All cancer cures and treatments: Curcumin for Cancer Prevention & Cure 09370322999

Available online at www.sciencedirect.com Cancer Letters 267 (2008) 133–164 www.elsevier.com/locate/canlet Curcumin and cancer: An ‘‘old-age” disease with an ‘‘age-old” solutionPreetha Anand, Chitra Sundaram, Sonia Jhurani, Ajaikumar B. Kunnumakkara, Bharat B. Aggarwal * Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Received 11 March 2008; received in revised form 11 March 2008; accepted 12 March 2008Abstract Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is nowwell recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usuallyinvolve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medi-cines are safe, what are the active principles in them and how do they mediate their eﬀects against cancer is perhaps bestillustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inﬂammatory conditions. Cur-cumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called ‘‘curry powder”) that has beenshown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activationof caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival(PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) andinﬂammation (NF-jB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia andlymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cellcarcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reﬂects its ability to aﬀect multiple targets. Thusan ‘‘old-age” disease such as cancer requires an ‘‘age-old” treatment.Ó 2008 Elsevier Ireland Ltd. All rights reserved.Keywords: Curcumin; Cancer; Inﬂammation; Anticancer activity; Chemoprevention; Chemosensitization; Radiosensitization1. Introduction for cancer, it has involved the use of harmful sub- stances, such as poisonous mustargen introduced Studies have estimated that genetic factors cause in 1941; chemotherapy, introduced in 1971; andonly 5–10% of all human cancers, while the remain- then now targeted therapies, introduced in 1991.ing percentage is caused by lifestyle. In spite of an The progress in cancer research is determined byextensive search for safe and eﬃcacious treatments the number of approvals from the U.S. Food and Drug Administration (FDA), as indicated by very * Corresponding author. Tel.: +1 713 792 3503; fax: +1 713 794 few in 1970; seven in 1987; 16 in 1996; 21 in 1998,1613. and 28 in 2006 [1]. More than 70% of the FDA E-mail address: aggarwal@mdanderson.org (B.B. Aggarwal). approved anticancer drugs can be traced back to0304-3835/$ - see front matter Ó 2008 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.canlet.2008.03.025
2. 134 P. Anand et al. / Cancer Letters 267 (2008) 133–164their origin in plant-derived natural products, which Curcumin is a hydrophobic polyphenol derivedwere traditionally used as ancient remedies for var- from turmeric: the rhizome of the herb Curcumaious ailments. Vinblastine from Vinca rosea is one of longa. Chemically, it is a bis-a,b-unsaturated b-the earliest example that originated from an Ayurv- diketone (commonly called diferuloylmethane)edic medicine described for cancer and paclitaxel is that exhibits keto-enol tautomerism, having a pre-perhaps one of the most recent example that origi- dominant keto form in acidic and neutral solu-nated from Chinese paciﬁc yew plant. tions and a stable enol form in alkaline media. Cancer is well recognized as a disease of old age Commercial curcumin is a mixture of curcumi-(Fig. 1). It is estimated that the process of tumori- noids, containing approximately 77% difer-genesis starts at around the age of 20 and detection uloylmethane, 18% demethoxycurcumin, and 5%of cancer is normally around the age of 50 or later bisdemethoxycurcumin. Traditionally, turmeric(Table 1); thus with an estimated incubation time and other curcuminoids have been used in thera-of around 20–30 years. Recent studies indicate that peutic preparations for various ailments in diﬀer-in any given type of cancer 300–500 normal genes ent parts of the world. Numerous therapeutichave been modiﬁed somehow to result in the cancer- eﬀects of curcumin/turmeric have been conﬁrmedous phenotype. Although cancers are characterized by modern scientiﬁc research. Herein, we presentby the dysregulation of cell signaling pathways at a systematic review of the clinical and experimen-multiple steps, most current anticancer therapies tal data on the use of curcumin in the treatmentinvolve the modulation of a single target. The inef- of cancer.fectiveness, lack of safety, and high cost of monotar-geted therapies have led to a lack of faith in these 2. Molecular targets of curcuminapproaches. As a result, many pharmaceutical com-panies are increasingly interested in developing Extensive research conducted within the pastmultitargeted therapies. Many plant-based prod- two decades has revealed that cancer is a resultucts, however, accomplish multitargeting naturally of the dysregulation of multiple cell signalingand, in addition, are inexpensive and safe compared pathways. Curcumin is a highly pleiotropic mole-to synthetic agents. However, because pharmaceuti- cule that modulates numerous targets (Fig. 2),cal companies are not usually able to secure intellec- including the activation of transcription factorstual property rights to plant-based products, the (e.g., NF-jB, STAT3, AP-1, NRF-2, PPAR-c,development of plant-based anticancer therapies and HIF-1), receptors (e.g., HER-2, IL-8, andhas not been prioritized. Nonetheless, curcumin, a CXCR-4), kinases (e.g., EGFR, ERK, JAK,plant-based product, has shown signiﬁcant promise and AAPK), cytokines (e.g., TNF, IL, MIP,against cancer and other inﬂammatory diseases. and MCP), enzymes (e.g., MMP, iNOS, GST, 40 Prostate cancer % Incidence of cancer 30 Lung cancer Urinary bladder cancer 20 Lymphoma 10 0 0 4 4 4 4 4 4 5 <2 -3 -4 -5 -6 -7 -8 >8 20 35 45 55 65 75 Age (Years) Fig. 1. Age dependency of cancer incidence. Data presented in the ﬁgure is based on the cancer statistics published in 2007 [3].
3. P. Anand et al. / Cancer Letters 267 (2008) 133–164 135Table 1 3. Anticancer potentialMedian age at which most cancers are diagnosed in Americanpopulation Curcumin has been shown to exhibit therapeuticCancer site Median age at diagnosis (years) potential against variety of diﬀerent cancers includ-Breast cancer 61 ing leukemia and lymphoma; gastrointestinal can-Gastrointestinal cancers cers, genitourinary cancers, breast cancer, ovarian Esophagus cancer 69 Stomach cancer 71 cancer, head and neck squamous cell carcinoma, Intestine cancer 67 lung cancer, melanoma, neurological cancers and Liver cancer 65 sarcoma (Fig. 3). The current status of curcumin’s Pancreatic cancer 72 anticancer potential against various cancers is sys- Colorectal cancer 71 tematically analyzed and presented below under dif-Genitourinary cancers ferent headings. Bladder cancer 73 Kidney cancer 65 3.1. Breast cancer Prostate cancer 68Gynecologic cancers Breast cancer is the most common and frequently Cervical cancer 48 Ovarian cancer 63 diagnosed cancer at a median age of 61 years in Uterine cancer 67 women [3]. In the United States, breast cancer accounts for about 26% of all newly diagnosed neo-Thoracic/Head and neck cancer Lung cancer 70 plasms [4]. Even though substantial advances in Oral cancer 62 therapy and diagnosis have enhanced the survival Thymus cancer 50 rate of patients with breast cancer, late recurrencesHematologic cancers of the disease account for more than 60% of deaths Leukemia 67 from breast cancer [5]; the survival rate among Lymphoma 64 patients with metastatic disease does not seem to Multiple Myeloma 70 be signiﬁcantly aﬀected by the current treatmentMelanoma 59 modalities [6]. Indeed, further studies are neededBone cancer 39 to optimize therapeutic interventions in patientsBrain tumor 56 with metastatic breast cancer.Data presented in the table is based on the cancer statistics Several reports have described the anticarcino-published in 2007 [3]. genic activity of curcumin in a variety of breast cancer cell lines. One of our early studies estab- lished that the antiproliferative eﬀect of curcuminand ATPase), and growth factors (e.g., EGF, in human breast cancer cell lines, including hor-NGF, HGF, and PDGF). Because of its ability mone-dependent, hormone-independent, and mul-to interact with a diverse range of molecular tar- tidrug-resistant cells, was time- and dose-gets, curcumin can aﬀect numerous molecular and dependent and correlated with curcumin’s inhibi-biochemical cascades. One of our recently pub- tion of ornithine decarboxylase activity [7]. Severallished reviews presents a more detailed descrip- mechanisms have been proposed to account fortion of the molecular targets of curcumin [2]. the action of curcumin in breast cancer cells.Extensive research conducted during the past cen- For example, curcumin was found to inhibit thetury has established the complexity and involve- aryl hydrocarbon receptor and cytochrome P450ment of multiple signaling pathways in the 1A1 [7]; the tyrosine kinase activity of p185neu;cancer growth and progression, which in turn the expression of Ki-67, PCNA, p53 mRNAs;suggests that a drug, which can interact with COX-I and COX-II enzymes. Curcumin alsomultiple target molecules, will be more eﬃcacious induced p53-dependent Bax expression, inhibitedthan the current monotargeted anticancer drugs. vascular endothelial growth factor (VEGF), basicCurcumin’s multitargeting ability may be the ﬁbroblast growth factor (b-FGF) [8,9], disruptedkey to its therapeutic potential against cancer. mitotic spindle structure and induced micronucle-In the next section of this review, we analyze ation [10]. It has been shown to inhibit telomerasethe current status of curcumin’s potential against activity through human telomerase reverse trans-various cancers. criptase [11], downregulate the expression of
4. 136 P. Anand et al. / Cancer Letters 267 (2008) 133–164Fig. 2. Molecular targets of curcumin. These include, NF-jB, nuclear factor-kappa B; AP-1, activating protein1; STAT, signaltransducers and activators of transcription; Nrf-2, nuclear factor 2-related factor; Egr-1, early growth response gene-1; PPAR-c,peroxisome proliferator-activated receptor-gamma; CBP, CREB-binding protein; EpRE; CTGF, connective tissue growth factor; EGF,epidermal growth factor; EGFRK, epidermal growth factor receptor-kinase; FGF, ﬁbroblast growth factor; HGF, hepatocyte growthfactor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF-b1, transforming growth factor-b1; VEGF, vascularendothelial growth factor; AR, androgen receptor; Arh-R, aryl hydrocarbon receptor; DR-5, death receptor-5; EGF-R, epidermal growthfactor-receptor; EPC-R, endothelial protein C-receptor; ER-a, estrogen receptor-alpha; Fas-R, Fas receptor; H2-R, histamine (2)-receptor; InsP3-R, inositol 1,4,5-triphosphate receptor; IR, integrin receptor; IL-8-R, interleukin 8-receptor; LDL-R, low densitylipoprotein–receptor; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase-3; iNOS, inducible nitric oxideoxidase; COX-2, cyclooxygenase-2; LOX, lipoxygenase; Gcl, glutamate-cysteine ligase; NAT, arylamine N-acetyltransferases; IAP,inhibitory apoptosis protein; HSP-70, heat-shock protein 70; TNF-a, tumor necrosis factor alpha; IL, interleukin; MCP, monocytechemoattractant protein; MIF, migration inhibition protein; MIP, macrophage inﬂammatory protein; ERK, extracellular receptor kinase;IARK, IL-1 receptor-associated kinase; cAK, autophosphorylation-activated protein kinase; CDPK, Ca2+-dependent protein kinase;cPK, protamine kinase; JAK, janus kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; TK, protein tyrosinekinase; FAK, focal adhesion kinase; PhK, phosphorylase kinase; pp60c-src, pp60c-src tyrosine kinase; PKA, protein kinase A; PKB,protein kinase B; PKC, protein kinase C; FPTase, farnesyl protein transferase; GST, glutathione S-transferase; HO, hemeoxygenase;ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; ELAM-1, endothelial leukocyte adhesionmolecule-1; SHP-2, Src homology 2 domain-containing tyrosine phosphatase 2, uPA, urokinase-type plasminogen activator.matrix metalloproteinase-2 (MMP-2), upregulate LOX pathways [17], induce the degradation oftissue inhibitor of metalloproteinase-1 (TIMP-1) cyclin E expression through a ubiquitin-dependent[12], and block NF-jB and AP-1 activation [13– pathway, upregulate cyclin-dependent kinase16]. Studies have also shown curcumin to inhibit inhibitors p21 and p27 [18] and downregulate
5. P. Anand et al. / Cancer Letters 267 (2008) 133–164 137 Fig. 3. Various cancers against which curcumin has potential for prevention and treatment.the insulin-like growth factor-1 (IGF-1) [19] in of mammary DMBA–DNA adducts in the femalebreast cancer cell lines. rat. Administration (i.p.) of curcumin at 100 and In a study by Zhang et al. [20], exposure of 200 mg/kg doses prevented the development of themouse breast tumor cells to curcumin caused a number of palpable mammary tumors and mam-dose-dependent increase in ubiquitinated exosomal mary adenocarcinomas signiﬁcantly. The in vivoproteins compared to those in untreated cells. The formation of mammary DMBA–DNA adducts alsoexosomes isolated from tumor cells pretreated with was depressed in animals administered with curcu-curcumin have a much attenuated inhibition of min and there was no signiﬁcant enhancement ofIL-2-stimulated-NK cell activation. The tumor exo- liver GST activity following curcumin administra-somes isolated from curcumin-pretreated tumor tion. However, it was also showed that animalscells had lower potency for inhibition of IL-2-stim- fed with diets containing 1.0% curcumin had noulated NK cell cytotoxicity compared to those from eﬀect on DMBA-induced mammary tumor. Innon-treated cells, suggesting that the partial reversal 1996, Pereira et al. showed that curcumin (8 andof tumor exosome-mediated inhibition of NK cell 16 g/kg in diet) was weakly eﬀective in DMBAtumor cytotoxicity may account for the anticancer induced mammary carcinogenesis. Another studyproperties of curcumin. The antitumor activities of evaluated the modulating eﬀects of turmeric (T),curcumin and its isoxazole analog were not aﬀected ethanolic turmeric extract (ETE) and curcumin-freeby multiple gene expression changes in a multidrug- aqueous turmeric extract (CFATE) on the initiationresistant (MDR) model of the MCF-7 breast cancer or post-initiation phases of DMBA-induced mam-cell line [21]. Treatment of breast cancer cells, hav- mary tumorigenesis in female Sprague–Dawley rats.ing up-regulated expression of nicotinamide N- Dietary administration of 1% turmeric/0.05% etha-methyltransferase (NNMT), with curcumin resulted nolic turmeric extract 2 weeks before, on the dayin reduction of the Nicotinamide N-methyltransfer- of DMBA treatment (day 55) and 2 weeks afterase (NNMT) level [22]. In addition to curcumin, the single dose (15 mg/animal) of DMBA (duringseveral derivatives [7,23–25] and analogs [7,21,26] the initiation period) resulted in signiﬁcant suppres-of curcumin were also found to have anticarcino- sion of DMBA-induced mammary tumorigenesis asgenic property against various breast cancer cell seen by a reduction in tumor multiplicity, tumorlines. burden and tumor incidence. In another study it Several in vivo studies have established the che- was showed that feeding 1% dibenzoylmethanemopreventive eﬀect of curcumin against breast can- (DBM), a derivative of curcumin in AIN 76A diet,cer. In 1998 a group studied curcumin’s capacity to inhibited both the multiplicity and incidence ofinhibit 7,12-dimethylbenzanthracene (DMBA) DMBA-induced mammary tumor by 97%. Ininduced mammary tumor and the in vivo formation 2001, it was also showed that feeding 1% DBM diet
6. 138 P. Anand et al. / Cancer Letters 267 (2008) 133–164inhibited formation of DMBA–DNA adducts in normally suitable for the xenograft model studies.mammary glands and the development of mammary Even though it is the only study reporting the inhi-tumors in Sencar mice. The chemopreventive eﬀect bition of tumor regression, further studies areof curcumin on diethylstilbestrol (DES)-induced needed to resolve the contradictions about the eﬀec-tumor promotion of rat mammary glands initiated tiveness of curcumin against breast cancer in vivo.with radiation was evaluated in a study. The admin- An early clinical trial, evaluated the eﬀectivenessistration of dietary curcumin signiﬁcantly reduced of topical application of a curcumin ointment inthe incidence (28.0%) of mammary tumors. Multi- seven patients with breast cancer. In this study,plicity and Iball’s index of mammary tumors were 71% of the patients showed a positive response mea-also decreased by curcumin. Rats fed with the cur- sured as reduction in lesion size, pain, itching andcumin diet showed a reduced incidence of the devel- exudates [7].opment of both mammary adenocarcinoma andER(+)PgR(+) tumors in comparison with the con- 3.2. Gastrointestinal cancerstrol group. Whole mounts of the mammary glandsshowed that curcumin yielded morphologically 3.2.1. Oesophageal cancerindistinguishable proliferation and diﬀerentiation Oesophageal cancer is the seventh leading causefrom the glands of the control rats. The eﬀect of cur- of death from cancer in men, with a mean 5-yearcumin on gamma-radiation induced mammary survival rate in the United States of 15.6%. In thetumors was also demonstrated in rats [2]. United States, there were an estimated 15,560 new In addition to the chemopreventive eﬀects, anti- cases of and 13,940 deaths from oesophageal cancermetastatic eﬀect of curcumin was also established in 2007 [4]. The standard treatment for surgicallyby the in vivo model studies. In a xenograft model resectable tumors is esophagectomy; radiochemo-study (nude mice) conducted in our own laboratory, therapy is used for locally advanced, unresectablethe primary tumor was surgically removed after 58– tumors. Even with these therapies, however, both60 days of tumor cell inoculation and dietary curcu- local regional tumor control and the overall survivalmin (2%) was given to the animals starting from of patients with oesophageal cancer remain poor,ﬁfth day to 5 week of primary tumor removal. We and treatments are associated with signiﬁcantobserved that administration of curcumin signiﬁ- adverse eﬀects, including treatment-related pneumo-cantly decreased the incidence of breast cancer nitis, postoperative pulmonary complications,metastasis to the lung and suppressed the expression oesophagitis, and pericarditis [28]. Innovative treat-of NF-jB, COX-2, and MMP-9. Another group ment strategies are needed to improve the outcomealso evaluated the eﬀect of curcumin on lung metas- of patients with oesophageal cancer.tasis of breast cancer. In this study, intercardiac Curcumin could be a potential candidate for useinoculation of breast cancer cells was done in the in the treatment of esophageal cancer, few studiesnude mice and the animals were fed with diet con- have examined it in this disease and no in vitro eval-taining 1% curcumin. Thirty-ﬁve days after tumor uations of its anticancer eﬀects in oesophageal can-implantation the animals were sacriﬁced and enu- cer cells have been reported. However, curcuminmerated the lung metastases. It was observed that was found to inhibit the cytokine-induced activationall the animals in the untreated group had lung of iNOS, JNK, VCAM, and NF-jB in humanmetastasis whereas 21% animals in the treated oesophageal microvascular endothelial cells isolatedgroup were metastases free. In the control group from normal human oesophageal tissues [29]. Sinceonly 17% animals were having few metastatic nod- inﬂammatory molecules-like NF-jB are overexpres-ules (metastatic score <3) whereas in curcumin-trea- sed in several tumor tissues, these results may beted group 68% animals had few metastatic nodules indirect evidence that curcumin may be eﬀective[2]. In contrast to the above in vivo studies, Somas- against oesophageal cancer. Two in vivo studiesundaram et al., [27] reported a signiﬁcant inhibition have been reported with curcumin in oesophagealof tumor regression in a xenograft mouse model of cancer. In one, dietary curcumin (500 ppm) fed dur-human breast cancer. These contradictory ﬁndings ing initiation and post-initiation stages inhibited thecould have been caused by the diﬀerence in admin- incidence of oesophageal carcinogenesis by 27% andistered doses as well as the time of treatment. For 33%, respectively, in rats [2]. In the other study, theexample, the authors studied the eﬀect of curcumin eﬃcacy of curcumin as a chemopreventive agentin a breast xenograft model for 3 days, which is not was assessed by measuring the modulation in the
7. P. Anand et al. / Cancer Letters 267 (2008) 133–164 139incidence of neoplastic change in rat oesophagus min modiﬁes apoptosis resistance, leading to the[30]. inhibition of tumor formation and the prevention of adenoma development in the intestinal tract.3.2.2. Gastric cancer The chemopreventive eﬀect of curcumin for intesti- In the United States, in 2007, there were an esti- nal tumors in Min/+ mice was investigated. A die-mated 21,260 new cases of and 11,210 deaths from tary level of 0.15% curcumin decreased tumorgastric cancer [4]. Current major modalities for the formation in MinÀ/À mice by 63%. Examinationtreatment of gastric cancer include surgery and che- of intestinal tissue from the treated animals showedmotherapy, but local recurrence and distant metas- the tumor prevention by curcumin was associatedtases, which lead to poor survival rates, are still with increased enterocyte apoptosis and prolifera-unresolved issues in this disease [31], indicating that tion. Curcumin also decreased expression of themodiﬁed treatment strategies are needed. The cyto- oncoprotein b-catenin in the erythrocytes of thetoxic eﬀect of curcumin on gastric carcinoma cell Min/+ mouse, an observation previously associatedlines has been established. In a study curcumin with an antitumor eﬀect. Curcumin enhanced PhIP-and 5-ﬂuorouracil (5-FU) synergistically inhibited induced apoptosis and inhibited PhIP-inducedthe growth of gastric carcinoma cells. In another tumorigenesis in the proximal small intestine ofstudy, curcumin reversed the MDR of a human gas- Apc (min) mice. Evaluation of the preventive eﬀecttric carcinoma cell line in correlation with a decrease of curcumin on the development of adenomas inin P-gp function and a promotion of caspase-3 acti- the intestinal tract using a Min/+mouse modelvation [7]. showed promising chemopreventive eﬀect. Mice Several in vivo chemoprevention studies have received dietary curcumin for 15 weeks and curcu-been reported with curcumin in gastric cancers. In min at 0.1% in the diet was without eﬀect whereassome of the chemoprevention studies, curcumin at 0.2% and 0.5% it reduced adenoma multiplicityfed as dietary turmeric (2% or 5%) to mice and Syr- by 39% and 40%, respectively. How curcumin isian golden hamsters signiﬁcantly inhibited the ben- metabolized in intact rat intestinal sacs in situ waszopyrene-induced forestomach tumors. evaluated and showed that curcumin undergoesFurthermore, the incidence and multiplicity of fore- extensive metabolic conjugation and reduction instomach tumors induced by benzopyrene in female the gastrointestinal tract and that the process ofSwiss mice were signiﬁcantly inhibited by pure cur- metabolism is more complex in human than in ratcumin given 2 weeks before, during and after the intestinal tissue [7]. Experiments performed oncarcinogen treatment. Other studies also revealed intestinal tumors in C57BL/6J-Min/+ (Min/+) micethe chemopreventive eﬀect of curcumin on benzopy- demonstrated that curcumin has a regulatory role inrene-induced forestomach cancer. A signiﬁcant lymphocyte-mediated immune function [33]. Fur-reduction in benzopyrene-induced forestomach pap- ther, levels of COX-2 protein expression have beenillomas in mice due to treatment with dietary tur- found to reﬂect the retardation of adenoma devel-meric extract containing curcumin was also opment in mouse intestines after treatment with cur-reported. It was also showed that curcumin inhib- cumin [34].ited MNNG-induced duodenal tumor in mice and In a phase I clinical trial six patients with intesti-gastric cancer in rats [7]. nal metaplasia of the stomach was treated with 0.5– 12 g/day of curcumin for 3 months. In this study3.2.3. Intestinal cancer one out of the six patients showed histologic According to the estimates of American Cancer improvement in precancerous lesions after the treat-Society, 5640 new intestinal cancers will have been ment [2].diagnosed and 1090 patients will have died fromintestinal cancer in 2007 [4]. Recent advances inneoadjuvant therapies have contributed to 3.2.4. Hepatic cancerimproved survival for patients with intestinal cancer Hepatocellular carcinoma (HCC) is an aggressive[32] and various adjuvant treatment modalities are cancer, and its incidence is increasing in the Unitednow being explored. States and worldwide. In 2007, an estimated 19,160 So far, the eﬃcacy of curcumin in intestinal can- new cases of HCC will have been diagnosed andcer has been shown in a few animal studies. In vivo 16,780 patients will have died from HCC in the Uni-studies using mouse models have proved that curcu- ted States [4]. Novel neoadjuvant treatments are
8. 140 P. Anand et al. / Cancer Letters 267 (2008) 133–164being investigated for the improvement of the cur- esis model, 5-week-old C3H/HeN mice wererent treatment strategies [35]. injected intraperitoneally with DENA. One group Several studies have examined the anticarcino- of the mice were fed with 0.2% curcumin-containinggenic activity of curcumin in hepatic cancer cells diet, starting 4 days before DENA injection andin vitro. In one of these studies, conducted in curcu- until termination of the experiment. At the age ofmin-treated human hepatoblastoma cells, several 42 weeks, the curcumin group had 81% less multi-hallmarks of apoptosis, including DNA laddering, plicity and 62% fewer hepatocarcinomas than thechromatin condensation, fragmentation, and apop- non-treated group. It also suppressed liver inﬂam-tosis-speciﬁc cleavage of 28S and 18S ribosomal mation in rats. Liver was identiﬁed as the major siteRNA were observed. Curcumin has also exhibited for the metabolism of curcumin, and the majorsigniﬁcant antiinvasion activity in human HCC metabolites in suspensions of human or rat hepato-SK-Hep-1 cells, an eﬀect that is associated with cur- cytes were identiﬁed as hexahydrocurcumin andcumin’s-inhibitory action on MMP-9 secretion. hexahydrocurcuminol. In rats, in vivo, curcuminCurcumin undergoes metabolic conjugation and glucuronide and curcumin sulfate were identiﬁedreduction in subcellular fractions of human and as the major products of curcumin biotransforma-rat hepatic tissues [7]. It has also been established tion, whereas hexahydrocurcumin, hexahydrocurcu-that the elevation of GSH levels mediates the eﬀect minol, and hexahydrocurcumin glucuronide wereof curcumin in hepatocytes [36]. present only in small amounts. Another in vivo Curcumin has also been found to interrupt the study showed that curcumin mixed into a diet couldcell cycle, to have cytotoxic eﬀects, and to have a achieve levels of the drug in the liver suﬃcient torole in antiproliferation and the induction of apop- explain its pharmacological eﬀects. Dietary curcu-tosis in a hepatocarcinoma cell line. Curcumin is a min increased the activity of hepatic UGT enzymes,potent inhibitor of phenol sulfotransferase which can detoxify carcinogens, in male Wistar rats.(SULT1A1) in human liver and extrahepatic tissues In an orthotopic implantation model, curcumin[37]. Curcumin inhibited the IL-6 production, his- suppressed both intrahepatic metastases and thetone acetyltransferase (HAT) activity, and AP-1 development of altered hepatic foci (AHF) in rat liv-activation [38] and prevented cell death and apopto- ers. Inhibition of tumor growth by systemic admin-tic biochemical changes, such as the mitochondrial istration of 20 lg/kg curcumin for 6 consecutiverelease of cytochrome c, the activation of caspase- days to rats bearing the highly cachectic Yoshida3, and the cleavage of PARP in human hepatoma AH-130 ascites hepatoma was also reported. Incells [7,39]. Another proposed mechanism for curcu- one of the studies, hepatocellular carcinoma cellsmin’s inhibition of tumor growth in HCC is through were injected subcutaneously in mice and 3 weeksthe inhibition of hypoxia-inducible factor-1 by after cell injection, a tumor fragment from the injec-degrading the aryl hydrocarbon receptor nuclear tion site was implanted to liver. Curcumin (100–translocator [40,41]. Further, it has been shown that 200 mg/kg) was administered after the implantationmitochondrial hyperpolarization is a prerequisite for 20 days and then the eﬀect of curcumin treat-for curcumin-induced apoptosis and that mtDNA ment was evaluated. Although the growth of tumorsdamage is the initial event in a chain leading to at the implanted site was not aﬀected by the curcu-apoptosis in HepG2 cells [42]. In an in vitro study min treatment there was a signiﬁcant and doseusing hepatic cancer cells, a combination of curcu- dependant decrease in number of intrahepaticmin and cisplatin had synergistic antitumor eﬀects, metastases [43].and that with doxorubicin additivity or sub-additiv- Curcumin also prevented the induction of hepaticity [7]. hyper plastic nodules, body weight loss, and hypo- A considerable number of reports have also proteinemia in carcinogen induced as well as xeno-described curcumin in HCC in vivo. In one of these graft hepatic cancer models. Both curcumin andstudies, curcumin signiﬁcantly reduced the number curcumin complexed with manganese preventedof gammaglutamyl transpeptidase-positive foci, a the increase of hepatic lipid peroxidation expressedcharacteristic considered to be the precursor of as MDA level in mice. The antiangiogenic activityhepatocellular neoplasm, in rats. Curcumin also of curcumin in hepatocarcinoma cells implanted inhad anticarcinogenic eﬀects mediated through the nude mice was found to be mediated through theinduction of glutathione-linked detoxiﬁcation reduction of biomarkers COX-2 and VEGF [43].enzymes in rat livers. In a murine hepatocarcinogen- In a pilot trial with 12 patients with hepatic metas-
9. P. Anand et al. / Cancer Letters 267 (2008) 133–164 141tases from colorectal cancer the concentrations of Two in vivo studies were reported showing thethe curcumin in normal and malignant human liver antitumor activity as well as chemosensitizationtissue after patients received 450–3600 mg of curcu- eﬀect of curcumin against pancreatic cancer. In amin daily for 1 week prior to surgery were not suf- xenograft model study, pancreatic cancer cells wereﬁcient to elicit pharmacologic activity, perhaps injected subcutaneously on the side of the abdomenbecause of the extensive degree to which curcumin of female nude mice. Once tumor masses becamewas metabolized in the intestine [7]. established, animals were randomized to receive intravenous liposomal curcumin (40 mg/kg, 3 time3.2.5. Pancreatic cancer per week) for 20 days. Treatment with liposomal Pancreatic cancer is one of the most common curcumin resulted in reduced tumor size and visiblecancers, and the fourth leading cause of cancer- blanching of tumors showing decreased expressionrelated mortality, accounting for about 6% of all of CD31 as well as VEGF and IL-8. These resultscancer-related deaths, in both men and women. indicate that curcumin suppressed pancreatic carci-The median age of diagnosis is 72 years [3]. Despite noma growth in murine xenograft models andadvances in molecular pathogenesis, patients with inhibited tumor angiogenesis [55]. A recent studypancreatic cancer have a mean relative 5-year sur- conducted in our group investigated the chemosen-vival rate of 5%, and the disease remains a major sitization eﬀect of curcumin using an orthotopicunsolved health problem [4]. In an attempt to pancreatic cancer model. After 1 week of implanta-improve survival rates, recent therapeutic tion, mice were randomized into the following treat-approaches have mostly focused on evaluating che- ment groups: untreated control (olive oil, 100 lLmotherapy regimens in which gemcitabine is com- daily), curcumin alone (1 g/kg/day), gemcitabinebined with a second cytotoxic agent. alone (25 mg/kg twice weekly by i.p. injection) and Research over the past decade has indicated that combination of curcumin and gemcitabine. The ani-curcumin has an anticarcinogenic eﬀect in various mals were sacriﬁced 6 weeks after tumor cell injec-pancreatic cell lines, with numerous mechanisms tion and 5 weeks from the date of treatment. Thehaving been proposed to account for this eﬀect. In tumor volume in the combination of curcumin andhuman pancreatic cancer MIA PaCa-2 cells, curcu- gemcitabine group was signiﬁcantly lower than themin was found to inhibit the farnesyl protein trans- gemcitabine alone or control group indicating theferase [7]. Also, NF-jB was found to be chemosensitizing eﬀect of curcumin. Our resultsoverexpressed in human pancreatic tumor tissues showed that curcumin in combination with gemcit-and cell lines; investigators suggested that this over- abine signiﬁcantly down-regulated the expressionexpression could be inhibited by curcumin because of cell proliferation marker Ki-67 in tumor tissuesit has the ability to suppress the NF-jB expression compared with the control group. Further, curcu-[44–46]. Likewise, curcumin reduces numerous IL- min alone signiﬁcantly suppressed the expression8 bioactivities that contribute to tumor growth of microvessel density marker CD31 and the pres-and the cell viability of pancreatic carcinoma cells ence of gemcitabine further enhanced the down-reg-[7,47]. Other mechanisms have been proposed to ulation of CD31 [2].account for the growth-inhibitory eﬀect of curcumin In a clinical trial, researchers evaluated the eﬀectalone [48] or in combination with celecoxib [49] of oral curcumin with piperine on the pain, and theincluding the down-regulation of COX-2, EGFR, markers of oxidative stress in patients with tropicalERK1/2 [50], and Notch-1 [51]. When coupled with pancreatitis (TP). 20 patients with tropical pancrea-gemcitabine, curcumin has been observed to have titis were randomized to receive 500 mg of curcuminsynergistic antiproliferative eﬀects in pancreatic can- with 5 mg of piperine, or placebo for 6 weeks, andcer cell lines [52,53]. Liposomal curcumin down-reg- the eﬀects on the pattern of pain, and on red bloodulated NF-jB machinery, suppressed growth and cell levels of malonyldialdehyde (MDA) and gluta-induced apoptosis of human pancreatic cells thione (GSH) were assessed. There was a signiﬁcantin vitro [2]. A polymeric nanocurcumin formulation reduction in the erythrocyte MDA levels followingalso demonstrated a therapeutic eﬃcacy comparable curcumin therapy compared with placebo; with ato that of free curcumin in a panel of human pancre- signiﬁcant increase in GSH levels. There was no cor-atic cancer cell lines in vitro, and the mechanisms of responding improvement in pain [2].action of nanocurcumin in pancreatic cancer cells The studies from our group [56] showed that cur-mirrored those of free curcumin[54]. cumin inhibited pancreatic cancer in patients. 25
10. 142 P. Anand et al. / Cancer Letters 267 (2008) 133–164patients were enrolled in this study. Patients curcumin [58]. Curcumin causes cell shrinkage,received 8 grams of curcumin by orally every day chromatin condensation, and DNA fragmentation,until disease progression, with restaging every 2 by enhancing DNA damage in HT-29 cells andmonths. Serum cytokine levels for interleukin IL- HCT-116 colonocytes; it also increases GADD1536, IL-8, IL-10, and IL-1 receptor antagonists and mRNA and protein expression [7,59]. Curcuminperipheral blood mononuclear cells (PBMC) expres- upregulates TRAIL-induced apoptosis via ROS-sion of NF-jB and COX-2 were monitored. Out of mediated DR5 activation in human renal cancer25 patients, 21 were evaluable for response. Circu- cells [7]. Likewise, curcumin enhanced the silencinglating curcumin was detectable in glucuronide and of hsp70 expression and may therefore prove to besulfate conjugates forms, albeit at low steady-state a valuable therapeutic agent for cancers whose resis-levels, suggesting poor oral bioavailability. Two tance is due to hsp70 expression [60]. EF24, a syn-patients demonstrated clinical biologic activity. thetic curcumin analog, induces apoptosis in HT-One had ongoing stable disease for more than 18 29 cells through a redox-dependent mechanism [7].months and, interestingly, one additional patient Similarly, the curcumin derivative HBC disrupts cellhad a brief, but marked, tumor regression (73%), cycle progression in HCT15 cells by antagonizingaccompanied by signiﬁcant increases (4- to 35-fold) Ca2+/CaM function [61].in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 The fact that curcumin-induced apoptosis is reg-receptor antagonists). No toxicities were observed. ulated by Bax suggests that the targeting of Bcl-xLCurcumin down-regulated expression of NF-jB, or Smac can be used to treat Bax-deﬁcient, chemo-COX-2 and phosphorylated STAT3 in PBMC from therapy-resistant cancers [62,63]. Together, curcu-patients (most of whom had baseline levels consid- min and either 5-FU or celecoxib downmodulateerably higher than those found in healthy COX-2 expression via the inhibition of prostaglan-volunteers). din formation by curcumin and curcuminoids [7,64]. Curcumin can also induce apoptosis via a3.2.6. Colorectal cancer parallel ceramide-associated pathway and ROS- Colorectal cancer is the third leading cause of associated mechanism that converges at JNK acti-cancer-related death in American adults, accounting vation [65]. In vitro, curcumin activates JNK, p38for 10% of all cancer deaths in the country. Patients MAPK, and AP-1 transcriptional activity. Simi-have a mean 5-year survival rate of 61% [4]. Because larly, it inhibits neurotensin-mediated activator pro-approximately 90% of all deaths from this cancer tein-1, NF-jB activation, Ca2+ mobilization, PGE-are a result of metastases from primary tumors 2, and EGFR and downregulates COX-1 and -2,and investigators are working to modify treatment MMP-2 and -9, IL-8 gene induction, and colon can-strategies speciﬁcally to control the metastatic cer cell migration [65–70]. Curcumin has also pro-activity. ven eﬀective at the mRNA level [71]. Curcumin Studies using various colorectal cell lines have downregulates sulfoconjugation and weakly inhibitsproven curcumin’s use as a therapeutic agent and the glucuronosyl conjugation of 1-naphthol inits ability to act through numerous target molecules. Caco-2 cells [72]. Curcumin coupled with ERRP sig-For example, curcumin has been shown to disrupt niﬁcantly regulates downstream eﬀectors, includingLovo cells in the S, G2/M phase and interrupt NF-jB, Akt, BAD activation, and procaspase-3,Wnt signaling and adhesion pathways causing G2/ in HCT-116 and HT-29 cells [73]. Curcumin in con-M phase arrest and apoptosis in HCT-116 cells, jugation with FOLFOX inhibits colon cancer cellsregardless of prostaglandin synthesis. Curcumin- by inhibiting the EGFR and IGF-1R signalinginduced apoptosis is a result of PARP cleavage, cas- pathways [74]. Treatment with curcumin and epigal-pase 3, reduction in Bcl-xL level, and increased locatechin gallate reduced the amount of viable Apcactivity of caspase-8, which encourages Fas signal- mutant cells by 220–430%, more than each agenting of apoptosis. Curcumin reduces NAT1 mRNA alone did [75].expression and AF-DNA adducts formation in Curcuminoids obstruct cell proliferation andhuman colon tumor cells. Curcumin was found to programmed cell death in primary colon cancer cellsinhibit the proliferation of and induce apoptosis in [76]. Liposomal curcumin attenuates colorectal can-colorectal cell lines; [7,57]. Heat shock aids colon cer by reducing CD31, VEGF, and IL-8 expression.cancer cells by inhibiting the discharge of apopto- This inhibition may be enhanced by the addition ofsis-inducing factors, an event that is enhanced by oxaliplatin for the treatment of p53wt and p53
11. P. Anand et al. / Cancer Letters 267 (2008) 133–164 143mutant colorectal tumors, as shown in HCEC, HT- colorectal cancer in rats [2]. An in vivo study by29, and HCT-116 cell lines [77,78]. Some curcumin Kwon and Magnuson [84] suggested that during ini-derivatives were also found to be eﬀective against tiation, AOM inhibits colonic COX-1 expressioncolon cancer cells. Dimethoxycurcumin, for exam- without aﬀecting COX-2 and dietary curcuminple, is more potent than curcumin in inhibiting pro- may increase COX-2 expression to compensateliferation and inducing apoptosis in HCT116 cells AOM-induced reduction of COX-1 expression in[79]. rats. In male rats, curcumin and curcumin analog Several in vivo studies were reported to show the increased celecoxib-mediated growth inhibition [7].chemopreventive as well as anticancer activity of Similarly, intragastric administration of a bisde-curcumin against colorectal cancer. Wargovich methoxy curcumin analog (BDMCA) or curcuminet al. [80] also showed the chemopreventive activity to DMH-treated rats signiﬁcantly decreased colonof curcumin against carcinogen-induced ACF in tumor incidence [85,86].rats. Sulindac, curcumin, and PEMC administered The preclinical anticancer activity of a liposomalduring promotion and progression have been found curcumin formulation in colorectal cancer was alsoto upregulate apoptosis in rat colonic tumors [7]. recently evaluated. This study also compared theDietary curcumin (0.2%) inhibited the formation eﬃcacy of liposomal curcumin (40 mg/kg adminis-of carcinogen-induced colorectal tumors in rats tered i.v.) with that of oxaliplatin, a standard che-[81]. In rodent models, curcumin hinders tumor sup- motherapeutic agent for colorectal cancer.pressor p53 function, but in AOM-induced rat mod- Signiﬁcant tumor growth inhibition was observedels, apoptosis is induced via a mitochondrial in Colo205 and LoVo xenograft models in mice.pathway [2,82]. The modulatory role of dietary cur- Tumors from animals treated with liposomal curcu-cumin on azoxymethane (AOM) induced aberrant min showed an antiangiogenic eﬀect measured ascrypt foci (ACF) formation in the colon of F344 attenuation of CD31, vascular endothelial growthrats was evaluated and showed that AOM-induced factor, and interleukin-8 expression. Thus, thiscolonic ACF were signiﬁcantly inhibited in the ani- study established the comparable or greatermals fed with the curcumin (2000 ppm/day) diet. growth-inhibitory and apoptotic eﬀects of liposomalThe chemopreventive activity of curcumin was also curcumin with oxaliplatin in vivo in colorectal can-observed when it was administered before, during, cer [77].and after carcinogen treatment as well as when it The pharmacodynamic and pharmacokineticwas given only during the promotion/progression eﬀect of oral Curcuma extract in patients with colo-phase of colon carcinogenesis in rats. The eﬀect of rectal cancer was evaluated. Fifteen patients withtetrahydrocurcumin (THC) on 1,2 dimethylhydra- advanced colorectal cancer refractory to standardzine (DMH) induced colon carcinogenesis was eval- chemotherapies received Curcuma extract daily foruated and the results showed that THC signiﬁcantly up to 4 months. The results showed that oral Cur-decreased both upper and lower half compartments cuma extract was well tolerated, and dose-limitingof colonic crypts. Several studies evaluated the eﬀect toxicity was not observed. Neither curcumin norof curcumin on azoxymethane (AOM) induced its metabolites were detected in blood or urine,colon cancer and showed a signiﬁcant inhibition but curcumin was recovered from feces. Curcuminof colon carcinogenesis after the treatment with cur- sulfate was identiﬁed in the feces of one patient. Acumin. Curcumin inhibited TNBS-, DNB-, and dose-escalation pilot study of a standardized formu-DNCB-induced colitis in rodents [2]. lation of Curcuma extract in 15 patients with Dimethylhydrazine (DMH)-induced rat colon advanced colorectal cancer revealed a dose depen-carcinogenesis model was used for evaluation of dant inhibition of COX-2 activity, measured asthe synergistic-inhibitory eﬀect between curcumin basal and LPS-mediated PGE(2) production, inand catechin in light of ACF formation and tumor blood revealing the eﬃcacy of curcumin in colorec-incidence. The results of this study indicated that tal cancer. Ingestion of 440 mg of Curcuma extractcurcumin, catechin and their co-treatment caused for 29 days was accompanied by a 59% decreasesigniﬁcant inhibition of DMH-induced ACF and in lymphocytic glutathione S-transferase activity.colon carcinogenesis as compared with untreated At higher dose levels, this eﬀect was not observed.DMH-induced rat models [83]. Similarly, in another Leukocytic M(1)G levels were constant within eachstudy it was showed that curcumin and celecoxib patient and unaﬀected by treatment. Radiologicallyadditively inhibits the growth of DMH-induced stable disease was demonstrated in ﬁve patients for
12. 144 P. Anand et al. / Cancer Letters 267 (2008) 133–1642–4 months of treatment. Another study showed referred to as renal cell adenocarcinoma (RCC). Inthat a daily dose of 3.6 g curcumin engendered 2007, 51,190 new cases of RCC will have been diag-62% and 57% decreases in inducible PGE(2) pro- nosed and 12,890 patients will have died of RCC induction in blood samples taken 1 h after dose on the United States [4]. Despite deﬁnitive surgicaldays 1 and 29, respectively, in advanced colorectal treatment, one third of the patients diagnosed withcancer patients. Yet another pilot trial, involving RCC develop postoperative metastases. The 5-year12 patients with hepatic metastases from colorectal overall survival for patients with metastatic RCCcancer who received 450–3600 mg of curcumin is 0–10%, with a median survival time of 10 monthsdaily, for 1 week prior to surgery, oral administra- [4]. Unresectable and metastatic RCC are associatedtion of curcumin results in concentrations of the with poor prognosis chemoresistance, and radiore-agent in normal and malignant human liver tissue, sistance, which leads to lower survival rates. Eﬀortswhich are suﬃcient to elicit pharmacological activ- are ongoing to overcome the chemo- and radioresis-ity. The results of this study suggested that hepatic tance of RCC using new treatment regimens.curcumin levels suﬃcient to exert pharmacological Curcumin has been shown to have apoptotic andactivity are not achieved in humans with the antiproliferative eﬀects against RCC in vitro andabove-mentioned dose of curcumin and that this in vivo. In human kidney cancer cells, curcuminmay be due to extensive intestinal metabolism of upregulates apoptotic events such as cell shrinkage,curcumin leading to lower bioavailability. Curcu- chromatin condensation, and DNA fragmentationmin coupled with quercetin signiﬁcantly decreased [93] and inhibits FPTase [94]. Curcumin serves asthe size and number of ileal and rectal adenomas a COX-I and COX-2 inhibitor [95]; inhibits micro-in patients with FAP [2,7]. somal lipid peroxidation and DNA damage [96]; deactivates the Akt pathway; downregulates Bcl-2,3.3. Genitourinary cancers Bcl-xL, and IAP proteins [97]; and increases TRAIL-induced apoptosis by augmenting DR53.3.1. Bladder cancer expression at the mRNA and protein levels by pro- More than 67,000 people in the United States are ducing reactive oxygen species (ROS) [98]. In HKCdiagnosed each year with bladder cancer [3]. Blad- cells, curcumin reduces tumor growth and the sideder cancer causes 14,000 deaths each year [4], many eﬀects when activated via the hydrolysis of prodrugsof which involve advanced, unresectable, chemo- [91]. An in vivo study demonstrated that dietarytherapy-resistant tumors [87]. Consequently, new curcumin treatment reduced risk for kidney cancerchemotherapeutic regimens are needed. metastasis in rats [99]. Numerous reports indicate that curcumin hasactivity against bladder cancer. For example, curcu- 3.3.3. Prostate cancermin has been shown to suppress the proliferation of Prostate cancer remains the second most lethalbladder cancer cells in culture either through the cancer after lung cancer [4]. Curcumin has shownsuppression of NF-jB [88,89] or through the activity against various prostate cancer cells, suchdown-regulation of cyclin A and up-regulation of as LNCaP, DU145, C4-2B, and PC3. Curcuminp21 [90]. Certain synthetic analogs of curcumin have can induce programmed cell death in androgen-been shown to exhibit activity against bladder can- dependent and androgen-independent prostate can-cer cell lines [91,92]. It was demonstrated that curcu- cer cells. It can inhibit capillary tube formation andmin eﬀectively inhibits tumor implantation and cell migration and exert signiﬁcant eﬀects on actingrowth in a murine bladder tumor model [7]. A cytoskeletons in prostate cancer cells [7,100–102].phase I clinical trial in patients with resected blad- Several mechanisms have been proposed to explainder cancer has indicated that up to 12 g per day of curcumin’s anticancer eﬀects in prostate cancercurcumin for 3 months is pharmacologically safe, cells. For example, curcumin upregulates the expres-and the investigators also noted an indication of his- sion of the maspin gene and downmodulates thetologic improvement of precancerous lesions in one expression of androgen receptor (AR), AP-1, cyclinout of two patients [2]. D1, NF-jB, and camp response element binding (CREB)-binding protein and EGFR tyrosine kinase3.3.2. Kidney cancer activity [7,103]. By inducing p21 and C/EBPbeta The most common type of kidney cancer devel- expression and suppressing NF-jB activation, cur-ops within the small tubes of the kidneys and is cumin augments the cytotoxicity of chemotherapeu-
13. P. Anand et al. / Cancer Letters 267 (2008) 133–164 145tic agents in prostate cancer cells and induces the for up to 6 weeks. At the endpoint, mice were killed,degradation of cyclin E expression [7]. and sections taken from the excised tumors were In prostate cancer cells curcumin was found to evaluated for pathology, cell proliferation, apopto-act as an inhibitor of arachidonate 5-lipoxygenase sis, and vascularity. Curcumin induced a marked[104]. Likewise, curcumin and TRAIL together decrease in the extent of cell proliferation as mea-cause apoptosis via both receptor-mediated and sured by the BrdU incorporation assay and a signif-chemical-induced pathways, owing to an enhanced icant increase in the extent of apoptosis as measuredsensitivity of tumor cells to NF-jB [105–107]. Cur- by an in situ cell death assay. Moreover, microvesselcumin interferes with osteoblastic and osteoclastic density as measured by CD31 antigen stainingcell components, inhibiting growth factor collabora- decreased signiﬁcantly [18]. In vivo, PEITC and cur-tion between prostate cancer cells [108]. Due to its cumin alone or in combination possess signiﬁcantorganic structure as a Michael acceptor, curcumin cancer-preventive characteristics in PC-3 prostateserves as a HAT inhibitor [109]. Curcumin down- tumor xenografts in mice [125]. In another studyregulates the expression of NKX3.1 via AR expres- [126] researchers subcutaneously injected highlysion and DNA-binding activity [110]. Curcumin metastatic androgen-independent prostate cancerupregulates MKP5, thus decreasing cytokine- cell lines into the footpads of SCID mice. The miceinduced p38-dependent proinﬂammatory changes were grouped in to control and experimentalin normal epithelial cells [111]. Curcumin inhibits groups. The control group was given a placebo viaVIP-induced COX-2 expression and VIP-stimulated oral gavage. And the experimental group receivedVEGF mRNA expression via the inhibition of AP-1 an equal volume of placebo, mixed with curcumin,binding [112–114]. In PC3 cells, curcumin downreg- at a dosage of 5 mg/kg. All mice continued toulates MDM2 proteins and mRNA. enhances the receive placebo or curcumin (three times per week)expression of the tumor suppressor p21, and inhibits for 10 weeks. The mean tumor volumes at 4 weeksIjBa [101,115]. Curcumin can also inhibit prostate after tumor inoculation in the control and experi-cancer via the Akt pathway or the induction of mental animals were determined to beapoptosis by Bcl-2 family members and mitochon- 168.6 ± 40.7 mm3 and 99.5 ± 27.2 mm3, respec-drial p53 [102,116,117]. tively. Curcumin was shown to induce a marked A curcumin derivative, HMBME, also targets the reduction of MMP-2, and MMP-9 activity in theAkt and NF-jB pathway [118]. Likewise, other cur- tumor-bearing site. The metastatic nodules in vivocumin derivatives, diacetyldemethoxycurcumin, tri- were signiﬁcantly fewer in the curcumin-treatedacetyldemethylcurcumin, and 4- group than untreated group. Li et al. [115] evaluatedethoxycarbonylethyl curcumin may exhibit greater the antitumor, chemosensitizing and radiosensitiz-activity against prostate cancer cells than curcumin ing eﬀect of curcumin using a xenograft prostateitself and serve as potential agents against prostate cancer model. The xenograft model was establishedcancer [24,119,120]. Another curcumin analog, by injecting prostate cancer cells into the left ingui-EF24, shows anticancer eﬀects that are regulated nal area of nude mice. Mice bearing tumors ofby the redox-mediated induction of apoptosis, while 100 mg were randomly divided into multiple treat-other analogs act as AR antagonists [121,122]. Still ment and control groups. Curcumin, dissolved insome curcuminoids may reduce the sprout forma- cottonseed oil, was given by gavage (5 mg/day, 5tion of endothelial cells via the inhibition of P-12- days per week) for 4 weeks. Gemcitabine (160 mg/LOX [123]. Curcumin and its derivatives possess kg) was given by i.p. injection on days 7, 14, andtherapeutic abilities as potent radiosensitizers by 21, and radiation (3 Gy) was administered on daysovercoming the eﬀects of radiation-induced prosur- 4, 6, and 10. Analysis of tumors collected at thevival gene expression in prostate cancer [7]. PEITC end of the experiment showed that curcuminand curcumin inhibit cell proliferation and cause reduced the expression of MDM2 oncogene inapoptosis by targeting EGFR, Akt, and NF-jB sig- xenografts treated with curcumin alone, and innaling pathways [124]. xenografts treated with combinations of curcumin In order to investigate the anticancer potential of plus gemcitabine or irradiation. These results indi-curcumin against prostate cancer, androgen-depen- cate a novel mechanism of action that may be essen-dent LNCaP prostate cancer cells were injected sub- tial for curcumin’s chemotherapeutic eﬀects.cutaneously to mice. The experimental group The eﬀect of zyﬂamend, a herbal preparationreceived a synthetic diet containing 2% curcumin containing curcumin against high-grade prostatic
14. 146 P. Anand et al. / Cancer Letters 267 (2008) 133–164intraepithelial neoplasia (HGPIN) was evaluated in has been attributed largely to limitations in cyto-patients. A patient with HGPIN was treated with toxic therapy, including intrinsic and acquired drugzyﬂamend, three times a day for 18 months. After resistance and the lack of speciﬁcity of agents target-6 months the biopsy revealed benign prostatic ing mechanisms of disease progression [132]. Thehyperplasia alone and after 18 months biopsy was treatment of recurrent disease often prioritizes palli-negative for cancer and PIN indicating that the ative care and seeks to provide symptom control,patient was cancer and HGPIN free [2]. trigger tumor regression, and improve quality of life.3.4. Gynecologic cancers Some in vitro studies over the past decade have shown that curcumin [7,133,134] and a curcumin–3.4.1. Cervical cancer paclitaxel conjugate [135] had therapeutic eﬀects in Cervical cancer is important not only because it ovarian cancer cell lines. Curcumin was found tois the most prevalent cancer in women in several act through the down-regulation of NF-jBdeveloping countries, but also because it is often [7,136,137] and allied gene products [138–140]. Fur-diagnosed in young patients – the age at diagnosis thermore, curcumin was found to increase the sensi-48 years – giving the treatment of this disease a tivity of chemotherapy-resistant ovarian cancer celldegree of societal importance [3]. The understand- lines to standard chemotherapeutic agents by acti-ing that infection with human papillomaviruses vating both the cells’ extrinsic and intrinsic path-(HPVs) leads to the development of cervical cancer, ways of apoptosis [7,141]. A recent study of ourspredominantly through the action of viral onco- also showed that curcumin had therapeutic andgenes, may lead to eﬀective treatment strategies. If chemosensitization eﬀects and reversed multidrugapplied wisely, HPV-related technology should min- resistance both in vitro and in vivo in athymic mice.imize the incidence of cervical cancer, along with the In the in vivo study, tumors were grown by ortho-morbidity and mortality associated with the disease. topic injection of cells and 1 week after orthotopicThe in vitro antitumor activity of curcumin in HPV- implantation animals were treated with curcuminassociated cells has been established [127]. Curcu- (500 mg/kg/day, gavage) alone or in combinationmin modulates the in vitro expression and function with docetaxel (35–50 lg/animal/week, i.p.) for 4of P-gp in multidrug-resistant human KB-V1 cells weeks. Curcumin alone resulted in 49–55% reduc-[7,128] and sensitizes cisplatin-resistant SiHa cells tions in mean tumor growth compared with controlsto cisplatin-induced apoptosis [129], indicating its whereas when combined with docetaxel 77% reduc-ability to reverse MDR in cervical cancer cells. tions in mean tumor growth compared with controlsThe eﬀect of curcumin in HPV-associated cells was was obtained for curcumin in normal ovarian tumorfound to involve the down-regulation of viral onco- models. In these ovarian tumors, curcumin alonegenes, NF-jB and AP-1 [7,130]. Similarly, a major and with docetaxel decreased both proliferationmetabolite of curcumin called THC increased the and microvessel density and increased tumor cellsensitivity of vinblastine, mitoxantrone, and etopo- apoptosis. In mice with multidrug-resistant ovarianside in a drug-resistant human cervical carcinoma tumors, treatment with curcumin alone and com-cell line [131]. In a phase I clinical trial, a daily bined with docetaxel resulted in signiﬁcant 47%0.5–12 g dose of curcumin taken orally for 3 months and 58% reductions in tumor growth, respectivelyresulted in the histologic improvement of precancer- [142].ous lesions in one out of four patients with uterinecervical intraepithelial neoplasms [2]. 3.4.3. Uterine cancer Among women in the United States, uterine can-3.4.2. Ovarian cancer cer is the third most common cancer diagnosis and Ovarian cancer is the eighth most commonly the eighth most common cause of death from cancerdiagnosed cancer in women in the United States. [4]. Uterine carcinosarcoma is a rare, fast-growingOf the estimated 22,430 women who will have been form of uterine cancer that contains a mix of twodiagnosed with ovarian cancer in 2007, the majority types of cancer cells, an unusual feature of this dis-will present with advanced-stage disease [4]. Early- ease. Surgery to remove the uterus can cure thesestage ovarian cancer has a good prognosis, but the mixed uterine tumors if the disease has not spreadmajority of patients with advanced-stage disease beyond the uterus. When the disease has spread,have relapses despite optimal primary therapy. This however, it usually does not respond well to chemo-
15. P. Anand et al. / Cancer Letters 267 (2008) 133–164 147therapy, and the outlook for patients is poor. Sev- wise, treatment with curcumin induces apoptosiseral single-agent chemotherapeutic regimens, such and inhibits growth in A549 and H1299 cells [149].as those based on cisplatin, ifosfamide, and paclit- In A549 cells, curcumin interferes with cell growthaxel, have been reported to have response rates of and downregulates NAT activity and STAT1 acti-10–40% in clinical trials, Consequently, newer com- vation [150–152]. Curcumin regulates the invasivebination regimens are being tested to achieve higher activity of CL1-5 cells and demonstrates antiprolif-response rates. In a phase III clinical trial, although erative properties in NCI-H460 and -H520 cells,the overall survival of women with disseminated suggesting its suitability as an adjunct chemothera-carcinosarcoma of the uterus improved after treat- peutic agent [7,153,154].ment with a combination of paclitaxel and ifosfa- Orthotopic implantation of a metastatic cell linemide, the authors of that study proposed that the of Lewis lung carcinoma (LLC-MLN), which waspoor overall survival rates for the disease still isolated by an in vivo selection method, resulted inrequires the development of new active agents [143]. greater metastatic growth in mediastinal lymph On the basis of the ability of curcumin to aﬀect nodes as compared with that of the original LLCmultiple targets, it is tempting to speculate that cur- cells. Oral administration of curcumin signiﬁcantlycumin may serve as an eﬀective agent for use in inhibited the mediastinal lymph node metastasis ofcombination chemotherapy for uterine cancer. orthotopically implanted LLC cells in a dose-depen-However, very few studies on the anticancer activity dent manner, but did not aﬀect the tumor growth atof curcumin against uterine cancer have been the implantation site. Combined treatment with cur-reported. In one of the few that have, curcumin dis- cumin and cis-diamine-dichloroplatinum (CDDP),played in vitro apoptosis-inducing activity against resulted in a marked inhibition of tumor growthan endometrial cancer cell line [57] by the down-reg- at the implanted site and of lymphatic metastasis,ulation of Ets-1 and Bcl-2 expression [144]. Further. and a signiﬁcant prolongation of the survival timein vitro studies revealing other molecular mecha- [147]. Deshpande and Maru [155] showed that cur-nisms of curcumin activity in uterine cancer cells, cumin can inhibit BP-derived DNA adducts byanimal model studies, and clinical trials have yet interfering with the metabolic enzymes and its phys-to be reported. ical presence is essential for this eﬀect. In the year 1999 one group [7] studied the activity of curcumin3.5. Thoracic/head and neck cancers as chemopreventive agent against lung tumor induc- tion in A/J mice by the tobacco smoke carcinogens3.5.1. Pulmonary cancer benzopyrene (BaP) and 4-(methyl-nitrosamino)-1- Lung cancer is the most commonly diagnosed (3-pyridyl)-1-butanone (NNK). The treatment ofand leading cause of death by cancer in men in curcumin (2000 ppm) 1 week after carcinogen treat-the United States [4]. The median age of diagnosis ment until termination had no eﬀect on lung tumoris 70 years [3]. Although many patients achieve dis- multiplicity. In another study, oral administrationease-free survival, some experience a long-term of curcumin (200 nmol/kg body weight) was, how-impairment of their quality of life, and disease ever, found to inhibit the lung metastasis of mela-recurrence is common [145]. Numerous chemother- noma maximally as seen by the reduction in theapeutic combination regimens are continuously number of lung tumor nodules (80%). Consequentbeing introduced for the treatment of advanced lung to the inhibition of the lung tumor nodules, the lifecancer to improve patient outcomes. span of animals treated with curcumin was also Curcumin exhibits anticancer eﬀects in various found to be increased (143.85%). The results indi-lung cancer cells through a variety of molecular tar- cate a possible use of these compounds in arrestinggets. At the cellular level, curcumin derivatives inhi- the metastatic growth of tumor cells. In Wistar rats,bit FPTase in A549 cells. Curcumin inhibits AP-1 however, marker enzymes and plasma lipid levelstranscription and mediastinal lymph node metasta- decreased after treatment with 80 mg/kg of curcu-sis in Lewis lung carcinoma cells and ornithine min or a curcumin analog [7].decarboxylase activity in rat tracheal epithelial cells[146,147]. Curcumin eradicated the DNA-binding of 3.5.2. Oral cancerNF-jB, IjBa kinase activation, IjBa deterioration Oral cancer accounts for 2–4% of the cancersand phosphorylation, and p65 nuclear transloca- diagnosed annually in the United States. In 2007,tion, and it down-regulated COX-2 [7,148]. Like- an estimated 34,360 patients will have been diag-
16. 148 P. Anand et al. / Cancer Letters 267 (2008) 133–164nosed with the disease; approximately 7550 will the incidence of oral squamous cell carcinomahave died. Only half of the patients diagnosed with (SCC) and reduced the number of oral SCC lesionsoral cancer will be alive 5 years after they receive the by 51.3%. In this study, curcumin treatment resulteddiagnosis. Ninety-ﬁve percent oral cancers occur in inhibition of tumor angiogenesis in the case ofamong persons older than 40 years, and the mean papilloma and SCC. Decrease of tumor prolifera-age at diagnosis is 62 years [3]. Tobacco smoking, tion index in hyperplasia, displasia and papillomaparticularly when combined with heavy alcohol was also observed due to curcumin treatment [7].consumption, has been identiﬁed as the primary risk Reports of two clinical trials have also revealedfactor for approximately 75% of oral cancers in the the eﬀectiveness of curcumin in human oral carci-United States [156]. The most common treatments noma. In an early clinical trial topical applicationfor oral cancer are surgery and chemotherapy. After of a curcumin ointment showed decrease in pain,surgical ablation, recurrence and metastasis are fre- exudates, itching, and lesion size. In another phasequent events; and this clearly indicates the need for I clinical trial, it was reported histologic improve-a standardized multimodality therapy for oral ments in precancerous lesions (in 29% of thecancer. patients) after treatment with curcumin (0.5–12 g/ Curcumin inhibited the growth of oral cancer cell day) for 3 months [2].lines in vitro [7,157,158] by blocking the S/G2Mphase. It acted synergistically with a G1 phase 3.5.3. Thymic cancerblocker, epigallocatechin-3-gallate [7]. Curcumin Cancer of the thymus is associated with a highinhibited the growth of and DNA synthesis in risk of recurrence and a poor survival rate.SCC-25 oral cancer cells [7,159]. Curcumin Advanced invasive thymomas are not usually man-increased both the expression and function of cyto- ageable using surgical resection and radiotherapychrome P450 (CYP) 1A1 and/or CYP1B1 in oral [164]. An appropriate multidisciplinary treatmentcancer cells, indicating that it has chemopreventive approach is essential for the long-term survival ofproperties mediated by the inhibition of carcinogen patients with recurrent disease. The anticancer eﬀectbioactivation [160]. Further, curcumin exhibited of curcumin in murine thymoma cells was found toradiotherapy-sensitizing eﬀects on SCC cells be due to the blocking of interleukin-1 (IL-1) signal-in vitro [161]. Moreover, the ability of curcumin to ing by the inhibition of the recruitment of the IL-1induce apoptosis in oral cancer cells was associated receptor-associated kinase IRAK [165]. A recentwith the inhibition of COX-2 [162]. A recent study study showed that curcumin could prevent tumor-of ours also revealed that curcumin downregulates induced thymic atrophy in thymic T cells, leadingsmokeless tobacco-induced NF-jB activation and to the neutralization of tumor-induced oxidativeCOX-2 expression in human oral premalignant stress and the restoration of NF-jB activity andand malignant cells [163]. the re-education of the TNF-a signaling pathway, Several in vivo studies have also revealed the resulting in thymic protection [166]. We were unablepotency of curcumin against oral cancer. Curcumin to locate animal or clinical studies on curcumin inalone or in combination with other has acted as a cancer of the thymus.chemopreventive agent in oral cancer models in ratsand hamsters. It was showed that male F344 rats fed 3.6. Hematologic cancerswith dietary curcumin (0.5 g/kg) during the initia-tion and post-initiation stages exhibited 91% reduc- 3.6.1. Leukemiation in the frequency of 4-nitroquinoline-1-oxide- Cancer of the blood or bone marrow, or leuke-induced tongue carcinoma with a decrease in inci- mia, is characterized by the atypical proliferationdence of oral preneoplasia [7]. Another study of blood cells. An estimated 44,240 new cases of leu-showed that curcumin alone or in combination with kemia will have been diagnosed in the United Statescatechin inhibited methyl-(acetoxymethyl)-nitrosa- in 2007. Chronic leukemias account for 7% moremine (MNA)-induced oral mucosal tumors in Syr- cases than do acute leukemias. Most cases occurian golden hamsters. In Syrian golden hamsters, in older adults; more than half of all cases occur10 mmol curcumin (applied topically 3 times/week) after age 67 years. It is anticipated that approxi-decreased the number of visible oral papillomas mately 21,790 deaths in the United States will haveand papilloma volume by 39.6% and 61.3%, respec- been attributed to leukemia in 2007 [4]. Primarytively. Further, curcumin treatment also decreased therapy usually involves a combination of several
17. P. Anand et al. / Cancer Letters 267 (2008) 133–164 149drugs but treatment approaches are undergoing [187,188]. In TK-10, and UACC-62 cell lines, curcu-intensive study throughout the world, as investiga- min initiates apoptosis via telomerase II poisoning,tors attempt to achieve complete disease remission. resulting in DNA damage [189]. Acute leukemia In vitro, curcumin has been shown to have syner- cells exposed to curcumin for 4 h have increasedgistic and remedial properties in leukemia. In HL-60 nitric oxide (NO) levels [190]. This increased NOcells, a regimen of 10 lM curcumin for 48 h has production by macrophages and the inhibition ofbeen the most eﬀective in decreasing cell prolifera- Th1 cytokines in NK cells in the presence of curcu-tion and increasing diﬀerentiation. These eﬀects min lead to signiﬁcant tumoricidal results [191].were exacerbated when curcumin was given in con- Likewise, MDR1 mRNA levels were reduced morejunction with RA, vitamin D3, and vitamin D3 ana- signiﬁcantly in leukemia cells from patients withlogs [127,167–169]. Curcumin alone causes a higher MDR1 gene groups [192]. The proliferationsigniﬁcant reduction in NF-jB expression, Bcl-2 of Jurkat cells was reduced with curcumin treat-activity, and TPA-induced DNA binding. It also ment, resulting in chromatin condensation and cas-induces ER stress bax and caspases 3 and 8; and pase-3 induction via the prevention of a decrease indegrades PARP [7,168,170–172]. The proposed glutathione levels [193,194]. In Bcr-Abl-transfectedmechanism involves the interruption of G0/G1 mouse progenitor 32D cells, curcumin inhibits pro-phases associated with the up-regulation of P27kipl, liferation by arresting cells in the G(2)-M phase ofP21waﬂ, and pRbp-expression and the down-regu- the cell cycle, resulting in irregular chromatin orga-lation of cyclin D3 [7,173]. nization, multipolar chromosome segregation, aber- Within HL-60 cells, curcumin and its analog, rant cytokinesis, and multinucleated cells withalpha-diisoeugenol, induced ROS levels, and curcu- morphologic changes [195]. Like curcumin, curcu-min alone up-regulated Ca2+ production and the min analogs in KBM-5 cells blocked TNF-inducedrelease of cytochrome c and lowered MMP levels NF-jB activation and proliferation, and curcumi-[162,174,175]. When coupled with TSA, curcumin noids inhibited COX-I and COX-II enzymes [7,196].increased histone acetylation, increasing cytotoxic- Studies have also demonstrated curcumin’s ther-ity for HL-60 cells [176]. In Raji cells, curcumin apeutic properties in vivo. In 6-week-old mice, theselectively blocks tumor cells in the G0/G1 and administration of a 2% curcumin diet via oralG2/M phases; dose-dependently upregulates Ac-his- gavage resulted in a 53% reduction in lymphomastone H4 expression; inhibits the proliferation and and leukemias. When topically applied prior to thedegradation of IjBa and Notch 1; and inhibits the administration of TPA in mice, curcumin down-reg-translocation of the NF-jB/p-65 subunit via the ulated TPA-induced NF-jB and AP-1. It was alsodownmodulation of HDAC1 and p300/Notch 1 sig- showed that oral administration of curcumin (50–nal molecules [177–180]. Similarly, in the presence 200 mg/kg) inhibits the development of leukemiaof curcumin, TERT is translocated, causing a loss (HL-60) cells induced xenografts in nude mice [7].of telomerase activity, and the expression of In a group of 10 male smokers, 10 male non-smok-STAT3, -5a, and -5b are reduced without altering ers, and 10 non-smoking women between 25 and 45STAT1 or the phosphorylation states of STAT1, - years of age, curcumin reduced BP-stimulated3, or -5 in the K562 cell line via the release of cyto- strand breaks in a sex-dependent manner [197]. Inchrome c from mitochondria [181,182]. Curcumin 70 samples of childhood leukemia from patients,also aﬀects GST-modulated lipid peroxidation, curcumin reduced WT1 gene expression in 35 sam-AP-1 and NF-jB binding to GSTP1-1 promoters, ples [198].ADP ribose polymerase cleavage, and pro-caspases8 and 9 induction in K562 cells [183,184]. 3.6.2. Lymphoma Curcumin dose-dependently downregulates JAK The American Cancer Society estimated thatand STAT phosphorylation, causing growth inhibi- 71,380 cases of lymphoma will have been diagnosedtion and apoptosis in T cell leukemia, HTLV-I– in the United States in 2007, and 19,730 people willtransformed T cell leukemia, MT-2, HuT-102, and have been expected to die of the disease. LymphomaSLB-1 cell lines. It does so by inhibiting cyclin D1, is the ﬁfth most common cancer in the Unitedcdk1 Cdc25C, and XIAP and Survin expression States, with the elderly having the highest risk of[185,186]. Curcumin suppresses the proliferation of developing lymphoma [3,4]. The most commonWEHI-3B cells and blocks STAT5 mRNA expres- treatment approach today is to use chemotherapysion and STAT5 activation in CML cells and radiotherapy. Patients with fast-growing,
18. 150 P. Anand et al. / Cancer Letters 267 (2008) 133–164aggressive lymphomas are frequently treated with Numerous reports suggest that curcumin exhibitschemotherapy that consists of four or more drugs. antiproliferative eﬀects against MM cells. TheNew approaches to therapy are under study to mechanisms of the antiproliferative eﬀects of curcu-improve treatment outcomes and reduce side eﬀects. min in MM cells have been studied and described Curcumin was found to inhibit cellular prolifera- extensively. The role of the NF-jB and STAT3tion and enhance apoptosis in a variety of lym- pathway as a target for curcumin in MM cells hasphoma cell lines in vitro [7,199–201]. The been demonstrated [7,204,205]. Curcumin hasproposed mechanism of curcumin’s action in the shown activity against not only MM cell lines butmajority of these studies involves the suppression also against fresh CD138+ MM cells derived fromof the expression of NF-jB-regulated gene prod- patient bone marrow. Curcumin was also found toucts. One study suggested a novel function for cur- synergize with the dexamethasone used routinelycumin as a suppressor of JAK-1 and STAT3 in the treatment of MM patients [7]. Curcumin isactivation in primary eﬀusion lymphoma cells, a known to suppress both the production and signal-function that would lead to the inhibition of prolif- ing of IL-6, a critical growth factor for MM cellseration and the induction of caspase-dependent [39]. Curcumin also interrupts the interactionapoptosis [202]. It was showed that oral administra- between MM cells and endothelial cells by reducingtion of curcumin (50–200 mg/kg) inhibits the devel- TrjB expression in endothelial cells and inhibitingopment of lymphoma (SGC7901) cells induced brain-derived neurotrophic factor (BDNF) produc-xenografts in nude mice [2]. Curcumin inhibited tion in MM cells, eventually resulting in the inhibi-the growth of both murine and human B lymphoma tion of angiogenesis [206].cells in vitro and murine B lymphoma cells in vivoby the down-regulation of spleen tyrosine kinase 3.7. Melanoma(Syk) activity accompanied by the down-regulationof Akt activation [203]. In 2007, it is estimated that 59,940 patients in the United States will have been diagnosed with mela-3.6.3. Multiple myeloma noma, and 8110 will have died of the disease [4]. Multiple myeloma (MM) is a B cell malignancy It is the most deadly form of skin cancer, and is verycharacterized by the latent accumulation of secre- aggressive and resistant to present therapies. Severaltory plasma cells in bone marrow that have a low reports describe the antitumor activity of curcuminproliferative index and an extended life span. About and of a formulation of the synthetic curcumin ana-19,900 patients in the United States will have been log, EF24 [26] in various melanoma cell lines. Thediagnosed with MM in 2007; approximately eﬀects of curcumin were found to be mediated10,790 will have died of MM in the same year [4]. through the inhibition of glutathione S-transferaseThe agents used to treat have included combina- activity [207], the inhibition of COX-1 and COX-2tions of vincristine, BCNU, melphalan, cyclophos- enzymes, the induction of apoptosis through thephamide, adriamycin, and prednisone or Fas receptor/caspase-8 pathway and the down-regu-dexamethasone. Aggressive, high-dose chemother- lation of the NF-jB pathway [7,208,209]. The mod-apy, bone marrow transplantation, and intensive ulation of integrin receptors and collagenasesupportive care can increase median survival rates. activity, the expression of Nm23 and E-cadherinMore recently, agents with novel mechanisms of [210], the down-regulation of FAK, and the reduc-action, such as the proteasome inhibitor bortezomib tion of MMP-2 activity [211] were found to beand immunomodulatory drugs like thalidomide and responsible for the antimetastatic eﬀect of curcuminits derivative, lenalidomide, have shown promise for in melanoma cells. Curcumin was found to reversethe treatment of patients with refractory and the resistance of melanoma cells to multiple drugsrelapsed disease as well as for patients with previ- by inhibiting glutathione-S-transferases [212,213].ously untreated MM. Recent combinations of tha- The chemopreventive eﬀects of curcumin on sev-lidomide, bortezomib, and lenalidomide with or eral carcinogen-induced skin cancer models havewithout alkylating agents, anthracyclines, and ste- been investigated. Topical application of curcuminroids have produced rapid remissions (within 1–3 (even lower doses of 20–100 nmol) together withcycles), resulting in improvements in both overall tumor promoter TPA, twice weekly for 20 weeksresponse rates (75–95%) and complete response to female CD-1 mice strongly inhibited TPA-rates of 5–25 in patients receiving induction therapy. induced papilloma formation. Further, in female
19. P. Anand et al. / Cancer Letters 267 (2008) 133–164 151Swiss mice dietary administration of 2% turmeric Curcumin induced apoptosis by inhibiting NF-jBsigniﬁcantly inhibited DMBA plus TPA-induced [214] and the expression of IL-6 and IL-11 [215]skin tumor formation. In this benzopyrene-initiated and by abolishing the inhibitory eﬀect of TGF-band TPA-promoted two-stage skin tumorigenesis on GR-mediated gene expression [216,217] in ﬁbro-model, curcumin reduced the number of tumors sarcoma cells. Curcumin suppressed MMP-13per mouse and decreased the number of tumor- expression in chondrosarcoma cells. Synthetic cur-bearing mice. Another study conducted showed that cumin analogs were also found to be potent againstcurcumin inhibited UV-induced dermatitis in mouse bone cancer cells. In ﬁbrosarcoma cells, syntheticskin [2]. curcumin analogs inhibit activator protein-1 tran- The in vivo antimetastatic eﬀect of curcumin was scription and tumor-induced angiogenesis byalso established. In one study, oral administration down-regulating the expression of angiogenesis-of curcumin (200 nmol/kg body weight) was found associated genes, VEGF and MMP-9. Further, into inhibit the lung metastasis, induced by B16F10 human osteosarcoma cells curcumin was found tomelanoma cells, measured as the reduction in the inhibit the ERK expression. Curcumin was foundnumber of lung tumor nodules (80%) and there to induce apoptosis in a variety of osteosarcomawas an increase in the life span of mice by cells by down-regulating the Bcl-2 expression143.85%. The lung metastasis inhibition of curcu- [7,218].min was correlated with its ability to inhibit the In an in vivo study in rats, dietary curcumin withinvasion of B16F10 melanoma cells by inhibiting cisplatin modulated tumor marker indices of ﬁbro-the metalloproteinases. The ability of curcumin to sarcoma towards normal controls [219]. Treatmentinhibit melanoma growth and tumor-speciﬁc angio- with radiotherapy and curcumin resulted ingenesis in mouse models was also reported. The enhanced tumor cell-killing and reduced radioresis-eﬀectiveness of a prophylactic immune preparation tance in mice bearing ﬁbrosarcoma, as indicated byof soluble proteins from B16-R cells, or a treatment the signiﬁcant inhibition of radiation-induced ERKwith curcumin alone or in combination was evalu- and NF-jB expression [220].ated using a mouse melanoma model. The combina-tion treatment resulted in substantial inhibition ofmelanoma growth compared to each treatment by 3.9. Brain tumoritself. A signiﬁcant percentage increase in the med-ian survival time was also observed in the combina- Malignant gliomas are a debilitating class oftion group (>82.8%) as opposed to the 48.6% brain tumors that are resistant to radiation and che-increase in immunization only group and 45.7% motherapeutic drugs. In the United States, theincrease in the curcumin only group [7,43]. annual incidence of brain cancer generally is 15–20 cases per 100,000 people. Brain cancer is the leading3.8. Bone cancer cause of cancer-related death in patients younger than age 35 [4]. The therapeutic eﬃcacy of curcumin Bone cancer and its subtypes aﬀect fewer than in various human malignant glioblastoma cells has200,000 people in the United States, qualifying it been established [221], and curcumin was found toas a rare disease according to the Oﬃce of Rare Dis- inhibit the NF-jB signaling pathways in these celleases (ORD) of the National Institutes of Health lines [222–224].(NIH). According to 2007 cancer statistics, 2370 Numerous other mechanisms, like the inductionnew cases for bone/joint cancer were expected in of heat shock proteins [7], the inhibition of MMPthe United States, and 1330 deaths were expected transcriptions [225,226], TRAIL-induced apoptosisfrom this disease in the same year [4]. Surgery with [227], the inhibition of G6PT gene expressionpreoperative and/or postoperative chemotherapy is [228], the activation of both receptor-mediated andconsidered standard treatment. As in most other mitochondria-mediated proteolytic pathways [229],cancers, new chemotherapeutic regimens are being the induction of histone hypoacetylation leadingexplored to improve treatment outcomes. to apoptosis in a (PARP)- and caspase 3-mediated Curcumin and its analogs were found to have manner [230], the inhibition of the ING4 signalingantitumor eﬀects in bone cancer cells. Numerous pathway [231], and the induction of non-apoptoticmechanisms have been proposed for the activity of autophagic cell death [232,233] have also beencurcumin against ﬁbrosarcoma cells in particular. established. Further, curcumin was found to sensi-
20. 152 P. Anand et al. / Cancer Letters 267 (2008) 133–164tize glioma cells to several chemotherapeutic agents inﬂammatory cytokines appear to play a major roleand to radiation therapy [224]. in it. For example, TNF has been identiﬁed as an In an in vivo study, curcumin signiﬁcantly important mediator of neuropathic pain [238].decreased the incidence of radiation-induced pitui- Nociceptors (pain receptors) are activated by vari-tary tumors in rats [7]. In the subcutaneous xeno- ous inﬂammation-associated factors, such as TNF-graft model of glioblastoma cells, curcumin a [239,240], IL-1, and IL-6 [239,241], which areinhibited tumor growth signiﬁcantly and induced released from damaged tissue and/or tumors [242].autophagy. In this study, tumor cells were injected Various chemotherapeutic drugs including vincris-and when the tumors reached 50–70 mm3 in volume, tine, taxanes, and cisplatin have been associatedintratumoral injections of curcumin (100 mg/kg in with neuropathic pain [243,244]. More recently,DMSO/PBS) were administered every 24 h for 7 the administration of bortezomib to patients withdays. Evaluation of the eﬀect was performed on MM was also found to result in neuropathic painday 16 of the initial curcumin treatment. An [245,246]. Although pain in advanced MM is usu-approximate three fold decrease in mean tumor vol- ally attributed to bone destruction (prominentlyume was observed in the curcumin-treated group contributed to by IL-6) inﬂammation also plays acompared to the controls [233]. role in the transmission of pain and in the hyperal- gesia associated with some treatments (bortezomib)4. Control of cancer symptoms by curcumin for MM. Numerous studies indicate that curcumin may Patients with cancer suﬀer from various treat- have potential activity against neuropathic pain.ment-related symptoms, including neuropathic In experiments using tail immersion and hot-platepain, depression, fatigue, decreased appetite, and assays in mice, curcumin (15–60 mg/kg) was foundsleep disturbance. Many of these symptoms may to alleviate neuropathic pain, which correlated withcause treatment delays and prevent the delivery of the down-regulation of TNF and the release of NOfull-dose therapy in the scheduled time. In the [247]. Besides inﬂammatory cytokines, curcumincourse of targeting cancer, most chemotherapeutic may also mediate its eﬀects through interaction withagents activate NF-jB and induce TNF release. CD13/aminopeptidase N (APN), a membrane-Consequentially, many of the symptoms related to bound, zinc-dependent metalloproteinase linkedcytokine dysregulation are aﬀected by both the dis- with neuropathic pain through the inactivation ofease and the treatment. For example, chemotherapy opioid peptides, such as enkephalins [248]. Interest-commonly causes neuropathic pain, depression, ingly, curcumin was found to directly bind to APNfatigue, decreased appetite, and sleep disturbance, and irreversibly inhibit its activity [7]. This may beall of which have been linked to proinﬂammatory another novel mechanism by which curcumin medi-pathways that include NF-jB and TNF, as well as ates its eﬀects.other key factors, such as IL-1 and IL-6 [234,235].Animal models of ‘‘sickness behavior” support this 4.2. Depressionthesis [236,237], in that ﬂuctuations in inﬂammatorycytokines, primarily IL-1, IL-6, and TNF-a, are Some patients with cancer exhibit IFN-2b-related to ﬂuctuations in components of sickness induced depression and an increase in IL-2 levelsin animals (e.g., anorexia, disturbed sleep, hyperal- [249–252] Cancer patients with depression havegesia, and disrupted learning). The administration markedly higher plasma concentrations of IL-6 thanof these cytokines can produce sickness behavior, do healthy comparison subjects and cancer patientswhich, in turn, can be eliminated by antibodies to without depression [253]. The plasma IL-2 was asso-these cytokines. The fact that curcumin can sup- ciated with mood state, and the plasma TNF-apress the activation of NF-jB and NF-jB-regulated increased after pharmacotherapy in depressedTNF, IL-1, and IL-6 expression, indicates that it patients [254]. Endogenous IFN-a may play a rolecould have potential eﬀects against these symptoms. in sleep alteration [255]. Curcuma longa is a major component constituent4.1. Neuropathic pain of the traditional Chinese medicine, Xiaoyao-san, which is used to treat stress and depression-related Although the exact etiologic factors responsible symptoms in China. Behavioral despair tests in micefor neuropathic pain are not fully understood, (tail suspension test) showed that curcumin had
21. P. Anand et al. / Cancer Letters 267 (2008) 133–164 153antidepressant activity [256,257]. Curcumin has also Inﬂammation has been linked to exercise-inducedbeen shown to inhibit the activity of monoamine fatigue [266]. The systemic injection of TNF inoxidase, (MAO) which plays a central role in vari- patients with cancer has been shown to causeous psychiatric neurological disorders, including increased fatigue [267]. In patients, cancer treatmentclinical depression and anxiety [258]. In the forced with chemotherapeutic agents such as docetaxel canswimming test and in bilateral olfactory bulbectomy also cause fatigue; this correlates with NF-jB-med-models of depression in rats, the oral administration iated TNF expression [268,269]. Chronic fatigueof 1.25–10 mg/kg curcumin when administered syndrome (CFS) has been linked with the increasedfrom 1.25–10 mg/kg orally, was found to be quite activation of NF-jB [270]. Similarly, IL-6 expres-eﬀective at counteracting symptoms of depression sion has been shown to increase after repeated bouts[19,259]. In subsequent studies, the same investiga- of eccentric exercise. Both TNF blockers and NF-tors showed that curcumin alleviates stress-induced jB blockers have been found to reduce chemother-depressive behavior by acting on the hypotha- apy-induced fatigue [269,271,272]. Using an eccen-lamic–pituitary–adrenal axis by down-regulating trically biased downhill treadmill running model inthe expression of brain-derived neurotrophic factor mice, Davis et al. showed that curcumin decreased(BDNF) and inhibiting the phosphorylation of the expression of IL-1, IL-6, and TNF and oﬀsetcamp response element-binding (CREB) protein in the performance [273]. It was showed that the sys-rats [73,260]. Another study showed that chronic temic administration of curcumin stimulates musclemild stress in rats leads to an increased production regeneration after traumatic injury, which is com-of serum IL-6 and TNF levels, whereas the admin- monly associated with fatigue through the inhibi-istration of curcumin reverses these eﬀects [261]. tion of NF-jB [7]. The use of curcumin has beenThese reports indicate that curcumin’s eﬀects on proposed for patients with CFS [270].depression could be mediated through multiplemechanisms. 4.4. Neurodegeneration4.3. Fatigue Inﬂammatory mechanisms within the central ner- vous system have been proven to contribute to cog- Patients with cancer-related fatigue exhibit over- nitive impairment via interactions between neuronsexpressed IL-6, IL-1 receptor antagonist (IL-1RA), and glial cells that are mediated by cytokines, whichIL-1, TNF, and albumin [262]. Fatigued breast can- are vital to the activation of the hypothalamic–pitu-cer survivors who reported having the behavioral itary–adrenal axis relevant to stress and depression.problems concurrent with fatigue had signiﬁcantly This is consistent with the role of cytokines as thehigher serum levels of several markers, such as IL- mediators of bidirectional communication between1RA, soluble TNF receptor type II (sTNF-RII), the central nervous system and the peripheraland neopterin [263]. Later studies in fatigued immune system. Peripheral and central cytokinepatients demonstrated that increase in plasma-solu- dysregulation can aﬀect cognition in many ways,ble IL-6 receptor (sIL-6R) levels resulted from the such as by impairing the regulation of sleep, sup-shedding of the receptor and were accompanied by pressing appetite such that it results in a deﬁciencysigniﬁcant reductions in cell surface expression of of micronutrients, and stimulating an array of otherIL-6R on CD14+ monocytes. IL-6 was discrimina- endocrine interactions [274].tive only when ﬂow cytometry was used to measure Oxidative damage and inﬂammation have boththe stimulated intracellular production of IL-6 in been identiﬁed as having roles in age-related neuro-monocyte populations [264]. Evidence from chronic degenerative diseases such as Alzheimer’s diseasefatigue syndrome and studies of sickness behavior (AD). In rat models of AD, curcumin has beensuggest that immune and neuroendocrine factors found to be quite eﬀective [7]. Wu et al. showed thatmay play a causative role in the development of fati- dietary curcumin can counteract the outcome ofgue. Prechemotherapy and chemotherapy-induced traumatic brain injury on oxidative stress, synapticchanges in inﬂammation are related to changes in plasticity, and cognition [275]. Another study [276]fatigue and quality of life in response to chemother- found that curry consumption resulted in betterapy [265]. cognitive function in non-demented elderly Asians. There is increasing evidence that inﬂammatory Kumar et al. demonstrated that curcumin had apathways may be involved in fatigue response. neuroprotective eﬀect in that it attenuated 3-nitro-
22. 154 P. Anand et al. / Cancer Letters 267 (2008) 133–164propionic acid (NP)-induced neurotoxicity [277]. cancers. In vitro, in vivo, and human clinical studiesThe intraperitoneal administration of 3-NP resulted have all established curcumin’s promise andin a loss of body weight, reduced motor function, revealed its therapeutic value. More extensive ran-poorer memory retention, and changes in the oxida- domized clinical trials are now needed. The safety,tive stress (lipid peroxidation, reduced glutathione, low cost, and already proven eﬃcacy of this ‘‘age-and nitrite level) parameters in the brain. Chronic old” natural medicine makes it a promising agenttreatment with curcumin (10, 20, and 50 mg/kg) for the treatment of an ‘‘old-age” disease likegiven orally once daily for 8 days dose-dependently cancer.improved the 3-NP-induced motor and cognitiveimpairment. Thus, these reports suggest that curcu- Referencesmin has the potential to improve cognitive function. 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