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D. Anderson Cancer Center, Houston, Texas, USA To cite this Article Goel, Ajay and Aggarwal, Bharat B.(2010) 'Curcumin, the Golden Spice From Indian Saffron, Is a Chemosensitizer and Radiosensitizer for Tumors and Chemoprotector and Radioprotector for Normal Organs', Nutrition and Cancer, 62: 7, 919 — 930To link to this Article: DOI: 10.1080/01635581.2010.509835URL: This article may be used for research, teaching and private study purposes. Any substantial orsystematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply ordistribution in any form to anyone is expressly forbidden.
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Nutrition and Cancer, 62(7), 919–930Copyright C 2010, Taylor & Francis Group, LLCISSN: 0163-5581 print / 1532-7914 onlineDOI: 10.1080/01635581.2010.509835 Curcumin, the Golden Spice From Indian Saffron, Is a
Chemosensitizer and Radiosensitizer for Tumors and
Chemoprotector and Radioprotector for Normal Organs
Ajay Goel
Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons
Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA
Bharat B. Aggarwal
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
directly quench free radicals, and inhibit p300 HAT activity. These
Curcumin (diferuloylmethane), the yellow pigment in Indian
preclinical studies are expected to lead to clinical trials to prove the
saffron (Curcuma longa; also called turmeric, haldi, or haridara in
potential of this age-old golden spice for treating cancer patients.
the East and curry powder in the West), has been consumed by peo-
ple for centuries as a dietary component and for a variety of proin-
flammatory ailments. Extensive research within the last decade in
cell culture and in rodents has revealed that curcumin can sensi-
INTRODUCTION
tize tumors to different chemotherapeutic agents including doxoru-
bicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin,
heptadiene-3,5-dione), a polyphenol, is a natural compound celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfino-
that is derived from turmeric, the powdered rhizome of the sine, thalidomide, and bortezomib. Chemosensitization has been
observed in cancers of the breast, colon, pancreas, gastric, liver,
medicinal plant Curcuma longa Linn (also known as turmeric).
blood, lung, prostate, bladder, cervix, ovary, head and neck, and
The yellow-pigmented fraction of turmeric primarily consists brain and in multiple myeloma, leukemia, and lymphoma. Similar
of various curcuminoids including curcumin I (or curcumin, studies have also revealed that this agent can sensitize a variety of
≈77%), curcumin II (demethoxycurcumin, ≈17%) and cur- tumors to gamma radiation including glioma, neuroblastoma, cer-
cumin III (bisdemethoxycurcumin, ≈3%). The curcuminoid vical carcinoma, epidermal carcinoma, prostate cancer, and colon
cancer. How curcumin acts as a chemosensitizer and radiosensi-
complex, collectively, is frequently referred to as Indian saffron, tizer has also been studied extensively. For example, it downreg-
yellow ginger, yellow root, and haldi. Curcumin has been used ulates various growth regulatory pathways and specific genetic
for centuries throughout Asia as a food additive, cosmetic, and targets including genes for NF-κB, STAT3, COX2, Akt, antiapop-
as a traditional herbal medicine. As a spice, it provides curry totic proteins, growth factor receptors, and multidrug-resistance
with its distinctive color and flavor. Furthermore, traditional proteins. Although it acts as a chemosensitizer and radiosensitizer
for tumors in some cases, curcumin has also been shown to pro-
Indian medicine has considered curcumin a drug effective for tect normal organs such as liver, kidney, oral mucosa, and heart
various respiratory conditions (asthma, bronchial hyperactivity, from chemotherapy and radiotherapy-induced toxicity. The pro-
and allergy) as well as for other disorders including anorexia, tective effects of curcumin appear to be mediated through its abil-
coryza, cough, hepatic diseases, and sinusitis (1,2). Over the ity to induce the activation of NRF2 and induce the expression of
past decade, several studies have substantiated the potential antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxi-
dase, modulatory subunit of gamma-glutamyl-cysteine ligase, and
prophylactic or therapeutic value of curcumin and have NAD(P)H:quinone oxidoreductase 1, increase glutathione (a prod-
unequivocally supported reports of its anti-inflammatory (3,4), uct of the modulatory subunit of gamma-glutamyl-cysteine ligase),
antioxidant (5), anticarcinogenic (6–8), hepatoprotective (9),thrombosuppressive (10), cardioprotective (11), antiarthritic(12), and anti-infectious (13) properties. One of the most com- Submitted 27 February 2010; accepted in final form 16 July 2010.
pelling reasons for continued interest in exploring the cancer Address correspondence to Bharat B. Aggarwal, Cytokine Research chemopreventive and therapeutic uses of curcumin has been Laboratory, Department of Experimental Therapeutics, and Depart- curcumin’s ability to influence a diverse range of molecular tar- ment of Radiation Oncology, The University of Texas, M. D. AndersonCancer Center, Houston, TX 77030. Phone: 713-792-3503. Fax: 713- gets within cells. To date, no studies have reported any toxicity 794-1613. E-mail: [email protected] associated with the use of curcumin in either animals or humans.
Undisputed scientific evidence suggests that curcumin sup- frequent cause of cancer-related deaths in these patients. There- presses all 3 stages of carcinogenesis: initiation, promotion, fore, understanding the molecular basis of MDR and developing and progression. Several genetic targets may mediate cancer- drugs and treatment regimens to prevent tumor resistance is an related efficacy of curcumin, but inhibition of nuclear factor kappa B (NF-κB) and subsequent downregulation of various Drug resistance and toxicity can also be dictated by several NF-κB-related proinflammatory pathways are very likely the factors including metabolism and excretion of the drug, inade- primary features accounting for its efficacy (14). Curcumin has quate or poor access of the drug to the tumor, and the role of been studied for its chemopreventive potential in a wide variety various drug metabolizing enzymes such as cytochrome P450s, of cancers, in both preclinical studies and in clinical trials (re- which are often overexpressed (24). In recent years, a new con- viewed in Goel et al. (15)). However, recent data indicate that cept has been proposed that suggests that another important in addition to its chemopreventive role, curcumin has tremen- reason why cancer therapies might fail and tumors develop re- dous potential as a chemosensitizer and radiosensitizer as well lapse is because these strategies do not target rare tumor cells or as chemoprotector and radioprotector. This is of great interest so-called cancer stem cells. According to this hypothesis, which given the plethora of diverse molecular targets curcumin can is still in its nascent stages, a small fraction of tumor cells has regulate. The fact that curcumin can achieve all of these effects the unlimited capacity to self-renew, have extensive unlimited without any toxicity makes developing curcumin as an adjunct slow proliferation potential, and can give rise to phenotypically to standard chemotherapy and radiotherapy an important goal.
diverse progeny of cancer cells with variable proliferative ca- It may offer a therapeutic advantage in the clinical management pacity (25,26). It is believed that these cancer stem cells are of various refractory tumors over other, standard modalities.
often resistant to chemotherapy and radiation, and treatments Constant challenges in cancer chemotherapy and radiother- that substantially reduce tumor mass by removing proliferating apy are the adverse toxicity and resistance associated with these tumor cells often fail to target these stem cells and cure patients treatment regimens. Among these are hair loss, diarrhea, fatigue, completely with certain cancers. According to this viewpoint, mouth sores, and low blood counts. Many patients experience these cancer stem cells are immune to any therapies, maintain chemotherapy-induced toxicity because these drugs are heavily their “stemness,” and continue to repopulate tumor mass with protein bound and can damage normal cells and tissues in many a continuous supply of new cancer cells (27). This new under- ways. As much as we understand now that tumor initiation and standing has promoted researchers and pharmaceutical compa- development is a multistep process involving a series of ge- nies to shift their efforts to develop targeted or more effective netic and epigenetic events, why most therapeutic approaches anticancer therapies that could either induce differentiation of become increasingly ineffective over the course of treatment cancer stem cells to lose their stemness or completely eliminate remains poorly understood. Regardless, cancer cells become re- sistant to chemotherapeutic drugs through mechanisms that may In this context, curcumin seems to offer an ideal agent be- involve mutation or overexpression of the drug’s specific target, cause over the last two decades, significant evidence has indi- drug inactivation, or efflux of the drug out of the cell (16).
cated anticancer potential of curcumin. In fact, it is very encour- Historically, chemotherapeutic strategies have used a variety aging to notice that unlike many “targeted” chemotherapeutic of single drugs or drug combinations that interfere with cellular drugs that suffer from toxicity and resistance concerns, curcumin machinery in order to achieve the desired effect. Knowledge by itself can target several of these molecular targets/pathways gained from these studies and improved understanding of the without any associated toxicity or resistance. In fact, newer data molecular alterations that are present within tumor cells have suggest that in addition to its chemopreventive ability, curcumin paved the way for the development of targeted therapies. Inter- can sensitize many human cancers to chemotherapy and radi- estingly, resistance appears to occur not only with traditional ation, as well as afford protection against the toxicity of these chemotherapy but also to targeted chemotherapies such as her- treatment regimens. This review summarizes the potential role ceptin, which targets human epidermal growth factor receptor 2 of curcumin as both a chemosensitizer and radiosensitizer as (HER-2) in breast cancer (17); tamoxifen, which targets estro- well as its ability to function as a chemoprotector and radiopro- gen receptor (ER) in breast cancer (18); remicade or infliximab, tector in different forms of tumors.
which targets tumor necrosis factor (TNFα) in multiple inflam-matory diseases (19,20); gleevac, targeted against the kinase ac-tivity of BCR-ABL gene in chronic myelogenous leukemia (21); CURCUMIN AS A CHEMOSENSITIZER
and erbitux or gefitinib, which inhibits epidermal growth fac- Curcumin not only acts as a cancer preventive, but data sug- tor receptor (EGFR) kinase (22). In some instances, it becomes gest that curcumin treatment may be able to eliminate chemore- even more complex when tumors in some patients recur after sistant cancers by sensitizing these tumors to chemotherapy and therapy and show resistance to multiple drugs, a phenomenon radiation by increasing the rate of apoptosis. In this section, often referred to as multidrug resistance (MDR) (23). MDR we summarize the current state of the biomedical literature on tumors are not only resistant to many combinations of can- curcumin as a chemosensitizer. Data from both in vitro and cer chemotherapy, but they also tend to metastasize and are a in vivo studies have supported the potential chemosensitizing Curcumin potentiates the effect of chemotherapya Potentiates cytotoxic effects of doxorubicin, 5-FU, and paclitaxel against prostate cancer cells Sensitizes multiple myeloma cells to vincristine and melphalan Enhances cytotoxicity of cisplatin against ovarian cancer cells in culture Potentiates antitumor effects of sodium butyrate against erythroleukemic cells Potentiates growth inhibition effects of 5-FU against human gastric carcinoma cells in culture Exhibits both additive and sub-additive antitumor and apoptotic effects of doxorubicin against liver Potentiates the antitumor and apoptotic effects of cisplatin against hepatocellular carcinoma cells Enhances antitumor effects of taxol against cervical cancer cells in culture Potentiates the cytotoxicity of paclitaxel toward breast cancer cells in culture Potentiates apoptotic effects of celecoxib against human pancreatic cancer cells Synergistic effects with celecoxib in growth inhibition in colon cancer cells Enhances apoptotic effects of cisplatin against cervical cancer SiHa cells, but not HeLa cells Enhances apoptotic effects of vinorelbine against human squamous cell lung carcinoma cell line Augments apoptotic effects of cisplatin against ovarian cancer and breast cancer cell lines Has no effect on cytotoxic effects of paclitaxel against human ovarian cancer and breast cancer cell lines Enhances antitumor effects of 5-FU and 5-FU plus oxaliplatin (FOLFOX) against colon cancer cells Potentiates apoptosis induced by gemcitabine and paclitaxel in bladder cancer cells in culture Potentiates antitumor activity of docetaxel against ovarian cancer cell lines Increases antitumor effects of oxaliplatin against colorectal cancer cells in culture Augments cytotoxic effects of gemcitabine on pancreatic adenocarcinoma cell line Enhances the antitumor effects of gemcitabine against prostate cancer cells in culture Potentiates cytotoxicity of cisplatin, etoposide, camptothecin, and doxorubicin against human and rat Enhances antitumor effects of oxaliplatin against colorectal cancer cell lines Enhanced the antitumor effects of vincristine and PDE4 inhibitors in B-CLL from patients Enhances antitumor effects of 5-FU and FOLFOX against colon cancer cells Augments effects of sulfinosine on multi drug resistant human non-small cell lung carcinoma cells Potentiate effects of gemcitabine in pancreatic cancer cells Sensitizes lung cancer cells to cisplatin-induced apoptosis in lung cancer cells Potentiates the effect of thalidomide and bortezomib in multiple myeloma cells Augments growth inhibitory effects of celecoxib against colorectal cancer in rats Enhances antitumor effects of oxaliplatin against colorectal cancer in mice Potentiates antitumor activity of gemcitabine against pancreatic cancer in mice Potentiates antitumor activity of docetaxel against ovarian cancer in mice Enhances the antitumor effects of gemcitabine against prostate cancer in mice Potentiates the effect of thalidomide and bortezomib against multiple myeloma in nude mice Antagonizes apoptotic effects of camptothecin, mechlorethamine, and doxorubicin in human breast Reduces nephrotoxicity of cisplatin in rats Antagonizes apoptotic effects of cyclophosphamide in mice aAbbreviations are as follows: 5-FU, 5-fluorouracil; HeLa, a cervical carcinoma cell line derived from Henrietta Lacks; SiHa, a cervical ability of curcumin in multiple cancers and have provided ev- ment with curcumin and 5-FU in HT-29 cells. The importance idence for curcumin’s use singly or as an adjunct to current of the Cox-2 pathway in mediating efficacy of curcumin was chemotherapeutic drugs. Table 1 summarizes these data in or- further highlighted in another report in which curcumin po- der of appearance of these reports in the published literature.
tentiated the growth inhibitory effect of celecoxib in multi-ple colon cancer cell lines (33). In a follow-up study, these Colon Cancer
investigators determined the chemopreventive effects of cele- Cancers of the gastrointestinal tract, especially colon can- coxib and curcumin alone and in combination using the 1,2- cer, remain leading causes of cancer-related deaths in the devel- dimethylhydrazine (DMH) rat model (34). In this in vivo study, oped nations, including the United States (28). Although current curcumin augmented the growth inhibitory effect of celecoxib chemotherapeutic regimens targeting colon cancer have contin- as indicted by significantly fewer aberrant crypt foci in the com- uously evolved and have significantly improved survival rates bined curcumin and celecoxib group compared to when these by limiting the spread of metastatic disease over the last decade, agents were fed individually (34). Such effects of curcumin are a large majority of patients develop chemoresistance to these not limited to colon cancer, but others have shown similar results platinum-based and/or 5-fluorouracil (5-FU)-based drug regi- in gastric (35), pancreatic (36–38), and liver cancers (39) as well.
mens over the course of chemotherapy. Use of curcumin singlyor in combination with chemotherapeutic drugs may help over-come some of the resistance issue and improve the efficacy of Gastric Cancer
current chemotherapeutic drugs. In one study, Howells and col- Using physiologically relevant and very small doses of cur- leagues (29) investigated the antiproliferative potential of both cumin together with 5-FU, much stronger G2/M cell cycle block curcumin and oxaliplatin singly and in combination in normal was achieved in AGS gastric cancer cells compared to the block colonic (HCEC) and colon cancer cell lines (HT29, p53 mutant in control groups in which cells were treated with single agents and HCT116, p53 wild type). Both curcumin and oxaliplatin dis- played significant antiproliferative potential in both HT29 andHCT116 cells; and the order of sensitivity to oxaliplatin wasHCT116>HT29>HCEC, whereas order of sensitivity to cur-cumin was HT29>HCT116>HCEC. Apoptosis was enhanced Pancreatic Cancer
by both compounds, and up to 16-fold increase in expression Pancreatic adenocarcinoma is a fatal disease with very of p53 protein was observed when the two agents were used poor prognosis. Data indicate that specific Cox-2 inhibitors in combination. This study suggested that when used in com- (such as celecoxib) may have some promise in this disease.
bination with oxaliplatin, curcumin may enhance efficacy of However, sustained and robust Cox-2 inhibition for the long this drug in both p53 mutant and wild type colorectal tumors.
term is a practical challenge in managing these individuals. In Since curcumin in its free form may be poorly absorbed in the this regard, Lev-Ari et al (36) questioned whether curcumin gastrointestinal tract, a liposomal encapsulated preparation of may potentiate growth inhibitory effects of a celecoxib in a curcumin was evaluated individually and in combination with panel of Cox-2-expressing (P-34) and low/nonexpressing (MIA oxaliplatin in LoVo and Colo205 human colorectal cancer cell PaCa and Panc-1) human pancreatic cell lines. Curcumin syn- lines (30). Liposomal curcumin treatment showed a synergistic ergistically augmented growth inhibition of celecoxib in Cox- effect with oxaliplatin at a ratio of 4:1 in LoVo cells in vitro 2-expressing cell lines, suggesting that celecoxib may be used and a significant tumor growth inhibition in Colo205 and LoVo at much lower and safer concentrations. The same group of in- xenografts in mice, substantiating the chemosensitizing ability vestigators later reported similar effects of curcumin when used in combination with the first-line chemotherapeutic agent gem- When curcumin treatment was evaluated in conjunction with citabine in pancreatic cancer cells (36). These data were further either 5-FU alone or 5-FU + oxaliplatin (FOLFOX), it resulted substantiated by other studies in which it has been demonstrated in significantly greater growth inhibition and increased apopto- that curcumin potentiated the antitumor effects of gemcitabine in sis in HCT116 and HT29 colon cancer cells than that caused cultured pancreatic adenocarcinoma cells by suppressing cellu- by curcumin, 5-FU, curcumin + 5-FU, or FOLFOX alone (31).
lar proliferation and activating NF-κB and other genetic targets Such effects were associated with decreased expression and of the NF-κB signaling pathway (37,38,40) In vivo studies with activation of EGFR, HER-2, HER-3, and insulin-like growth tumors from nude mice injected with pancreatic cancer cells and factor 1 receptor (IGF-1R), together with their downstream sig- treated with both curcumin and gemcitabine showed significant naling targets such as Akt and cyclooxygenase-2 (Cox-2) (31).
reduction in tumor volume, Ki-67 proliferation index, NF-κB It was concluded that the potentiation of curcumin’s effect with activation, expression of NF-κB gene products [cyclin D1, c- FOLFOX were due to attenuation of EGFR and IGF-1R sig- myc, B-cell non-Hodgkin lymphoma-2 (Blc-2), Bcl extra large naling pathways (31). Similarly, Du and coworkers (32) re- (Bcl-xl), CIAP-1, Cox-2, matrix metalloproteinase (MMP), and cently demonstrated synergistic inhibition of cell growth and vascular epithelial growth factor (VEGF)], and suppression of sixfold reduction in Cox-2 expression after combination treat- angiogenesis compared to tumors from control animals (38).
Liver Cancer
mechlorethamine-, and doxorubicin-induced apoptosis of MCF- While investigating antitumor effects of curcumin, singly or 7, MDA-MB-231, and BT-447 human breast cancer cells together with cisplatin or doxorubicin, it was noticed that the (45). In animal experiments, curcumin significantly inhibited combination of curcumin with cisplatin resulted in synergis- cyclophosphamide-induced tumor regression, suggesting that tic activity against liver cancer; whereas with doxorubicin, the dietary curcumin can inhibit chemotherapy-induced apoptosis effects were at best additive (39). Such effects were in part via inhibition of ROS generation and blocking JNK signaling.
mediated by downregulation of expression of different genesincluding c-myc, Bcl-xl, c-IAP-2, NAIP, and XIAP (39).
Ovarian Cancer
High levels of certain serum proinflammatory cytokines, in- Prostate Cancer
cluding IL-6, have been associated with poor prognosis and The literature on similar potential for curcumin in other cisplatin resistance in multiple human cancers. Since curcumin solid organ malignancies has grown continuously over the last inhibits production of many cytokines, its effects were studied decade. In this context, while studying the modulatory effects of in CAOV3 ovarian cancer cells, singly, and in combination with curcumin on the cytotoxic effects of chemotherapeutic agents cisplatin (46). As anticipated, curcumin inhibited IL-6 produc- (5-FU, doxorubicin, and paclitaxel) in androgen-independent tion in cisplatin-treated cells, suggesting that one mechanism prostate cancer cell lines (PC-3 and DU-145), a significant for curcumin action is by reduction of autologous production of degree of G1-cell cycle arrest was observed in the combina- IL-6, which has potential for enhancing drug sensitivity in mul- tion treatment group (41). It was proposed that such cell cycle tiple human cancers. In another study, curcumin when given changes may be associated with an increase in p21 and C/EBP together with docetaxel to HeyA8 and HeyA8-MDR athymic β and inhibition of constitutive and TNFα-induced NF-κB ac- mice, significantly reduced tumor growth, cellular proliferation, tivation (41). Curcumin treatment in combination with gemc- and microvessel density compared to controls, emphasizing the itabine in PC-3 cells inhibited growth and increased apoptosis potential of curcumin-based therapies in patients with ovarian but via downregulation of MDM2, an ubiquitin E3 ligase of p53 gene (42). In further support of these data, when experi-ments were performed in tumor-bearing nude mice, curcumin Cervical Cancer
inhibited growth of PC3 xenografts and enhanced the antitumor NF-κB activation plays a pivotal role in drug-mediated apop- efficacy of gemcitabine and radiation (42).
tosis and possible resistance in various human cancers. Usinga cervical cancer model of HeLa and SiHa cells that differ in Breast Cancer
their response to cisplatin treatment, it was demonstrated that Presently, other than radiation and chemotherapy, there is SiHa cells, which are more resistant to cisplatin, showed much no effective therapy for metastatic breast cancer. Curcumin is a lesser cell viability when NF-κB binding was blocked by cur- potent NF-κB suppressor, while most conventional chemother- cumin (48). Such effect was not evident in cisplatin-responsive apeutic agents activate NF-κB. Keeping this in mind, Aggarwal HeLa cells. These data suggest that NF-κB may contribute to and colleagues (43) hypothesized that curcumin potentiates the cisplatin-induced chemoresistance in cervical cells and high- effects of chemotherapy in advanced breast cancer and inhibits lights the potential applicability of combination therapy with lung metastasis. Using paclitaxel (Taxol)-resistant breast cancer NF-κB inhibitors such as curcumin in this scenario. Curcumin cells and a human breast cancer xenograft model, they showed was also shown to downregulate taxol-induced activation of NF- that curcumin inhibited paclitaxel-induced NF-κB activation, κB and phosphorylation of serine/threonine kinase Akt in 293 and these effects were mediated through inhibition of IκBα ki- cervical cells and 293 embryonic kidney cells (49).
nase activation and IκBα phosphorylation and degradation (43).
In addition, curcumin also suppressed the paclitaxel-induced Lung Cancer
expression of several antiapoptotic (XIAP, IAP-1, IAP-2, Bcl- Due to toxicity concerns and older age, some lung cancer 2, and Bcl-xl), proliferative (Cox-2, c-myc, and cyclin D1), patients are not suited for classical cancer chemotherapy. Com- and metastatic (VEGF, MMP-9, and ICAM-1) proteins (43).
bination approaches using phytochemicals such as curcumin Curcumin also inhibited the mono-ubiquitination of the are being advocated as a possible alternative to get around some FANCD2 protein and sensitized ovarian and breast tumor cells of the practical constraints posed by conventional chemother- lines to cisplatin through enhanced apoptotic death (44).
apeutic drugs. Pretreatment of squamous cell lung carcinoma Generation of reactive oxygen species (ROS) and activa- H520 cells with curcumin, followed by chemotherapy using tion of the c-Jun N-terminal protein kinase (JNK) pathway vinorelbine, enhanced the apoptotic capacity of this drug (50), is a frequent manifestation of proapoptotic ability offered by suggesting that curcumin can act as an adjuvant chemotherapeu- many chemotherapeutic drugs. Somasundaram et al. (45) asked tic agent and enhance the chemotherapeutic drugs in a subset of whether curcumin may antagonize the antitumor effects of var- ious chemotherapeutic drugs in both cultured cells and an ani- MDR is a frequent limiting factor for a successful chemother- mal model of breast cancer. Curcumin inhibited camptothecin-, apeutic regimen. However, data indicate that curcumin can overcome MDR induced by sulfinosine in NCI-H460/R non- CURCUMIN AS A RADIOSENSITIZER
small-cell lung carcinoma cells (51). Combination of curcumin In addition to its role as a potent chemosensitizer, increasing and sulfinosine produced more pronounced S and G2/M cell evidence suggests that curcumin can also function as a very cycle arrest compared to treatment with these agents individ- promising radiosensitizing agent in a wide variety of human ually. When cisplatin was used as a chemotherapeutic drug, curcumin sensitized cisplatin-induced apoptosis in non-small-cell lung cancer H460 cells via downregulation and degradation Colon Cancer
Radiation therapy, alone or in conjunction with chemother- apy, is one of the preferred modalities in patients with coloncancer who develop resistance to individual chemotherapies.
Brain and Bladder Cancers
Mechanisms for developing such resistance are unclear, but it Since NF-κB serves as nexus in human cancers, in another has been suggested that some of this resistance may be mediated interesting study by Kamat and coworkers (53), it was shown by NF-κB and its gene products. Because curcumin has been that curcumin blocked both gemcitabine- and TNFα-induced shown to suppress activation of NF-κB, it was hypothesized activation of NF-κB in KU-7 bladder cancer cells. Curcumin’s that curcumin may sensitize colon cancer to gamma-irradiation ability to overcome glioma cell resistance and chemoresistance in a xenograft nude mice model (60). Curcumin significantly was investigated in a panel of human (T98G, U87MG, and enhanced the effectiveness of radiation therapy by prolonging T67) and rat (C6) glioma cell lines (54). It was demonstrated tumor regrowth, by reducing Ki-67 proliferation index, and by that curcumin sensitized glioma cells to several chemotherapeu- suppressing NF-κB activity and its gene products (60). Com- tic agents (cisplatin, etoposide, camptothecin, and doxorubicin) bined curcumin and radiation treatment also suppressed angio- and radiation by reducing the expression of Bcl-2 and IAP fam- ily member proteins as well as DNA repair enzymes (MGMT, Prostate Cancer
DNA-PK, Ku70, Ku80, and ERCC-1) (54).
Curcumin has also been shown to have radiosensitizing ef- fects in prostate carcinoma. In this regard, curcumin signif-icantly improved radiation-induced clonogenic inhibition and Hematological Cancers
apoptosis in cultured prostate cancer PC3 cells (61). Curcumin, As is the case with solid organ malignancies, NF-κB also in combination with radiation treatment, inhibited TNFα- plays a central role in cell survival and proliferation in hema- mediated NF-κB activity, downregulated Bcl-2 protein, but had tological cancers. As curcumin is a potent NF-κB inhibitor, no effect of Bax protein in PC3 cells. Collectively, these data Bharti et al. (55) explored the effects of curcumin in multiple suggest that curcumin is a potent radiosensitizing agent, and myeloma (MM) cell lines, which express NF-κB in a constitu- it acts by negating the effects of radiation-induced prosurvival tively active manner. Curcumin induced significant apoptosis, genes in prostate cancer. In another study, curcumin showed anti- suppressed the constitutive IκBα phosphorylation, and down- cancer and radiosensitization effects by downregulating MDM2 regulated several NF-κB gene products. Similarly, in a recent levels in cultured PC3 prostate cancer cells, as well as growth study, when chemosensitizing effects of curcumin were eval- of xenografts in nude mice, by enhancing the antitumor effects uated in cell culture and xenograft model of MM, curcumin overcame chemoresistance and sensitized MM cells to thalido-mide and bortezomib by downregulating NF-κB and its gene Cervical Cancer
products (56). These data provided a molecular basis for treat- Cervical cancer is the second leading cancer among women, ment of MM patients with curcumin, that is, its ability to down- and these cancers are typically very radioresistant. Conse- regulate NF-κB. Curcumin also potentiated antitumor effects quently, for locally advanced disease, radiation therapy is often of sodium butyrate by reducing overall cell growth in human used in conjunction with chemotherapy, which is severely toxic.
erythroleukemic cells (57). In a more recent study, curcumin Curcumin may be an ideal adjunct for radiation therapy if it has treatment reduced basal NF-κB levels and augmented both vin- radiosensitizing properties. In support of this, it was recently cristine and PDE4 inhibitor rolipram-induced apoptosis in cul- demonstrated that pretreatment of 2 cervical cancer cell lines tured primary chronic lymphocytic leukemia cells (58). Taken HeLa and SiHa with curcumin prior to ionizing radiation re- together, all of these studies have indicated a potent chemosensi- sulted in radiosensitization of cancer cells but had no effect on tizing potential of curcumin in overcoming resistance afforded normal human diploid fibroblasts (62). Such effects of curcumin by standard chemotherapeutic drugs. In a more recent study, were due to its ability to sensitize cancer cells for increased pro- curcumin treatment reduced basal NF-κB levels and augmented duction of ROS, which in turn led to activation of ERK1 and both vincristine and PDE4 inhibitor rolipram-induced apopto- ERK2. These data provide a novel mechanism of curcumin- sis in cultured primary chronic lymphocytic leukemia (B-CLL) mediated radiosensitization and suggest that curcumin may be an effective radiosensitizer in cervical cancer.
Curcumin potentiates the effect of radiotherapya Inhibits UV-radiation induced oxidative stress and apoptotic changes in epidermal carcinoma cells Inhibits apoptotic effects of photodynamic therapy against human epidermal carcinoma cells Enhances the antitumor effects of irradiation against prostate cancer cells in culture Radiosensitizes squamous cell carcinoma cells in culture Enhances the antitumor effects of irradiation against prostate cancer cells in culture Potentiates cytotoxicity of radiation (5 Gy) against human and rat glioma cell lines Increases anti-proliferative effects of radiation (UVA and visible light) against human keratinocyte cell line Increases apoptotic effects of radiation (UVB) against human keratinocyte cell line Enhances antitumor effects of radiation (2 Gy) against human neuroblastoma cells in culture Enhances antitumor effects of ionizing radiation against cervical carcinoma cells in culture Enhances the antitumor effects of irradiation against prostate cancer cells in mice Enhances antitumor effects of fractionated radiation therapy (4 Gy) against colorectal cancer in mice In combination with visible light inhibits tumor growth in xenograft tumor model aAbbreviations are as follows: UV, ultraviolet; Gy, gray units; UVA, UV A light; UVB, UV B light.
Brain Cancer
had similar radiosensitization effect in inhibiting photodynamic Malignant gliomas are a debilitating class of neoplasms that treatment (PDT)-induced caspase activation in A431 cells (65).
are often resistant to standard radiation and chemotherapeu-tic regimens. High levels of NF-κB and AP-1 expression ingliomas is in part responsible for increased chemoresistance andradioresistance. Due to its strong NF-κB inhibitory properties,Dhandapani and colleagues (54) determined whether curcumin Skin Cancer
can sensitize human and rat glioma cells by shortening their One of the unfortunate but relatively frequent manifestations survival in cultured cells. Interestingly, combined curcumin and of excessive exposure to UV or visible light is the possibil- radiation treatment of T98G, U87MG, and T67 cells reduced ity of skin cancers. Because curcumin has traditionally been cell survival and inhibited AP-1 and NF-κB signaling pathways, used for different cosmetic applications and has been proposed suggesting a role for curcumin as an adjunct to traditional radia- to possess skin-healing properties, multiple studies have hy- tion therapy in brain cancers (54). Similar effects were indepen- pothesized that some of its effect may be attributable to its dently validated in another study in which curcumin inhibited radiosensitizing ability. Experimental evidence in this regard NF-κB-mediated radioprotection and modulated expression of was provided in a recent study in which cultured human skin apoptosis-related genes in human neuroblastoma cells (63).
keratinocytes treated with curcumin in combination with UVor visible light increased apoptosis and fragmented cell nuclei,activated caspase-9 and caspase-8, and inhibited NF-κB activ- Epidermal Cancer
ity (66). Subsequently, these investigators performed similar Ultraviolet (UV) light is known to be a trigger for apop- studies in an animal model system and reported that curcumin totic signaling, which results in induction of caspase-dependent in combination with visible light inhibited tumor growth in a biochemical changes in cells. UV irradiation can not only ac- xenograft tumor model (67). Curcumin-induced radiosensitiza- tivate caspase-3 but also cleave and activate p21-activated ki- tion resulted in increased apoptosis, and this correlated with nase 2 (PAK2) in human epidermoid carcinoma (A431) cells.
reduced Ki-67 expression, as well as lower levels of extracel- Given the anti-inflammatory and antioxidant potential of cur- lular regulated kinases (ERK1 and 2), and epidermal growth cumin, curcumin was studied for its ability to prevent UV factor receptor (EGFR). Park and Lee (68) showed similar re- irradiation-induced apoptotic changes, JNK activation, caspase- sults when curcumin was combined with photodynamic therapy 3-activation, and cleavage/activation of PAK2 in the A431 in which synergism was observed between curcumin and UVB- cell line (64). Curcumin significantly inhibited UV irradiation- irradiation in HaCaT cells. Taken together, these results indicate induced generation of ROS and blocked JNK activation, cas- that a combination of curcumin and light is a possible therapeutic pase activation, and subsequent apoptotic changes (64). In a approach to enhance the overall efficacy of treatment regimens follow-up study, these investigators demonstrated that curcumin Squamous Cell Cancer
gested a safe use of curcumin and CAPE in combination with Radiosensitization of cancer cells is in part dictated by the distribution of cells in various phases of the cell cycle, with Curcumin has also been used to attenuate acute Adriamycin- much better responses in cells that are in G2/M phase. It seems induced myocardial (11) and nephrotoxicity (71) in rats. In these prudent that if cancer cells are pretreated with curcumin, this studies, curcumin pretreatment reversed the increase in lipid may result in enhanced radiosensitization as one of its secondary peroxidation and catalase, with simultaneous decrease in glu- effects. Khafif et al (69) studied whether curcumin can sensitize tathione content and glutathione peroxidase activity caused by squamous cell carcinoma cells exposed to 1 to 5 Gy of ionizing Adriamycin in cardiac tissues of rats (11). Curcumin pretreat- irradiation. Curcumin treatment of cells exposed to such doses ment also restored renal function in Adriamycin-treated rats of ionizing radiation decreased cell growth and reduced ability by inhibiting Adriamycin-induced increase in urinary excretion to form colonies, an effect that may have been partly due to of N-acetyl-beta-D-glucosaminidase, fibronectin, glycosamino- curcumin’s ability to block cells in G2/M cell cycle phase (69).
glycan, and plasma cholesterol (71). These data indicate thatcurcumin may serve as an adjunct to Adriamycin therapy byreducing myocardial toxicity and nephrosis.
In another model of nephrotoxicity, when cisplatin was used CURCUMIN AS A CHEMOPROTECTOR
as a chemotherapeutic drug, pretreatment of rats with various NF-κB activation is a common feature of most cancers, and does of curcumin protected against cisplatin-induced nephro- inhibiting its activation and suppressing its downstream gene toxicity by preventing alterations in various biochemical and targets is one of the goals for most cancer preventive and ther- inflammatory markers (59). Oral treatment with curcumin 10 apeutic approaches. Although many of the current chemother- days before, or daily after a single intratracheal installation apeutic drugs may inhibit NF-κB in tumor cells, their toxic of bleomycin, protected against bleomycin-induced pulmonary effects on surrounding peritumoral mucosa and other normal fibrosis, as evidenced by protection against changes in total cells is one of the limiting factors and concerns. However, pre- lung hydroxyproline, alveolar macrophage production of TNFα treatment of cancer patients with the potent NF-κB inhibitor superoxide, and nitric oxide (72). Collectively, these reports curcumin may preferentially affect tumor cells and at the same clearly highlight the chemoprotective role of curcumin and sup- time afford sufficient protection for normal cells (Table 3).
port its potential use as an adjunct to chemotherapy for multiple One of the limitations of cisplatin-based chemotherapy is development of nephrotoxicity. Data suggest that increased in-flammatory and oxidative stress may in part be responsible forcisplatin-induced acute renal failure. Because curcumin is a CURCUMIN AS A RADIOPROTECTOR
promising anti-inflammatory and antioxidant, Kuhad et al. (59) Accumulating evidence suggests that curcumin may not only investigated the effect of curcumin in an animal model of re- have a chemoprotective role, but several studies have indi- nal injury induced by cisplatin. Curcumin treatment reverted all cated its potential as a radioprotective agent as well (Table 3).
cisplatin-induced alterations including significant lowering of Parshad and colleagues (73) were among the first to suggest a serum TNFα levels, restoring renal function, reducing lipid per- radioprotective role for curcumin when they studied radiation- oxidation, and enhancing the levels of glutathione and activities induced chromosomal defects in human skin fibroblasts and of superoxide dismutase and catalase (59).
blood lymphocytes. It was demonstrated that pretreatment with Van’t Land and colleagues (70) hypothesized that in gastroin- curcumin and other plant polyphenols to cultured skin fibrob- testinal cancers, mucosal barrier injury is initiated and propa- lasts or PHA-stimulated lymphocytes reduced the frequency of gated by multiple proinflammatory cytokines and chemokines radiation-induced chromatid breaks. It was surmised that such as well as NF-κB-regulated mediators. To address this, these effects of curcumin were due to its strong antioxidant capac- researchers undertook a study of curcumin’s ability to inhibit ity, which scavenged toxic free radicals induced by radiation NF-κB in the onset of arabinoside cytosine- and methotrexate- exposure of these cells (73). Similar effects of curcumin on induced mucosal barrier injury in human intestinal epithelial blood cells were investigated in a later report in which it was (IEC-6) cells. Both drugs resulted in NF-κB activation as well shown that pretreatment of cultured peripheral blood lympho- as induction of TNFα and other downstream targets (70). Inter- cytes with very low doses of curcumin (1–10 µg/ml) protected estingly, NF-κB inhibition increased the susceptibility of IEC-6 against even up to 2 Gy dose of gamma radiation (74). In this cells to the drug-induced cell death upon addition of caffeic acid study, curcumin pretreatment protected against increases in mi- phenethyl ester (CAPE) but not that induced by curcumin. In cronuclei and dicentric nuclei formation, increases in lipid per- addition, in an animal model of methotrexate-induced mucosal oxidation, and decreases in superoxide dismutase, catalase, and barrier injury, treatment with curcumin resulted in NF-κB inhi- glutathione peroxidase activities induced by radiation treatment bition and partial amelioration of villous atrophy. These results (74). Findings from the study by Kunwar et al (75) reiterated provided evidence that inhibition of NF-κB does not necessarily the radioprotective role of curcumin when these investigators increase intestinal side effects of the anticancer drugs and sug- reported delayed activation of PKCδ and NF-κB in splenic Curcumin protects from the toxic effects of chemotherapy and radiotherapy Protects against radiation-induced DNA damage in cultured human cells Reduces apoptotic effects of arabinoside cytosine (Ara-C) against human intestinal epithelial cells Enhances radioprotection in cultured human lymphocytes Enhances radioprotection in mice splenic lymphocytes Protects against gamma radiation induced chromosomal damage in mice Reduces lung toxicity of whole-body irradiation in rats Reduces genotoxicity of whole-body irradiation in mice Reduces cardiotoxicity of doxorubicin in rats Prevents doxorubicin nephrotoxicity in rats Inhibits bleomycin-induced pulmonary fibrosis in rats Decreases acute toxicity of whole-body irradiation in rats Reduces radiation-induced oral mucositis in rats Reduces mucosal barrier injury from methotrexate in rats Enhances repair of wounds in mice exposed to whole-body γ -irradiation Enhances repair of wounds in mice exposed to hemibody γ -irradiation Protects against radiation-induced cutaneous cytotoxicity in mice Reduces nephrotoxicity of cisplatin in rats lymphocytes by curcumin and a curcumin:copper complex (1:1 Wound healing following radiation therapy is a frequent con- ratio) in radiation-exposed lymphocytes.
cern, as radiation treatment often disrupts normal response to In addition to in vitro evidence, data from several animal injury and results in delayed recovery periods. Radioprotective studies have now confirmed that curcumin has a strong ra- effects of curcumin have been investigated on wound healing in dioprotective function. Abraham and colleagues (76) used the mice exposed to 2 to 8 Gy doses of whole-body gamma radiation mouse bone marrow micronucleus test to interrogate the pro- (81,82). Pretreatment with curcumin significantly enhanced the tective role of 3 dietary agents including curcumin in mice ex- rate of wound contraction; shortened wound healing duration; posed to gamma radiation. The data from this study indicated and increased collagen synthesis and hexosamine, DNA, and that oral administration of curcumin 2 h before or immediately nitric oxide formation (81). In a related study, the same group of after exposing the animals to whole-body, high-energy gamma researchers used hemibody radiation exposure combined with irradiation significantly reduced the frequency of micronucle- curcumin pretreatment to make similar observations on wound ated polychromatic erythrocytes (76). Similar protective effects healing (83). In an effort to better understand these radioprotec- were noticed in mice pretreated with curcumin before expo- tive effects on a molecular level, it was shown that curcumin pre- sure to gamma irradiation in which curcumin helped reduce the treatment protected against radiation-induced acute and chronic number of bone marrow cells with chromosomal aberrations cutaneous toxicity in mice by decreasing gene expression of and other chromosomal fragments (77).
inflammatory (IL-1, IL-6, IL-18, TNFα, and lymphotoxin-β) Such radioprotective effects of curcumin were still notice- and fibrogenic cytokine (TGFβ) at 21 days postradiation (84).
able when much higher radiation doses (up to 10 Gy) were used Taken together, these studies have indicated a potential use of in rats in which curcumin pretreatment significantly reduced the curcumin as a radioprotective agent in patients with radiation- number of micronucleated cells and inhibited superoxide dis- mutase activity with a concomitant increase in catalase activityin liver tissues (78). Curcumin treatment for 3 days before and/or2 days after irradiation in female rats also inhibited levels of uri- CLINICAL IMPLICATIONS AND CONCLUSIONS
nary 8-hydroxy-2 -deoxyguanosine and significantly decreased Given the shortcomings of current chemotherapy and radia- the incidence of mammary and pituitary tumors (79). In another tion treatments for cancer management, it is obvious that such study, curcumin treatment of animals exposed to localized ir- treatments in the future must be combined with more effective radiation of their tongues resulted in an overall improvement and safer drugs/compounds. In this regard, given all the encour- against radiation-induced oral mucositis (80).
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