF, aberrant crypt foci; AKT, AKT8 virus oncogene cellular homolog; ALDH, aldehyde dehydrogenase; AML, acute myeloid leukemia;AP-1, activator protein-1; Atgs, autophagy-related genes; Bcl-2, B-cell lymphoma-2; CAM, chorionallantoic membrane; CDF, difluorinated-curcumin; CML,chronic myelogenous leukemia; CSC, cancer stem cell; Erbb3, erythoblastic leukemia viral oncogene homolog 3; ERK, extracellular signal-regulated ki-nase; ESR1, estrogen receptor 1; EZH2, enhancer of zeste homologue 2; FOLFOX, 5-Fluorouracil plus oxaliplatin; GSH, glutathione; GSH-Px, glutathioneperoxidase; GSK-3b, glycogen synthase kinase-3b; GST, glutathione S-transferase; HAT, histone acetyltransferase; HIV, human immunodeficiency virus;IGF, insulin-like growth factor; IKKb, IkappaB kinase beta; IL, interleukin; LC3, microtubule-associated protein 1 light chain 3; MDA, malondialdehyde;miRNA, microRNA; MT1-MMP, membrane type-1 matrix metalloproteinase; mTOR, mammalian target of rapamycin; NB-UVB, narrowband ultraviolet B;NF-jB, nuclear factor kappa-light-chain-enhancer of activated B cells; OncomiRs, oncogenic microRNAs; p70S6K, p70 ribosomal protein S6 kinase;Pdcd4, programmed cell death protein 4; PhK, phosphorylase kinase; PI3K, phosphoinositide 3-kinase; PPAR-c, peroxisome proliferator-activated recep-tor-gamma; PSA, prostate specific antigen; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; Sp1, specificity protein 1; STAT3,signal transducers and activators of transcription protein 3; TGF-b, transforming growth factor beta; TNF-a, tumor necrosis factor-a; VCAM1, vascular celladhesion molecule 1; Wnt, wint; WT1, wilms' tumor 1 2013 International Union of Biochemistry and Molecular Biology, Inc.
Volume 000, Number 000, Month/Month 2013, Pages 000-000 *Address for correspondence to: Bharat B. Aggarwal, Ph.D., Cytokine Research Laboratory, Department of Experimental Therapeutics, The University ofTexas MD Anderson Cancer Center, Houston, TX. Tel.: 713-794-1817; Fax: 713-745-6339; E-mail: firstname.lastname@example.org.
Received October 2012; accepted 4 December 2012 DOI: 10.1002/biof.1079 Published online in Wiley Online Library (wileyonlinelibrary.com)
Various curcumin-based products being marketed in various countries. These preparations include, but are not limited to, cap- sules, tablets, ointments, energy drinks, soaps, and cosmetics.
‘‘yellow coloring-matter'' from the rhizomes of Curcuma longa evidence that whole turmeric may exhibit superior activities (turmeric) . Traditionally, turmeric has been used to flavor compared with curcumin alone.
food preparations, especially in South Asian cuisine . In Curcumin is a highly pleiotropic molecule with the poten- Asian medicines, curcumin has been used for the treatment of tial to modulate the biological activity of a number of signaling acne, psoriasis, dermatitis, and diaper rash .
molecules . Chemically, pure curcumin is a diferuloyl Besides curcumin, more than 300 different components, methane molecule (1,7-bis (4-hydroxy-3-methoxyphenol)-1,6- including phenolics and terpenoids, have been identified in heptadiene-3,5-dione) containing two ferulic acid residues turmeric [5,6]. Although curcumin is one of the major compo- joined by a methylene bridge. However, commercially avail- nents, research during the past decade has revealed that some able curcumin also contains approximately 17% demethoxy- of the activities of turmeric are independent of curcumin. For curcumin and 3% bisdemethoxycurcumin. Curcumin is now instance, curcumin-free aqueous turmeric extract suppressed marketed in several countries including the United States, benzo[a]pyrene-induced tumorigenesis in mice . Curcumin- India, Japan, Korea, Thailand, China, Turkey, South Africa, free turmeric also inhibited 7,12-dimethylbenz(a)anthracene- Nepal, and Pakistan in the form of capsules, tablets, ointments, induced mammary tumorigenesis in rats . Studies from our energy drinks, soaps, and cosmetics (Fig. 1). Curcumin has laboratory using cell-based assays have indicated that curcu- shown efficacy against a number of human ailments; more min is less potent than turmeric containing equivalent than 65 human clinical trials of curcumin have been com- amounts of curcumin in inhibiting cancer growth . Likewise, pleted, and more than 35 other clinical trials are under way to whole turmeric had higher peroxisome proliferator-activated further evaluate its efficacy. How a single molecule can receptor-gamma (PPAR-c) ligand binding activity than did pure possess such diverse activities has been an enigma over the curcumin . Turmeric was also more effective than curcu- years; however, studies have indicated that bis-a, b-unsatu- min in suppressing streptozotocin-induced diabetic cataracts rated b-diketone, two methoxy groups, two phenolic hydroxy in rats  and in reducing blood glucose levels in type 2 dia- groups, and two double-conjugated bonds may contribute to betic KK-A mice . Overall, these studies provide sufficient the biological activities of curcumin . Furthermore, recent Emerging Roles of Curcumin studies have indicated that curcumin can target numerous expression . Curcumin mediated up-regulation of miRNA- newly identified signaling pathways including those associated 22 suppressed the expression of its target genes specificity with microRNA (miRNA), cancer stem cells (CSCs), and autoph- protein 1 (Sp1) transcription factor and estrogen receptor 1 agy. In the following sections, we provide evidence for the (ESR1). Furthermore, inhibition of miRNA-22 by anti-sense oli- pharmaceutical uses of curcumin from both preclinical and gonucleotide enhanced Sp1 and ESR1 expression, suggesting clinical studies; we also discuss the newly identified signaling that Sp1 and ESR1 are the target genes of miRNA-22. Authors pathways modulated by curcumin.
of this study speculated that modulation of miRNA expressionmay be an important mechanism by which curcumin mediatesits effects on cell growth and apoptosis. However, the role of 2. Pharmaceutical Uses of Curcumin miRNA in the anti-growth and anti-apoptotic effects of curcu-min was not demonstrated experimentally.
2.1. In Vitro Preclinical Studies Zhang et al.  reported that curcumin can induce apo- Studies from cell-based models have indicated the pleiotropic ptosis in A549 cells through down-regulation of miRNA-186. In nature of curcumin. At the molecular level, curcumin has been a subsequent study, the group found that silencing miRNA-186 shown to modulate numerous signaling molecules either promoted apoptosis whereas overexpressing miRNA-186 signifi- directly by binding to them or indirectly by modulating the cantly inhibited curcumin-induced apoptosis in multidrug-resist- expression of other proteins. The indirect targets of curcumin ant human lung adenocarcinoma cells . MicroRNA-21 is include transcription factors, enzymes, growth factors, recep- overexpressed in many tumors and has been associated with tors, inflammatory mediators, protein kinases, drug resistance tumor progression. In one study, the potential of curcumin in proteins, adhesion molecules, cell-survival proteins, chemo- regulating miRNA-21, tumor growth, invasion, and in vivo me- kines and chemokine receptors, invasive and angiogenic pro- tastasis in colorectal cancer was investigated . Curcumin teins, and cell-cycle regulatory proteins . Curcumin, treatment reduced miRNA-21 promoter activity and expression through its a-, b-unsaturated b-diketone moiety, carbonyl and in a dose-dependent manner by inhibiting activator protein-1 enolic groups of the b-diketone moiety, methoxy and phenolic (AP-1) binding to the promoter and inducing the expression of hydroxyl groups, and phenyl rings, has been shown to directly the tumor suppressor programmed cell death protein 4 (Pdcd4).
interact with numerous signaling molecules. More specifically, Treatment of Rko and HCT116 cells with curcumin was associ- this polyphenol has been shown to directly interact with protein ated with cell cycle arrest in the G2/M phase. Curcumin also kinases, protein reductases, histone acetyltransferase (HAT), inhibited tumor growth, invasion, and in vivo metastasis in the histone deacetylase, sarcoplasmic (endoplasmic) reticulum Ca2þ chicken-embryo-metastasis chorionallantoic membrane (CAM) ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier assay. Curcumin significantly inhibited miRNA-21 expression in proteins, inflammatory molecules, cell survival proteins, glyoxa- primary tumors generated in vivo in the CAM assay by Rko and lase I, xanthine oxidase, proteasome, human immunodeficiency HCT116 cells. The authors of this study concluded that curcu- virus (HIV) 1 integrase, HIV1 protease, and metal ions. Curcu- min inhibits the transcriptional regulation of miRNA-21 via AP- min can also bind directly to DNA and RNA . For the com- 1; suppresses cell proliferation, tumor growth, invasion, and in plete list of curcumin's molecular targets, please see articles vivo metastasis; and stabilizes expression of the tumor suppres- that we and others have published [14–17,12]. In this section, sor Pdcd4 in colorectal cancer .
we discuss newer targets of curcumin associated with miRNA, Although curcumin has shown promise as an anticancer CSCs, and autophagy pathways (Table 1).
agent, the poor bioavailability of this polyphenol limits its use inthis capacity. Difluorinated-curcumin (CDF), an analogue of cur- 2.1.1. Curcumin and miRNA.
cumin, has been shown to possess enhanced bioavailability com- MicroRNAs are small (22 nucleotides), endogenous, single- pared with curcumin in pancreatic tissues [23,24]. Previous stranded noncoding RNAs that negatively regulate gene studies have shown an association between attenuated expres- expression by binding to the 30 untranslated region of target sion of miRNA-200 [25,26], increased expression of miRNA-21 mRNA and inducing mRNA degradation or inhibiting transla- [27–31], and aggressiveness of numerous tumors. Therefore, up- tion . MicroRNAs play crucial roles during normal physio- regulating miRNA-200 and down-regulating miRNA-21 might be logical processes and may possess both oncogenic and tumor potentially useful to overcome resistance of cancer cells to can- suppressor activities. Extensive research throughout the past cer therapeutics. In one study, CDF was found to up-regulate two decades has indicated that miRNAs could regulate various miRNA-200b and miRNA-200c and to down-regulate miRNA-21 stages in tumorigenesis and thus represent an attractive target in both gemcitabine-sensitive (BxPC-3) and gemcitabine-resist- for cancer chemoprevention. Curcumin has been shown to al- ant (MIAPaCa-E and MIAPaCa-M) cell lines, which were associ- ter the expression of miRNAs, which may lead to either abro- ated with induction of apoptosis . Furthermore, the combi- gation of tumor growth or sensitization of cancer cells to che- nation of CDF with gemcitabine was found to be much more motherapeutic agents. For instance, in human pancreatic effective than was either agent alone, suggesting that CDF-medi- cancer cells, curcumin treatment was associated with up-regu- ated alterations in specific miRNAs could be a novel approach lation in miRNA-22 and down-regulation in miRNA-199a for the treatment of patients with pancreatic cancer.
MicroRNA targets of curcumin. Curcumin down-regulates oncogenic microRNA and up-regulates tumor suppressive microRNA.
The targets shown in orange are up-regulated (:) whereas those in blue are down-regulated (;) by curcumin.
The loss of expression of miRNA-200a, -200b, and -200c In MCF-7 breast cancer cells, curcumin was found to up- in chemoresistant pancreatic cancer cells BxPC-3, MIAPaCa-2, regulate the expression of miRNA-15a and miRNA-16 and to and MIAPaCa-2-GR has been associated with loss of phospha- down-regulate B-cell lymphoma-2 (Bcl-2) expression .
tase and tensin homolog (PTEN) and overexpression of mem- Furthermore, silencing miRNA-15a and miRNA-16 by specific brane type-1 matrix metalloproteinase (MT1-MMP). Because inhibitors restored the expression of Bcl-2, thus suggesting overexpression of MT1-MMP and loss of PTEN contribute to that curcumin suppresses Bcl-2 expression in MCF-7 cells aggressive behavior in tumor cells, agents with the potential to through up-regulation of miRNA-15a and miRNA-16. In Y79 up-regulate expression of miRNA-200a, -200b, and -200c may retinoblastoma cells, curcumin up-regulated tumor-suppressor have potential as cancer therapeutics. In one study, CDF was miR-22 . Transfection of Y79 cells with miR-22 was found found to significantly up-regulate miRNA-200 and PTEN while to inhibit the cell proliferation and reduced the migration of significantly down-regulating expression of MT1-MMP .
retinoblastoma cells. Furthermore, erythoblastic leukemia vi- Furthermore, forced overexpression or silencing of miR-200c, ral oncogene homolog 3 (Erbb3) was found to be the target followed by CDF treatment of MIAPaCa-2 cells, altered the gene of miR-22. In esophageal cancer cells, curcumin was morphology of the cells, colony formation, and the expression of MT1-MMP and PTEN. The authors of this study suggested miRNA-34a and to up-regulate tumor suppressor let-7a that CDF could be useful as a therapeutic agent against pan- miRNA in association with inhibition of proliferation of tumor creatic cancer .
In another study, CDF was found to induce let-7 and A high level of Wilms' tumor 1 (WT1), an oncogene that is miRNA-143 and to down-regulate miRNA-21 expression, con- detected in most cases of human acute myeloid leukemia sistent with the attenuation of Ras expression and its activity in (AML) and chronic myelogenous leukemia (CML), is associated pancreatic cancer cells . Because loss of expression of let-7 with poor long-term prognosis . Curcumin was found to and miRNA-143 as well as increased expression of miRNA-21 up-regulate the expression of miRNA-15a/16-1 and to down- and Ras are often correlated with tumor aggressiveness, these regulate the expression of WT1 in leukemic cells and in pri- observations suggested CDF as a novel agent for the treatment mary AML cells . The up-regulation of miRNA-15a/16-1 by of pancreatic cancer. The inhibition in growth of human pan- curcumin was an early event upstream to WT1 down-regula- creatic cancer cells by CDF was correlated with increased expression of let-7a, let-b, let-c, let-d, miRNA-26a, miRNA-101, partly abrogated the down-regulation of WT1 induced by curcumin in leukemic cells and promoted the growth of curcu- expression of enhancer of zeste homologue 2 (EZH2), a histone min-treated K562 and HL-60 cells. Overall, these observations methyltransferase and central epigenetic regulator of cell sur- vival, proliferation, and CSC function .
of WT1 partly by up-regulating miRNA-15a/16-1, which Emerging Roles of Curcumin Effects of curcumin on microRNA, cancer stem cells, and autophagy MicroRNA Up-regulated the expression of miRNA-22 and down-regulated miRNA-199a expression in human pancreatic cancer cells (19).
Induced apoptosis in A549 cells through down-regulation of miRNA-186 (21, 20).
Inhibited miRNA-21 expression via AP-1; suppressed cell proliferation, tumor growth, invasion, and in vivo metastasis; and sta- bilized expression of the Pdcd4 in colorectal cancer (22).
Up-regulated miRNA-200b and miRNA-200c expression, down-regulated miRNA-21 expression, and induced apoptosis in pan- creatic cancer cell lines (32).
Up-regulated miRNA-200 and PTEN and significantly down-regulated MT1-MMP expression in chemoresistant pancreatic can- cer cells (33).
Induced let-7 and miRNA-143 and down-regulated miRNA-21 expression, and attenuated the expression and activity of Ras in pancreatic cancer cells (34).
Inhibited the growth and increased the expression of let-7a, let-b, let-c, let-d, miRNA-26a, miRNA-101, miRNA-146a, miRNA- 200b, miRNA-200c, and decreased the expression of EZH2 in human pancreatic cancer cells (35).
Suppressed Bcl-2 expression through up-regulation of miRNA-15a and miRNA-16 in breast cancer cells (36).
Up-regulated miR-22 and inhibited the proliferation and migration of retinoblastoma cells (37).
Down-regulated miRNA-21 and miRNA-34a, up-regulated let-7a, and inhibited the proliferation of esophageal cancer cells (38).
Down-regulated WT1 expression by up-regulating miRNA-15a/16-1 and inhibited the proliferation of leukemic cells (40).
Cancer stem cells Inhibited the self-renewal of ALDH expressing breast CSCs through suppression of Wnt/b-catenin signaling (62).
Inhibited the growth, self-renewal, and clonogenicity of brain CSCs by blocking the Hedgehog signaling pathway (65).
In combination with dasatinib or FOLFOX decreased the expression of CD133, CD44, CD166, and ALDH in colon CSCs (68, 67).
Inhibited STAT3 phosphorylation, cell viability, and tumorsphere formation of colon CSCs (66).
Inhibited pancreatosphere formation, and attenuated the expression of CD44 and EpCAM in gemcitabine-resistant pancreatic cancer cells (64).
Reduced CD44 and CD166, inhibited growth, induced apoptosis, and attenuated colonosphere formation of chemoresistant co- lon cancer cells (69).
Triggered autophagy in a caspase-independent manner in human CML cells (75).
Increased the levels of beclin 1 and LC3-II and reduced the viability of leukemia cells (76).
Increased LC3-II/LC3-I expression and induced the formation of autophagosomes in mesothelioma cell line (77).
Induced autophagic cell death in malignant glioma cells through inhibition of the AKT/mTOR/p70S6K pathway and activation of the ERK1/2 pathway (78).
Induced autophagy in a mice model bearing U87-MG cells (78).
Degraded beclin-1 and induced LC3 expression in cutaneous T-cell lymphoma (79).
Induced cell death in colon cancer cells through ROS-dependent activation of autophagy (80).
Induced autophagy through induction of ROS production in oral cell carcinoma (81).
Induced autophagy in glioma-initiating cells (82).
AKT, AKT8 virus oncogene cellular homolog; ALDH, aldehyde dehydrogenase; AP-1, activator protein-1; CML, chronic myelogenous leukemia;CSC, cancer stem cell; EpCAM, epithelial cell adhesion molecule; ERK, extracellular signal-regulated kinase; EZH2, enhancer of Zeste homologue2; FOLFOX, 5-Fluorouracil plus oxaliplatin; LC3, microtubule-associated protein 1 light chain 3; MT1-MMP, membrane type-1 matrix metallopro-teinase; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal protein S6 kinase; Pdcd4, programmed cell death protein 4; PTEN,phosphatase and tensin homolog; Ras, rat sarcoma; STAT3, signal transducers and activators of transcription protein 3; Wnt, wint; WT1, Wilms'tumor 1.
Clinical efficacy of curcumin Pancreatic cancer Pancreatic cancer Pancreatic cancer Colorectal cancer Colorectal cancer Ulcerative colitis Ulcerative colitis contributes to the antiproliferation effects of curcumin in leu- transcription protein 3 (STAT3), phosphoinositide 3-kinase kemic cells.
(PI3K)/ AKT8 virus oncogene cellular homolog (AKT), glycogen It is clear from the above discussion that tumor cells com- synthase kinase-3b (GSK-3b), and HAT. Therefore, therapeutic monly have up-regulated expression of oncogenic microRNAs strategies that selectively target CSCs while limiting mistarget- (oncomiRs) and down-regulated expression of tumor-suppres- ing to normal stem cells are needed to reduce the risk of can- sive microRNAs. Curcumin has been shown to down-regulate cer relapse and recurrence.
oncomiRs (e.g., miR-21) and to up-regulate tumor-suppressive Curcumin has been shown to selectively target CSCs with- microRNAs (e.g., let-7) (Fig. 2). Thus, alteration in the expres- out a deleterious effect on normal stem cells in a number of sion of microRNA could contribute to the anticancer activities preclinical studies. For instance, the inhibition of self-renewal of curcumin. However, further studies are required to deter- of aldehyde dehydrogenase (ALDH)-expressing breast CSCs by mine whether curcumin modulates miRNA expression in clini- curcumin was mediated by suppression of Wnt/b-catenin sig- cally relevant animal models and in patients.
naling . On the contrary, curcumin had little effect on dif-ferentiated cells . Curcumin inhibited CD133-positive 2.1.2. Curcumin and CSCs.
medulloblastoma, glioblastoma, and pancreatic and colon CSC Cancer stem cells are a subpopulation of undifferentiated can- proliferation that was dependent on insulin-like growth factor cer cells that have the ability to self-renew and to generate (IGF), STAT3, Hedgehog, and EZH2 [63–66]. Nanoparticle- tumors through the processes of self-renewal and differentia- encapsulated curcumin has been reported to inhibit growth, tion [41,42]. Recent studies have indicated that CSCs may be self-renewal, and clonogenicity of brain CSCs by blocking the responsible for tumor relapse and are a major culprit in the Hedgehog signaling pathway .Combinations of dasatinib development of resistance to therapy [43,44].The first conclu- and curcumin were found to inhibit growth, invasion, and sive observation showing the existence of CSCs in human AML colonosphere formation of 5-Fluorouracil plus oxaliplatin was published in 1997 . Since then, studies have demon- (FOLFOX)-resistant colon cancer cells . The combination strated that diverse cancer types, including breast [46,47], therapy also reduced the CSC population as evidenced by the pancreatic [48,49], brain [50,51], colon [52–54], liver , decreased expression of CSC-specific markers (CD133, CD44, head and neck , ovarian [57,58], and melanoma [59,60], CD166, and ALDH) that further confirmed curcumin's efficacy are also driven and sustained by CSCs .The most common against CSCs . Curcumin, alone and together with FOLFOX, pathways that regulate self-renewal of CSCs include wint decreased the expression of CSC markers (CD44 and CD166) (Wnt), Notch, Hedgehog, signal transducers and activators of and reduced colonosphere formation of colon cancer cells .
Emerging Roles of Curcumin Curcumin and GO-Y030, a curcumin analogue, have been evidenced by substantially increased expression of a marker of reported to inhibit STAT3 phosphorylation, cell viability, and autophagy . The degradation of beclin-1 by curcumin has tumorsphere formation in colon CSCs . In gemcitabine- been associated with an accumulation of the autophagy-spe- resistant pancreatic cancer cells, CDF significantly inhibited cific marker LC3 in cutaneous T-cell lymphoma . Curcumin the sphere-forming ability (pancreatospheres), which was induced cell death in HCT116 colon cancer cells through reac- associated with attenuation of CSC markers (CD44 and tive oxygen species (ROS)-dependent activation of autophagy EpCAM) . In another study, CDF, together with 5-fluorour- . In oral cell carcinoma, curcumin induced autophagy that acil and oxaliplatin, was found to be more potent than was was mediated through induction of ROS production. Use of curcumin alone in reducing CD44 and CD166 in chemoresist- ant colon cancer cells that was associated with the inhibition confirmed the induction of autophagy by curcumin in oral cell of growth, induction of apoptosis, and disintegration of carcinoma . In glioma-initiating cells that are believed to colonospheres .
initiate glioblastoma, curcumin-induced autophagy led to In summary, the above studies suggest the potential of tumor suppression because of differentiation events .
curcumin in modulating stem cell fate, which may contribute Some other cancer types in which curcumin has been to its anticancer activities.
shown to induce autophagy alone or in combination with otheragents include oesophageal cancer , melanoma , 2.1.3. Curcumin and autophagy.
prostate cancer , hepatocellular carcinoma , and osteo- Autophagy is an evolutionarily conserved self-catabolic process sarcoma .
that involves sequestration of organelles and long-lived pro- In summary, the above discussion highlights that curcu- teins into autophagosomes and their subsequent delivery to min-induced autophagy is associated with cancer cell growth and degradation in lysosomes [70–72]. Autophagy is altered in suppression and death. Future studies using animal models cancer cells and is involved in both cell survival and cell death will further confirm the role of autophagy in the anticancer pathways . To date, 35 autophagy-related genes (Atgs) activities of curcumin.
have been discovered in yeast, all of which have mammalianhomologues .
2.2. Animal-Based Preclinical Studies Accumulating evidence over the past 5 years has indicated Curcumin has been most extensively investigated for its safety that curcumin can induce autophagy in cancer cells. For and efficacy in animal models. Animal studies have demon- instance, in human CML cells, curcumin triggered autophagy strated the potential of curcumin against such diseases as in a caspase-independent manner . In CML cell line K562, cancer, lung diseases, neurological diseases, liver diseases, curcumin inhibited the viability of cells in a dose- and time- metabolic diseases, autoimmune diseases, cardiovascular dis- dependent manner . The induction of cell death in these eases, and numerous other inflammatory diseases [88,89].
cells by curcumin was associated with the formation of the Although most of these studies have been conducted in apoptosome, the collapse of mitochondrial membrane poten- rodents, the efficacy of curcumin has also been demonstrated tial, and caspase-3 activation. Curcumin increased the protein in other animals such as monkeys , horses [91,92], rabbits levels of beclin 1 and microtubule-associated protein 1 light [93–95], and cats . In a recent study, curcumin exhibited chain 3 (LC3)-II. Furthermore, autophagy inhibitors bafilomy- anti-inflammatory activities in osteoarthritic-affected dogs cin A1 and the pan-caspase inhibitor suppressed curcumin- . In another study, curcumin was found to specifically bind induced K562 cell death. Overall, these results suggested that to the aggregated Ab molecules in various animals including both apoptotic and autophagic mechanisms contribute to the monkeys, dogs, and bears . In rabbits, administration of curcumin-induced death of K562 cells .
curcumin was found to reduce the contents of lipid and thio- In another study, curcumin dose-dependently reduced cell barbituric acid reactive substances in the liver and plasma viability but did not induce apoptosis in a malignant pleural induced by pure cholesterol . Liver glutathione peroxidase mesothelioma cell line. Instead, curcumin increased LC3-II/ (GSH-Px) and catalase activities were significantly decreased LC3-I expression and induced the formation of autophago- in purely cholesterol-fed rabbits, but the addition of curcumin somes. These changes were attenuated by gene silencing of to the pure cholesterol diet enhanced liver GSH-Px activity atg5, thus suggesting that induction of autophagy may be . Curcumin has also been shown to improve cardiac involved in the reduction of cell viability by curcumin . In function via up-regulating the expression of sarcoplasmic U87-MG and U373-MG malignant glioma cells, curcumin reticulum Ca2þ-ATPase in a rabbit model . In another induced cell cycle arrest at the G2/M phase . Non-apoptotic study, topical application of curcumin was useful in reducing autophagic cell death in these cells by curcumin was mediated experimental corneal neovascularization in rabbit eyes .
through inhibition of the AKT/ mammalian target of rapamycin(mTOR)/ p70 ribosomal protein S6 kinase (p70S6K) pathway 2.3. Clinical Studies and activation of the extracellular signal-regulated kinase The extensive studies from cell-based and animal models have (ERK)1/2 pathway. Curcumin also induced autophagy in the formed a solid basis for evaluating the safety and efficacy of subcutaneous xenograft mice model bearing U87-MG cells, as curcumin against a plethora of human diseases (Table 2).
Curcumin's clinical efficacy against human biliary diseases of the skin, uterine cervical intraepithelial neoplasm, oral leu- was first studied in 1937 . In this study, curcumin pro- coplakia, or intestinal metaplasia of the stomach . Curcu- duced remarkably good results against cholecystitis. Since this min was given orally for 3 months, and biopsy of the lesion initial discovery, observations from more than 65 human clini- sites was done immediately before and 3 months after starting cal trials of curcumin, which included more than 1000 curcumin treatment. There was no treatment-related toxicity patients, have been published, and more than 35 other clinical with doses up to 8 g/day. However, because of the bulky vol- trials are under way to further evaluate the efficacy of this pol- ume of the drug, doses larger than 8 g/day were unacceptable yphenol against human diseases . Among the most com- to patients. Our own group found that curcumin at 8 g/day in mon human diseases against which curcumin has exhibited combination with gemcitabine was safe and well-tolerated in activities include cardiovascular disease, arthritis, uveitis, can- patients with pancreatic cancer [110,111].
cer, ulcerative proctitis, Crohn disease, ulcerative colitis, pep- Curcumin has been used against human cancers including tic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudo- colorectal cancer, pancreatic cancer, breast cancer, prostate tumor, oral lichen planus, gastric inflammation, vitiligo, cancer, multiple myeloma, lung cancer, oral cancer, and head psoriasis, acute coronary syndrome, atherosclerosis, diabetes, and neck squamous cell carcinoma. In these studies, curcumin Dejerine-Sottas disease, diabetic nephropathy, diabetic micro- was used for both prevention and treatment of cancer. In a angiopathy, lupus nephritis, renal conditions, acquired immu- recent nonrandomized, open-label clinical trial in smokers, the nodeficiency syndrome, irritable bowel disease, tropical pan- polyphenol reduced the formation of aberrant crypt foci (ACF), creatitis, b-thalassemia, cholecystitis, and chronic bacterial the precursor of colorectal polyps . In this study, 44 prostatitis. In these clinical trials, curcumin was used either smokers were given curcumin orally in two different doses (2 alone or in combination with other agents such as gemcita- or 4 g/day) for 30 days. The levels of procarcinogenic eicosa- bine, soy isoflavones, bioperine, quercetin, mesalamine, acetyl- noids, prostaglandin E2, and 5-hydroxyeicosatetraenoic acid in cysteine, prednisone, lactoferrin, piperine, docetaxel, sulfasa- ACF or normal flat mucosa were unaffected by the 2 g/day lazine, and pantoprazole. Although the molecular basis for curcumin treatment. Curcumin at 4 g/day, however, signifi- curcumin's efficacy against some of these diseases is still not cantly reduced ACF formation, and this reduction was associ- completely known, this polyphenol has been shown to modu- ated with a significant five-fold increase in posttreatment late numerous signaling molecules including proinflammatory plasma curcumin/conjugate levels. Curcumin was well-toler- cytokines [tumor necrosis factor (TNF)-a, interleukin (IL)-1b, ated at both concentrations. These findings demonstrated the IL-6)], apoptotic proteins, nuclear factor kappa-light-chain- effect of curcumin against ACF formation in smokers .
enhancer of activated B cells (NF-jB), cyclooxygenase-2, In another recent study, curcumin was administered to STAT3, IkappaB kinase beta (IKKb), endothelin-1, malondial- patients with colorectal cancer after diagnosis and before sur- dehyde, C-reactive protein, prostaglandin E2, glutathione-S- gery (113). Curcumin (360 mg in capsule form) was given transferase (GST), prostate specific antigen (PSA), vascular cell three times a day for 10–30 days. Curcumin administration adhesion molecule 1 (VCAM1), GSH, pepsinogen, phosphoryl- ase kinase (PhK), transferrin receptor, total cholesterol, trans- increased the number of apoptotic cells, and enhanced expres- forming growth factor beta (TGF-b), triglyceride, creatinine, sion of p53 in tumor tissue. The authors of this study con- hemoxygenase-1, antioxidants, aspartate transaminase, and cluded that curcumin treatment can improve the general alanine transaminase in human participants. In most of the health of patients with colorectal cancer via the mechanism of clinical trials, either a mixture of curcuminoids or turmeric increased p53 expression in tumor cells .
from which curcumin is derived was used; pure curcumin has In some cases, curcumin has been used in combination been used in only a few studies.
with other agents. For example, a single-blind, randomized, Although curcumin has shown efficacy against numerous placebo-controlled study evaluated the effects of combinations human ailments, poor bioavailability due to poor absorption, of oral curcumin and piperine on the pain and markers associ- rapid metabolism, and rapid systemic elimination limits its ther- ated with oxidative stress in patients with tropical pancreatitis apeutic efficacy  As a result, numerous approaches includ- . Curcumin administration in patients was associated ing the use of adjuvants , nanoparticles , liposomes with a significant reduction in erythrocyte malondialdehyde , phospholipid complexes , and structural analogues (MDA) levels and an increase in GSH levels. The pain, how-  have been used to increase the bioavailability of curcumin ever, was not improved by curcumin administration .
in human participants. The bioavailability of curcumin has also In another study, the safety and feasibility of combinations been shown to be greatly enhanced by reconstituting curcumin of curcumin and gemcitabine were evaluated in 21 patients with the noncurcuminoid components of turmeric .
with gemcitabine-resistant pancreatic cancer. Curcumin at 8 The safety, tolerability, and nontoxicity of curcumin at g/day in combination with gemcitabine was safe and well-tol- high doses have been well-established by human clinical trials.
erated . Curcumin has been shown to suppress PSA pro- For instance, a phase I study evaluated the toxicology, phar- duction in men with increased PSA . Administration of a macokinetics, and biologically effective dose of curcumin in 25 1 g curcumin tablet for 1 week increased vitamins C and E lev- patients with resected urinary bladder cancer, Bowen disease Emerging Roles of Curcumin contents in the serum and saliva of patients with precancerous Fourth, curcumin at doses ranging from 0.45 to 3.6 g/day for lesions .
1–4 months was associated with nausea and diarrhea and The efficacy of curcumin as maintenance therapy in 89 caused an increase in serum alkaline phosphatase and lactate patients with quiescent ulcerative colitis was evaluated .
dehydrogenase contents in human subjects . Fifth, in Results indicated that relapse rates were 4.65% in the curcu- patients with high-risk or premalignant lesions, curcumin at min-treated group and 20.51% in the placebo group .
doses higher than 8 g/day was unacceptable . Sixth, in Ingestion of oral curcumin at 500 mg/day along with predni- one study of patients with advanced pancreatic cancer, 5 of 17 sone was associated with clinical and endoscopic remission of patients receiving curcumin (8 g/day) in combination with the disease in a patient with ulcerative colitis .
gemcitabine reported intractable abdominal pain after a few The efficacy of tetrahydrocurcuminoid in combination days to 2 weeks of curcumin intake . Seventh, curcumin with narrowband ultraviolet B (NB-UVB) against vitiligo, a has been shown to possess both pro-oxidant and antioxidant skin disorder, was investigated in one study . Ten activities in cancer cells that may be both good and bad patients with focal or generalized vitiligo were treated with because of the dual role of ROS for cancer . Thus, more either NB-UVB plus topical tetrahydrocurcuminoid cream or studies are needed to evaluate the efficacy of this polyphenol with NB-UVB alone. Although NB-UVB and NB-UVB plus tet- before it can be approved for human use.
rahydrocurcuminoid produced significant improvements, theoverall degree of repigmentation was slightly better in thecombination group, and the tetrahydrocurcuminoid was well- tolerated .
Since ancient times, curcumin has been used in Asian coun- The efficacy of a standardized preparation of curcuminoids tries. Modern science has delineated the molecular basis for (NCB-02) against various oxidative stress and inflammatory the pharmaceutical uses of curcumin against human ailments.
markers in patients with type 2 diabetes was evaluated .
Multiple studies over the past decade have indicated the safety The curcumin treatment significantly improved endothelial and efficacy of this polyphenol in rodents, monkeys, horses, function and reduced oxidative stress (MDA) and inflammatory rabbits, and cats and have provided a solid basis for evaluat- markers (IL-6, TNFa, endothelin-1) in these patients.
ing its efficacy in human clinical trials. In human clinical In summary, from the observations of some of the clinical trials, curcumin has been found to be safe at gram doses.
trials discussed in this section, the efficacy of curcumin against Although curcumin's safety and efficacy have already been human diseases seems promising. A search on www.clinical- proven by numerous clinical trials, the polyphenol has not yet trials.gov indicated that curcumin is being evaluated for been approved for the treatment of any human diseases. Fur- numerous human diseases including cancer, irritable bowel thermore, because of the fact that turmeric is more effective syndrome, inflammatory conditions, arthritis, neurological than curcumin, we believe that by using curcumin alone, we conditions, and diabetes. It is expected that these ongoing clin- might be limiting ourselves from the various utilities of ical trials will provide a deeper understanding of curcumin's turmeric. We hope that numerous ongoing studies will help to efficacy and mechanism of action against human diseases.
move this fascinating molecule to the forefront of therapeuticsfor human use.
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Emerging Roles of Curcumin
Compendio tratamiento EPOCEl presente compendio le ayuda a enfocar las enfermedades pulmonares crónicas desde un ángulo y con perspectivas diferentes. Le abre nuevas posibilidades diagnósticas y terapéuticas con metas realistas que lo puedan llevar a un mejor estar y a una mejor calidad de vida. Akademie für Gesundheit, Sport und Prävention e. V. (Academia para la salud, el deporte y la prevención. e.V)1. Edición
COMPLETE LIST OF ABSTRACTS Plenary sessions: Arvid Carlsson and Elias Eriksson University of Gothenburg, Sweden ABERRATIONS IN BRAIN NEUROTRANSMITTER FUNCTION AS A POSSIBLE ROOT OF NEUROPSYCHIATRIC ILLNESS – WHICH CONCLUSIONS MAY BE DRAWN AFTER 60 YEARS OF RESEARCH? One important incentive for the many attempts to monitor brain molecules that have been undertaken during the past decades has been the wish to shed light on the possible importance of specific neurotransmitter abnormalities in psychiatric and neurological disease. But why did we ever come to believe that the pathophysiology of brain disorders may be partly explained in terms of transmitter aberrations? In this interview, psychopharmacologist Arvid Carlsson, who once pioneered this way of thinking by suggesting dopamine to be of importance for Parkinson's disease, and who later made important scientific contributions with respect to the involvement of brain neurotransmitters in disorders such as schizophrenia and depression, will comment on the history of the transmitter-centred perspective on neuropsychiatric disorders, and discuss both the virtues and limitations of this approach.