[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY] The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease Volume 595 || ANTITUMOR, ANTI-INVASION, AND ANTIMETASTATIC

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ANTITUMOR, ANTI-INVASION, ANDANTIMETASTATIC EFFECTS OF CURCUMIN

Girija Kuttan, Kuzhuvelil B. Hari Kumar, ChandrasekharanGuruvayoorappan, and Ramadasan Kuttan

Abstract: Curcumin was found to be cytotoxic in nature to a wide variety oftumor cell lines of different tissue origin. The action of curcumin is dependenton with the cell type, the concentration of curcumin (IC50: 2–40 �g/mL), andthe time of the treatment. The major mechanism by which curcumin induces cy-totoxicity is the induction of apoptosis. Curcumin decreased the expression ofantiapoptotic members of the Bcl-2 family and elevated the expression of p53,Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor �B(NF-�B) into the nucleus there by decreasing the expression of cell cycle regula-tory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrestedthe cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Cur-cumin inhibited the growth of transplantable tumors in different animal modelsand increased the life span of tumor-harboring animals. Curcumin inhibits metas-tasis of tumor cells as shown in in vitro as well as in vivo models, and the possiblemechanism is the inhibition of matrix metalloproteases. Curcumin was found tosuppress the expression of cyclooxygenase-2, vascular endothelial growth factor,and intercellular adhesion molecule-1 and elevated the expression of antimetastaticproteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and E-cadherin. These results indicate that curcumin acts at various stages of tumor cellprogression.

1. INTRODUCTION

Curcumin (1, 7-bis(4-hydroxy-3-methoxypentyl)-1, 6-hepadiene-3, 5-dione), alsoknown as diferuloylmethane, belongs to the class of polyphenols present in therhizomes of turmeric (Curcuma longa L), and content of curcumin in the driedrhizomes is around 5–10%. Turmeric is extensively used in the Indian subcon-tinent in culinary art. Turmeric is also used as an indigenous medicine for thetreatment of various ailments for many centuries. Most of the biological activi-ties of turmeric are due to curcumin. Curcumin is demonstrated to have a widespectrum of pharmacological properties. There are several reviews that describethe different pharmacological properties of curcumin.1−4 In the present chapter,we describe the antiproliferative and antimetastatic activity of curcumin and itsimplication in cancer prevention and treatment.

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2. CYTOTOXIC AND ANTIPROLIFERATIVE ACTIVITYOF CURCUMIN

Curcumin is found to have antiproliferative and differentiation-inducing prop-erties in different types of cell line in vitro. The mode of action of curcuminvaries considerably with the cell type, the concentration of curcumin, and thetime of the treatment. One of the initial reports describing the cytotoxicity ofcurcumin was against Dalton’s lymphoma ascites cells (DLA) in vitro, in whichcurcumin (4 �g/mL) produced 50% cytotoxicity. Curcumin also inhibited thegrowth of Chinese hamster ovary cells and human leukemic lymphocytes inculture.5,6

Curcumin was found to be highly antiproliferative in nature to a variety of humanleukemic cell lines. The antiproliferative action of curcumin is best characterizedin a human chronic myelogenic leukemia cell line, namely K-562. At a concentra-tion of 20 �g/mL, curcumin produced 50% growth arrest as determined by 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2 H tetrazolium bromide (MTT) assay.7 Oneof the main mechanisms through which curcumin produces cell arrest is by in-ducing apoptosis. Curcumin liberates cytochrome-c from mitochondria, activatescaspases and Bax, and downregulates the Bcl-2 levels. Curcumin also downregu-lates the expression of Wilms’ tumor-1 (WT-1) gene, which is highly overexpressedin leukemic blast cells of myeloid and lymphoid origin and serves as a marker forleukemic detection.8 The downregulation of WT-1 by curcumin is dependent onconcentration. Moreover the expression of MEK-1, c-jun, and P210 bcr/abl weredecreased by curcumin, which ultimately retard the ras-mediated signal trans-duction cascade, thus affecting the process of cell proliferation.9 There are reportsdescribing the inhibitory effect of curcumin on STATs and telomerase.10 Curcuminalso decreases the expression of glutathione-S-transferase P1-1 (GSTP1-1) in K-562 cells, as seen by reporter gene assay. GSTP1-1 is implicated in the carcino-genesis and the resistance of cancer cells against conventional chemotherapeuticagents. Curcumin also elevates the levels some of the components of the apoptoticpathway such as of pro-caspases 8 and 9 as well as poly ADP ribose polymerase.11

All of these events contribute to the antiproliferative action of curcumin in K-562cells.

Curcumin also suppressed the growth of several T-cell leukemia cell lines ina dose-dependent manner. Curcumin was found to induce apoptosis in these celllines.12 Apart from this, curcumin inhibited the action of inhibitory apoptotic pro-teins (IAPs) and downregulated the JAK–STAT (Signal tranducers and activatorsof transcription) pathway.13 Curcumin suppressed the binding between AP-1 tran-scription factor and DNA.14 Curcumin was shown to induce cell cycle arrest byreducing the expression of cyclin D1, cdk1, cdc-25, and survivin, thus providinga way for the apoptotic machinery to act.15 The survival pathway mediated by theAkt-PI3K cascade was also inhibited by curcumin.12

Curcumin was found to be highly cytotoxic toward several malignant cell linesof colon origin. In the HCT 116 cell line, curcumin prevented the entry of nuclearfactor �B (NF-�B) into the nucleus.16. NF-�B is a sequence-specific transcription

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ANTITUMOR, ANTI-INVASION, AND ANTIMETASTATIC EFFECTS 175

factor and plays a central role in the regulation many types of immune, inflam-matory, and carcinogenic response. NF-�B activation is required for normal cellgrowth; abnormal activation is seen several types of pathological process.17 Thecytotoxic potential of curcumin in the HCT 116 line is a concentration- and time-dependent event, and curcumin either activates or deactivates several pathwaysthat are necessary for the normal growth of the cell. Curcumin activates Januskinase (JNK) and mitogen-activated protein kinase (MAPK).16 Curcumin blockedthe entry of the cell cycle from G2 to M by inhibiting the expression of cdc2/cyclinB.18 The proapoptotic members of the Bcl-2 family, such as Bax, were activatedand antiapototic genes like Bcl-X L were inhibited by curcumin.19 It also triggerscaspase-3-mediated cell death. Curcumin was found to activate GADD153, which,in turn, acts as an activator of apoptosis.20 Curcumin mediated the degradationof �-catenin, thus affecting the wnt signaling pathway. The cell–cell adhesionpathway mediated by E-cadherin was also blocked by curcumin.21 In conclu-sion, curcumin acts as a potent growth suppressive and cytotoxic agent to theHCT116 cell line and the action is mediated by (1) the induction of caspases-mediated apoptosis, (2) the impairment of wnt signaling events, (3) the inhibitionof cell–cell adhesion, and (4) the blocking of the transition of the cell cycle fromG2 to M.

In the human hepatoma G2 cell line (HepG2), the cytotoxic action of curcuminis mainly by inducing DNA damage of both nuclear and mitochondrial genomes.The extensive mitochondrial damage might be the initial triggering signal for theinduction of apoptosis.22. Curcumin also inhibited the hepatocyte growth factor(HGF) and its receptor c-met (HGFR).23

Curcumin in a dose- and time-dependent and fashion induces p53-mediatedapoptotic death in basal cell carcinoma lines, as evident from electrophoreticmobility shift assay (EMSA) and antisense studies.24

Human head and neck squamous cell carcinoma cell lines (HNSCC) is a type ofepithelial cancer with a very low survival rate. In the culture, curcumin inhibitedthe growth of these cells by triggering apoptosis. Curcumin decreased the eleva-tion of Bcl-2, matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2),interleukin (IL)-6, and cyclin D1 and arrested the cell cycle in the G1/S phase.HNSCC cells showed constitutive overexpression of NF-�B and treatment withcurcumin inhibited the NF-�B activation, which is the other mechanism throughwhich curcumin acts as a growth-inhibitory substance to HNSCC cells.25

Microarray analysis of human breast cancer carcinoma cell line (MCF-7) treatedwith curcumin revealed that curcumin upregulated 22 genes and downregulated17 genes, which are components of multiple signaling pathways that control vari-ous biological processes. The major upregulated genes were caspase-3, caspase-4, JNK, proliferating cell nuclear antigen (PCNA), death-associated protein-6,growth arrest and DNA damage inducible protein, and downregulated genes suchas tumor necrosis factor (TNF)-�, TNF receptor, protein kinase B, and caspase-9precursor.26

In several types human melanoma cell, curcumin produces cytotoxicity. In theA375 cell line, curcumin produces cell growth arrest in a time- and concentration-

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dependent manner and the major mechanism was found to be apoptosis.27 Cur-cumin induces apoptosis through the Fas receptor/caspase-8 pathway independentof p53 and suppresses the antiapoptotic gene XIAP.28 Curcumin prevents thetranslocation of NF-�B to the nucleus; downregulates the expression of c-mycand inducible nitric oxide synthase (iNOS), and induces G2/M arrest. Curcuminalso inhibits the activity of an antiapoptotic gene XIAP and elevates the levels ofp53, p21, p27 (KIP1), and check point kinase 2.29

In some other cell lines, curcumin mediates its cytotoxic action via generat-ing reactive oxygen species (ROS). Although curcumin is a potent scavenger offree radicals, there are reports describing the free-radical-generation potential ofcurcumin.30,31 In the human submandibular gland carcinoma (HSG) cell line, ata very low concentration (>15 �M), curcumin generates ROS that cause dam-age to mitochondria, as evident from the decrease in the mitochondrial membranepotential and externalization of phosphatydyl serine, and the whole process even-tually ends up in the initiation of apoptosis.32 In human gingival fibroblast also,treatment with curcumin produces a dose-dependent generation of ROS, and thisphenomenon was attributed to the cytotoxic activity.32 The growth-suppressiveeffect of curcumin on follicular lymphoma cells is also mediated by the gener-ation of ROS. Flow cytometry and Western blot analysis revealed that curcuminshifted the equilibrium of Bcl-2 family members in favor of apoptosis and initiateda caspases-mediated cell death in these cell lines.33

Curcumin act as a cytotoxic agent in vivo also. Curcumin inhibited a DLA-induced solid tumor, as seen from the reduction in tumor volume and also inhibitedascites tumor in mice. The administration of curcumin enhanced the percentageof survival of animals bearing ascites.5,6 When the three naturally occurring cur-cuminoids (curcumin I, II, and III) were compared for their cytotoxic, antitumor,and inhibition of tumor promotion activities, curcumin III was found to be moreactive than curcumin I and II.34,35 Curcumin was found to decrease the Ehrlich’sascites carcinoma (EAC) cell number by the induction of apoptosis in the EACcells, as seen from flow-cytometric analysis of cell cycle phase distribution ofnuclear DNA and oligonucleosomal fragmentation. Moreover, curcumin upreg-ulates the proapoptotic gene Bax, induces the release of cytochrome-c from themitochondria, and, finally, induces the activation of caspase-3.36

Curcumin inhibited spontaneous tumors developed in C57BL/6J−Min/+(Min/+) mice. These animals bear a germ-line mutation in the Apc gene and spon-taneously develop numerous intestinal adenomas by 15 weeks of age. Curcuminalso decreased the expression of �-catenin. Immunohistochemical analysis of thetissues revealed that treatment with curcumin increased the mucosal CD4+ Tcellsand Bcells, suggesting that curcumin modulates lymphocyte-mediated immunefunctions.37,38 Even though curcumin has been shown to inhibit transplantableand spontaneous tumors, the major action of curcumin is in the inhibition ofcarcinogenesis. Carcinogenesis is a complex process and involves the follow-ing steps; initiation, progression, and promotion. Even though the mechanismof action of curcumin during carcinogenesis is mainly ascribed to the inhibitionof the carcinogen metabolism and its increased excretion, it might be possible

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that curcumin also acts as an inhibitor of cell proliferation during carcinogenesis.Curcumin had an inhibitory effect on both the initiation and promotion stages ofcarcinogenesis, as seen from the 7, 12-dimethylbenz [a]anthracene (DMBA)- andcroton oil or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skincarcinogenesis.39−42 The TPA-induced epidermal lipoxygenase and cyclooxyge-nase activity was decreased by curcumin, thereby inhibiting the arachidonic acidmetabolism. Because the critical roles of prostaglandins, lipoxygenase, and COXin the development of cancer are well established now; the inhibition of these en-zymes by curcumin might be one of the mechanisms behind its anticarcinogenicpotential.43,44 Curcumin significantly delayed the onset of sarcoma produced by20-methylcholanthrene in mice.39 Curcumin has been shown to inhibit B[a]P-induced forestomach papilloma in mice.41 Curcumin decreased the elevated levelsof phase I enzymes, which are involved in the activation of B[a]P in the liver andincreased the activities of phase II enzymes, which are involved in the detoxifi-cation of metabolites derived from B[a]P.45 Topical administration of curcumindecreased the formation of B[a] P–DNA adducts on the mouse epidermis.40 Cur-cumin was found to inhibit N -ethyl-N ′-nitro-N -nitrosoguanidine-induced duo-denal tumorigenesis in C57BL/6 mice and azoxymethane (AOM)-induced colontumorigenesis in CF-1 mice. Histopathological analysis revealed that curcumininhibited the number of adenomas and adenocarcinomas of the duodenum andcolon.40 The AOM-induced colon carcinogenesis in F344 rats was significantlyinhibited by curcumin. Curcumin suppressed AOM-induced prostaglandin (PG)and thromboxane (Tx) formation in the liver, ornithine decarboxylase and tyro-sine protein kinase activity in the liver and colon, and the formation of aberrantcrypt foci in the colon.46 Curcumin also inhibited the N -nitrosomethylbenzylamine(NMBA)-induced esophageal carcinogenesis in male F344 rats and the adminis-tration of curcumin significantly decreased the expression of cell proliferationbiomarkers.47 Curcumin inhibited the hepatocarcinogenesis (HCC) in C3H/HeNmice induced by N -nitrosodiethylamine (NDEA), as evident from reduction inmultiplicity and incidence of the development of HCC. Curcumin downregulatedthe levels of p21(ras), PCNA, and CDC2 proteins that were elevated after NDEAadministration.48 The administration of curcumin has been shown to reverse thehepatic damage and hepatocarcinogenesis caused by aflatoxins, a group of potentmycotoxins, in ducklings, as seen by the assay of marker enzymes and histopatho-logical evaluation.49

Curcumin also acts as an immunomodulator. Immunomodulators are agentsthat modify host responses to antigens, with resultant therapeutic effects. Cur-cumin enhanced the natural killer cell activity. Curcumin has been shown to inhibitmitogen-stimulated cell proliferation. The phagocytic activities of macrophageswere increased by curcumin and treatment with curcumin was found to increasethe relative organ weights of lymphoid organs such as the spleen and thymus.The administration of curcumin also elevated the total white blood cell count,bone marrow cellularity, and levels of �-esterase-positive (a marker of maturingmonocytes) cells. Immunomodulaory action can be another mechanism behind thecytotoxic action of curcumin.50,51

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Cytokines play an important role in immunomodulation, and curcumin is knownto alter the cytokine profiles. Curcumin also inhibited the production of pro-inflammatory cytokines. In the human pancreatic carcinoma cell line SUIT-2, cur-cumin inhibited the constitutive production of IL-8 in a concentration-dependentmanner and reduced the NF-�B activity significantly.52 In the keratinocyte cell lineNCTC 2544, ultraviolet B (UVB) treatment was found to significantly enhancethe expression of TNF-�, IL-6, and IL-8, both at the mRNA and protein levels.Curcumin decreased the UVB-mediated overexpression of all of the three pro-inflammatory cytokines in a dose-dependent manner. The UVB-induced cytokineoverexpression was accompanied by the activation of NF-�B and AP-1 transcrip-tion factors, as assessed by electrophoretic mobility shift assays. The decrease inthe expression of cytokines by curcumin is probably mediated by the inhibitionof the activation of NF-�B and AP-1.53 Curcumin potently inhibited the produc-tion of IL-12 in a dose-dependent manner from mouse macrophages stimulatedwith lipopolysaccharide (LPS). The inhibition of IL-12 production might be a keytherapeutic strategy for modulating immunological diseases dominated by type 1cytokine responses.54 Curcumin, at a dose of 5 �M, inhibited LPS-induced pro-duction of TNF-� and IL-1 by a human monocytic macrophage cell line, MonoMac 6, and reduced the LPS-induced activation of NF-�B and the biological activ-ity of TNF-� in a L929 fibroblast lytic assay (bioassay)55 Curcumin also inhibitedthe delayed type of hypersensitivity reaction (type IV) mediated by TH1 subtypes.TH1 cells also produce pro-inflammatory cytokines. Inhibition of type IV hyper-sensitivity reactions by curcumin further substantiates its effect on the inhibitionof pro-inflammatory cytokines.50

3. ANTIMETASTATIC ACTIVITY OF CURCUMIN

Metastasis is the process by which cancer cells migrate from the tissue of originto other distant sites through blood flow to form new malignant lesions in otherorgans. A successful formation of metastatic foci consists of complex and there areseveral interconnected steps involved. During metastasis, the invasive tumor cellsmight have to penetrate a number of cellular barriers, which include the basementmembrane.56,57 A group of proteolytic enzymes, namely matrix metalloproteinases(MMPs), are involved in these processes. MMPs are a family of over 28 enzymesand are Zn2+-dependent. MMPs play a key role not only in normal processes ofextracellular matrix degradation but also in pathological processes such as tissueremodeling, cancer invasion, and metastasis. Expression of MMPs is generallyupregulated in a wide range of malignant tumors.57,58 The major component ofthe basement membrane is type IV collagen, and of the several classes of MMPs,two of them (MMP-2 and MMP-9) are the key players in the degradation of typeIV collagen. Tissue inhibitors of matrix metalloproteinases (TIMPs) are a class ofendogenously present inhibitors of MMPs.

Curcumin was found to be highly antimetastatic in nature. An early report fromour laboratory described the antimetastatic activity of curcumin against B16F-10melanoma cells-induced pulmonary metastasis in C57BL/6 mice. Curcumin

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inhibited the formation of lung nodules induced by B16F-10 melanoma cells by89.3% and increased the life span of animals by 143.9%. The invasive property ofB16F-10 melanoma cells across the collagen matrix was inhibited by curcumin, asseen from the Boyden chamber assay. Zymographic analysis showed that curcumininhibited the activities of MMP-2 and MMP-9.59,60 Curcumin also downregulatedthe activities of membrane type 1 MMP (MT1-MMP) and focal adhesion kinase(FAK), which plays a role in the integrin-mediated signal transduction cascadein B16F-10 melanoma cells.61 Curcumin-treated B16F-10 cells showed a markedreduction in the expression of alpha 5 beta1 and alpha 5 beta3 integrin receptors.Curcumin also enhanced the expression of antimetastatic proteins, TIMP-2, non-metastatic gene 23 (Nm23), and E-cadherin, which reduced the metastatic tendencyof the melanoma cells.62

Curcumin was also found to be highly antimetastatic against prostrate DU145cells both in vitro as well as in vivo. It reduced the metastatic ability of DU145in a xenograft tumor model. The administration of curcumin produced a markeddecrease in the tumor volume and the levels of MMP-2 and MMP-9.63 In a hu-man breast cancer xenograft model, the administration of curcumin markedlydecreased the metastasis to the lung and suppressed the expression of NF-�B,MMP-9, COX-2, vascular endothelial growth factor (VEGF), and intercellularadhesion molecule-1.64 12-O-Tetradecanoylphorbol 13-acetate (TPA) is a well-known tumor promoter and in human breast epithelial cells (MCF10A). TPA in-duces profound expression of COX-2 and MMP-9 and thereby elevated the levelsof PGs and the invasive and metastatic tendency of the cells. The increase in theexpression is mediated by the upregulation of the signal transducing events me-diated by extracellular signal-regulated protein kinase (ERK1/2) and NF-�B. Thetreatment of the cells with curcumin inhibits the above cascade, thereby decreas-ing the expression of COX-2 and MMP-9, which, in turn, alters the invasive andmetastatic properties of the cells.65 Osteopontin (OPN), a type extracellular ma-trix protein, has been shown to be overexpressed in various types of cancer. OPNplays an important role in the ability of tumor cells to survive and metastasize toother distant organs. OPN stimulated the expression of proMMP-2 and MT1-MMPthrough a NF-�B-mediated pathway in murine B16F-10 melanoma cells. TheOPN-mediated expression of NF-�B, proMMP-2, and MT1-MMP was suppressedby curcumin and it inhibited the OPN-mediated tumor growth in a nude micemodel.66

Curcumin reduced the metastasis of tumors in Long Evans Cinnamon (LEC)rats, which develop tumors in the kidney and the liver due to an aberrant copper-transporting ATPase gene. LEC rats accumulate copper in their body. Treatmentwith curcumin, although failing to prevent the induction of primary tumors in thekidney and the liver; reduced the metastasis of tumors to other distant sites.67

4. CONCLUSION

In conclusion, curcumin shows profound cytotoxic potential against tumor cellsboth in vitro and in vivo. The major mechanism of cytotoxicity is the induction of

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apoptosis. Curcumin either activates or represses several signaling events that arerequired for the normal cell function. Curcumin modulates these signaling path-ways in such a way that the final events will be the execution of death in these cells.In order to execute apoptosis, curcumin follows several routes such as inhibitingantiapoptotic proteins, inhibiting survival pathways, arresting the cell cycle beforethe mitotic phase, inhibiting the translocation of NF-�B to the nucleus, triggeringthe generation of ROS, induceing cytochrome-c release from mitochondria, andactivating the apoptotic machinery. Curcumin inhibits the metastasis of tumor cellsboth in vitro and in vivo and the possible mechanism is the inhibition of MMPs.Curcumin also acts as a good immunomodulator. It augments the natural killercell activity and inhibits the production of cytokines. These biological activitieswarrant further studies of curcumin in the treatment and prevention of humanneoplasm.

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[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY] The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease Volume 595 || ANTITUMOR, ANTI-INVASION, AND ANTIMETASTATIC