218 Current Pharmaceutical Biotechnology, 2012, 13, 218-228

1389-2010/12 $58.00+.00 © 2012 Bentham Science Publishers

Curcumin and Liver Cancer: A Review

Altaf S. Darvesha, Bharat B. Aggarwal

b and Anupam Bishayee

a,c,*

aCancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy,

Northeast Ohio Medical University, Rootstown, OH 44272, USA; bCytokine Research Laboratory, Department of Ex-

perimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; cDepart-

ment of Internal Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA

Abstract: Primary liver cancer, also known as hepatocellular carcinoma (HCC), is one of the most lethal cancers having

worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has

been an alarming increase in HCC cases in Western Europe as well as United States. Chronic liver diseases, viral hepati-

tis, alcoholism as well as dietary carcinogens, such as aflatoxins and nitrosoamines, contribute to HCC. Liver transplanta-

tion as well as surgical resection at best offer limited treatment options. Thus, there exists a critical need to investigate and

evaluate possible alternative chemopreventive and therapeutic strategies which may be effective in the control of liver

cancer. HCC, most often, develops and progresses in a milieu of oxidative stress and inflammation. Phytochemicals, such

as dietary polyphenols endowed with potent antioxidant as well as anti-inflammatory properties, provide a suitable alter-

native in affording alleviation of HCC. Curcumin, the principal polyphenolic curcuminoid, obtained from the turmeric

rhizome Curcuma longa has long been used to cure several chronic ailments, such as neoplastic and neurodegenerative

diseases. Studies suggest that curcumin may have antitumor, antioxidant, and anti-inflammatory properties. This article

reviews the effects of curcumin in preclinical in vitro and in vivo models of HCC with particular emphasis to its antioxi-

dant, apoptotic and anti-inflammatory effects as well as involvement in various molecular signaling mechanisms. This re-

view also discusses potential challenges involved in the use of curcumin in HCC, such as bioavailability, pharmacokinet-

ics, drug delivery as well as paucity of clinical studies.

Keywords: Chemoprevention, curcumin, inflammation, liver cancer, oxidative stress, therapy.

INTRODUCTION

Primary liver cancer, essentially hepatocellular carci-

noma (HCC), remains the fifth largest cause of cancer in

men and the eighth largest in women [1-3]. HCC remains the

third leading cause of cancer-related deaths worldwide with

about 700,000 deaths reported annually [4, 5]. HCC is a ma-

lignancy with extremely grim prospects and a five-year sur-

vival rate reported below 9% [6]. HCC incidence has shown

a precipitous increase worldwide especially in the develop-

ing countries of Asia, such as China, as well as sub-Saharan

Africa. An alarming increase in HCC cases has also been

reported in parts of Central and Southern Europe as well as

the North American continent [7, 8]. The past three decades

has witnessed a dramatic increase in the occurrence of hu-

man HCC in the United States. Current statistics predict ap-

proximately 25,000 new cases and 19,000 deaths due to liver

cancer in 2010 in this country [9]. Although, the majority of

HCC cases are a result of infections due to the hepatitis B

and C viruses, risk factors such as obesity, iron overload,

both alcoholic and non-alcoholic cirrhosis, as well as dietary

hepatocarcinogenes, such as aflatoxins and nitrosoamines,

have also been implicated as important key causes of HCC

[5, 10-13]. Both surgery and liver transplant offer limited

*Address correspondence to this author at the Department of Pharmaceuti-

cal and Administrative Sciences, School of Pharmacy, 1600 East Hill Street,

Signal Hill, CA 90755, USA; Tel: +562 988 2278, Ext. 2038; Fax: +562 988

1791; E-mail: abishayee@auhs.edu

treatment options for HCC. Several factors, such as tumor

size, multifocality along with vascular invasion limit the

option of surgical resection in only about 20% of HCC pa-

tients. The recurrence rates of post-surgery HCC are also as

high as 50% [14]. Although, liver transplantation is useful in

treatment of early-stage HCC, it is available only to a small

number of HCC patients primarily due to scarcity of donor

organs. The effectiveness of the transplant option is also se-

verely limited due to the swift and frequent reappearance of

HCC in the transplanted liver [11, 15]. Several alternative

treatment approaches, such as Yttrium-90 intra-arterial de-

livery as microspheres, arterial chemoembolization, micro-

wave coagulation, intra-tumor ethanol injection as well as

radiofrequency ablation, have limited usefulness, being ap-

plicable only to patients with localized liver tumors [11, 16-

20]. Sorafenib, a vascular endothelial growth factor receptor

and tyrosine kinase inhibitor, is currently approved in the

United States for the treatment of unresectable HCC.

Although sorafenib has been shown to prolong the medial

survival time by almost three months in patients with ad-

vanced HCC, its therapeutic usefulness is limited due to se-

vere adverse effects including a considerable risk of hemor-

rhage [21, 22] as well as unprecedented high cost [23]. In

view of the aforementioned limitations of the current treat-

ment options available for HCC, novel approaches, espe-

cially chemoprevention, has been suggested as the para-

mount approach in lowering the occurrence and mortality

associated with HCC [24, 25].

Curcumin and Liver Cancer Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 219

Primary liver cancer occurs in the milieu of oxidative

stress and inflammation (reviewed in ref. [26]). Hepatic in-

flammation, resulting from hepatropic viral infections,

chronic hepatitis, cirrhosis, as well as exposure to toxic hepa-

tocarcinogens, represents an early malignant step with the

consequent epigenetic events occurring as a consequence of

a protracted inflammatory response. Considerable evidence,

accumulated over the past several years, implicates inflam-

mation-driven processes such as production of cytokines,

chemokines, as well as both reactive oxygen and nitrogen

species which contribute to the process of hepatocarcino-

genesis [27-31]. Oxidative stress, due to environmental in-

sults including hepatotoxicants, generates reactive oxygen

species such as superoxide anion and the hydroxyl radical

and is a predisposing factor to hepatocarcinogenesis [32-34].

Besides the involvement of the oxidative stress and the in-

flammatory cascade, various molecular and signaling

mechanisms have been proposed in the pathogenesis of HCC

[35, 36].

Phytochemicals, obtained from both dietary and non-

dietary sources, have shown potential usefulness as therapeu-

tic as well as chemopreventive agents for several chronic

maladies such as cardiovascular, metabolic, neoplastic and

neurodegenerative diseases [37-44]. Dietary components,

present in fruits, vegetables, nuts and spices, have demon-

strated significant potential in their ability to suppress car-

cinogenesis in pre-clinical models and prevent and delay the

occurrence of cancer in high-risk populations [45-48]. Of

particular interest are a multitude of polyphenolic com-

pounds found in the aforementioned dietary resources. Die-

tary polyphenols, such as anthocyanidins obtained from ber-

ries, catechins present in green tea, curcumin in turmeric,

ellagic acid present in pomegranates, lycopene found in to-

matoes, resveratrol in peanuts, grapes and red wine, quer-

cetin present in apples and red onions and many others, have

shown considerable promise as both preventive and thera-

peutic agents in cancer affecting several organ systems such

as breast, liver, lung, prostate and skin [40, 47, 49-51]. Poly-

phenolic compounds exert anticarcinogenic effects primarily

due to their antioxidant and anti-inflammatory properties as

well as their ability to modulate diverse molecular signaling

mechanisms implicated in carcinogenesis [45, 52-55]. Glau-

ert et al. [56] have recently reviewed the preventive potential

of dietary antioxidants such as vitamin C, vitamin E, sele-

nium as well as several phytochemicals in preclinical animal

models of HCC as well as human studies. Mann and col-

leagues [57] have also documented the promising chemopre-

ventive and therapeutic properties of several phytochemicals,

including dietary polyphenols in hepatocarcinogenesis. In

this article, we review the potential role of curcumin as a

chemopreventive and therapeutic agent for HCC.

CURCUMIN

Turmeric (Curcuma longa), also known as Indian saffron

is a rhizomatous herbaceous plant of the ginger family,

Zingiberaceae, native to the Indian sub-continent, Southeast

Asia as well as several other tropical countries. The dried

rhizome is ground to yield a yellow powder, also known as

yellow ginger, yellow root or natural yellow, and is widely

used as a spice in ethnic South and Southeast Asian cuisine

[58]. India, the major producer of turmeric, consumes about

90% of it with the remainder exported to be utilized by the

food industry as additive, preservative, flavoring and color-

ing agent [59]. Turmeric has customarily been used in tradi-

tional Ayurvedic medicine, primarily in South Asia, for

thousands of years as an antiseptic, antibacterial, antiin-

flammatory agent in the treatment of infections, respiratory

ailments, swelling and rheumatism [60-64]. Turmeric has

also been attributed with antiarthritic, anticarcinogenic, an-

tilipidogenic, cardioprotective, hepatoprotective, hypogly-

cemic and thrombosuppressive properties [65-70]. Polyphe-

nolic, yellow-colored curcuminoids are the primary chemical

constituents present in turmeric. Along with curcumin (cur-

cumin I), the principal curcuminoid, three other curcumi-

noids, namely demethoxycurcumin (curcumin II), bisde-

methoxycurcumin (curcumin III) and the recently identified

cyclocurcumin are present in turmeric. Commercial curcu-

min is a mixture of curcuminoids containing approximately

77% curcumin, 18% demethoxycurcumin and 5% bisde-

methoxycurcumin [58, 68, 69, 71].

Curcumin, the most important and abundant curcuminoid

is chemically known as diferuloylmethane Fig. (1), and was

first isolated in 1815 and crystallized in 1870 followed by

structural elucidation in 1910. Curcumin, intensely yellow at

acidic pH and red at basic pH, exists primarily enolic as well

as -diketonic forms which is extremely critical for its prop-

erty as a free radical scavenger [62, 72]. Curcumin has been

widely studied over the past two decades and has been at-

tributed with therapeutic treatment in a wide array of chronic

disorders, such as cardiovascular and neurodegenerative dis-

eases, diabetes, autoimmune disorders, namely allergy,

asthama rheumatoid arthritis and psoriasis, hepatoprotection

as well as cancer. A multitude of both pre-clinical and clini-

cal studies have highlighted the significant anti-cancer poten-

tial of curcumin (reviewed in refs. [68-71, 73, 74]).

Fig. (1) Chemical structure of curcumin.

Antioxidant and Anti-Inflammatory Properties of Cur-

cumin

Curcumin owes its therapeutic effects to its potent anti-

oxidant, anti-inflammatory properties as well as its ability to

modulate an array of signaling mechanisms [74-77]. Oxida-

tive stress plays an important role in the pathogenesis of sev-

eral chronic ailments such as neurodegenerative diseases and

cancer. Free radical pathology has been implicated in the

process of carcinogenesis [43, 78]. Several studies have

demonstrated the potent free-radical scavenging ability of

curcuminoid compounds. Curcumin as well as its curcumi-

noid analogs have been shown to attenuate free-radical me-

diated lipid peroxidation in several experimental systems

[79-81]. The phenolic hydroxyl group, the methoxy group as

well as the 1,3 -diketone moiety have all been shown to be

220 Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 Darvesh et al.

important structural features in the antioxidant properties of

curcuminoids [82].

The inflammatory cascade has been held as a key media-

tor of the pathogenesis of several chronic illnesses such as

autoimmune, cardiovascular, neurodegenerative as well as

neoplastic diseases [83-86]. Kundu and Surh [30] in their

elegant review discuss the critical and multifaceted role of

inflammation in carcinogenesis. Curcumin has been shown

to possess potent antiinflammatory properties which contrib-

ute to its therapeutic effects in the aforementioned illnesses

[73, 87, 88]. Pioneering research by the Aggarwal laboratory

has highlighted the powerful anti-inflammatory properties of

curcumin [73, 89, 90]. One of the key findings to emerge

almost a decade ago is the curcumin-mediated suppression of

nuclear factor- B (NF- B), the master switch in the inflam-

matory cascade [91]. NF- B activation is known to regulate

several key inflammatory mediators such as cytokines,

chemokines and kinases, which have been shown to play a

critical role in the pathogenesis of most chronic illnesses [85,

92, 93]. The curcumin-mediated attenuation of the NF- B

activated inflammatory cascade is an extremely critical

mechanism of its widespread therapeutic profile [94]. Sev-

eral investigators have delineated the mechanisms involved

in curcumin-mediated attenuation of NF- B expression and

the NF- B gene products which suppress apoptosis and me-

diate cell proliferation, invasion and angiogenesis [95-99].

Curcumin treatment also leads to suppression of several in-

flammatory cytokines such as interleukin (IL)-1, IL-1 , IL-6,

IL-8, chemokines as well as tumor necrosis factor- and cy-

clooxygenases [95, 100-102]. Curcumin also affects a pleth-

ora of signaling mechanisms implicated in process of car-

cinogenesis. Curcumin interacts with multiple cell signaling

proteins such as transcriptional factors, protein kinases, cy-

tokine signaling receptors, growth factors, adhesion mole-

cules as well as anti-apoptotic proteins. The aforementioned

molecular effects of curcumin lead to inhibition of cell pro-

liferation, cell invasion and apoptosis causing suppression of

metastasis (reviewed in ref. [75]).

Pharmacokinetics and Bioavailability of Curcumin

The pharmacokinetic profile of curcumin has been a sub-

ject of detailed investigation over the past few decades [103-

107]. Studies reveal poor absorption and rapid metabolism to

form glucoronoid conjugates which result in limited

bioavailability of curcumin. The Aggarwal laboratory has

contributed several excellent articles which review the phar-

macokinetics and bioavailability of curcumin [68, 69, 73, 76,

108]. Several strategies have been utilized to enhance the

poor bioavailability of curcumin. Shoba and colleagues [109]

demonstrated that co-administration of piperine, a hepatic

and intestinal inhibitor of glucoronidation, significantly en-

hanced curcumin bioavailability. Use of nanoparticle tech-

nology, liposomal formulations, phosphotidylcholine and

cyclodextrin complexes, as well as synthetic analogs of cur-

cumin resulted in superior bioavailability [110-116]. Several

recent studies have investigated the potential anti-cancer

properties of synthetic curcumin derivatives. John and co-

workers [117] demonstrated the enhanced cytotoxic and anti-

tumor activity of four synthetic curcuminoids as well as their

copper complexes. In a recent study, Padhye et al. [118]

showed that novel difluoro Knoevenagel curcumin conden-

sates, their Schiff bases as well as copper complexes causes

both growth inhibition and induction of apoptosis in colon

and pancreatic cancer cell lines. Salicyl curcumin inhibited

tumor specific angiogenesis in C57BL/6 mice injected with

B16F-10 melanoma cells [119].

Several clinical trials conducted over the past several

years, as well as currently ongoing, have studied the chemo-

preventive and therapeutic effects of curcumin in cancer of

various organ systems such as colon, gall bladder, liver, pan-

creas, as well as the gastrointestinal tract. Although trial re-

sults remain encouraging, there exists a critical need to criti-

cally evaluate the clinical effects of curcumin. Several inves-

tigators are of the opinion that encouraging in vitro as well as

in vivo pre-clinical data has not been reflected in the clinical

results in curcumin studies essentially due to poor bioavail-

ability. Hence, it is important to utilize the various aforemen-

tioned novel drug delivery systems to enhance curcumin’s

bioavailability, which may result in improved clinical thera-

peutic effects [68, 76, 120].

Toxicity Studies

Curcumin is an extremely well tolerated, bioactive and

nontoxic evident from it being an integral component of the

South Asian diet for thousands of years [68, 121, 122].

However, it has been opined that the high doses administered

in clinical trials remain a cause for potential concern since

the genotoxic and long-term effects of curcumin administra-

tion have not been systematically investigated [123]. Also,

there exist rare anecdotal reports of curcumin-induced ad-

verse effects. Curcumin-induced allergic contact dermatitis

and urticaria has also been reported in humans [124-126].

Role of Synergy

The role of synergy in the chemopreventive and thera-

peutic effects of dietary polyphenols has been a subject of

recent investigation [127-130]. Besides curcumin, turmeric

also contains three known curcuminoids. Sandur and co-

workers [131] have systematically evaluated the antioxidant,

antiinflammatory and antiproliferative effects of curcumin as

well as other curcuminoids. Although, curcumin displayed

higher activity than the other curcuminoids, the combination

of all the curcuminoids was more potent than any individual

curcuminoid, including curcumin, indicating a role of syn-

ergy in the pharmacological effects of curcuminoids.

CURCUMIN AND LIVER CANCER: IN VITRO STUD-

IES

Numerous studies, over the past several years, have

evaluated the effects of curcumin and its analogs in several

rodent as well as human hepatoma cells. In one of the initial

studies, Lin et al. [132] showed that curcumin decreased the

secretion of matrix metalloproteinase-9 (MMP-9) and conse-

quently inhibited both the migration as well as invasion of

SK-Hep-1 cells (Table 1). The anti-invasive and anti-

migratory effects of curcumin have also been shown in

CBO140C12 cells. In this study, Ohasi and colleagues [133]

showed that curcumin-mediated decrease in MMP-9 secretion

was accompanied by a significant inhibition of the adhesion

Curcumin and Liver Cancer Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 221

Table 1. Biological Effects of Curcumin in Preclinical In Vitro Models of Liver Cancer

Biological Effects Mechanisms of Action Concentration Reference

Curcumin inhibited the migration as well as invasion of

HCC-SK-Hep-1 cells. MMP-9 secretion 10 M Lin et al. [132]

Curcumin abrogated the invasion and migration of

CBO140C12 cells.

MMP-9 secretion,

fibronectin migration,

laminin migration

0.1-10 M Ohasi et al. [133]

Curcumin inhibited histone acetylation in Hep3B cells. HAT, ROS 50, 100 M Kang et al. [134]

Curcumin showed antiproliferating effects in Bel7402,

SGC7901 and HL60 cells.

apoptosis,

telomerase activity 1-32 M Cui et al. [135]

Curcumin inhibited cell survival in Hepa1-6 cells with

downregulated VEGF-A expression. 10-40 g/ml Jia et al. [136]

Curcumin attenuated cell growth in Huh7, Hep3B, HepG2,

SK-Hep-1, QGY-7703 cells in which the G2/M arrest was

previously abrogated.

apoptosis 25 M Wang et al. [137]

Curcumin inhibited growth and produced dose-dependent

damage in both the mitochondrial and nuclear DNA in

HepG2 cells.

8-OHdG, ROS, TBARS 2.5-40 g/ml Cao et al. [138]

Curcumin produced mitochondrial hyperpolarization in

HepG2 cells. m, cyt. c 2.5-40 g/ml Cao et al. [139]

Curcumin inhibited the proliferation of HEP3B, SK-Hep-1

and SNU449 cells. Notch1 signaling, NICD 10-40 M Ning et al. [141]

Curcumin and its -diketone modified analogs inhibited

proliferation in HA22T/VGH cells. apoptosis 5-25 M Simoni et al. [142]

Curcumin as well as tetrahydrocurcumin attenuated the

proliferative activity of HepG2 cells. 20-180 mol/L Yoysungnoen et al. [143]

Curcumin and its novel analog GL63 inhibited growth in

HepG2 cells. apoptosis, CHOP 5, 10, 20 M Xiao et al. [144]

Curcumin, alone or in combination with cisplatin and

doxorubicin synergistically exerted cell growth inhibitory

effects in HA22T/VGH cells.

apoptosis,

NF- B (p65),

COX-2, c-myc,

Bcl-XL, Bcl-XS

10, 20, 25 M Notarbartolo et al. [145]

Abbreviations: CHOP, C/EBP homologous protein; COX-2, cycloxygenase-2; cyt. c, cytochrome c; m, mitochondrial membrane potential; 8-OHdG, 8-hydroxydeoxyguanosine;

HAT, histone acetyltransferase; MMP-9, matrix metalloproteinase-9; NF- B, nuclear factor-kappaB; NICD, Notch1 intracellular domain; ROS, reactive oxygen species; TBARS,

thiobarbituric acid-reactive substances, VEGF-A, vascular endothelial growth factor-A.

and migration of both fibronectin and laminin. Curcumin,

akin to other dietary polyphenols, possesses both antioxidant

as well as pro-oxidant properties as evidenced by the curcu-

min-mediated increase in reactive oxygen species (ROS). In

this study, Kang and co-workers [134] have observed an

increase in ROS levels and a decrease in histone acetyltrans-

ferase activity in curcumin-mediated histone hypoacetylation

in Hep3B cells. Cui et al. [135] demonstrated that the anti-

proliferative effects of curcumin were accompanied by pro-

nounced apoptosis and attenuation of telomerase activity in

Bel7402, SGC7901 as well as HL60 cells. Curcumin also

inhibited cell survival in Hepa1-6 cells with downregulated

expression of the vascular endothelial growth factor-A [136].

In an interesting study, Wang and coworkers [137] showed

that downregulation of the Chk1 protein expression and sub-

sequent abrogation of the G2/M arrest facilitated curcumin-

mediated apoptosis in several hepatoma cell lines. The cur-

cumin-mediated growth inhibition and DNA damage in both

mitochondria as well as the nucleus involved pro-oxidant

mechanisms as evidenced by increased ROS and lipid perox-

ide levels in HepG2 cells [138]. In a subsequent study, Cao

et al. [139] showed that curcumin produced mitochondrial

hyperpolarizaton, elevated mitochondrial membrane poten-

tial and also increased cytochrome c release in HepG2 cells.

Upregulation of the notch1 receptor and signaling pathways

in hepatocarcinogenesis result in increased cellular prolifera-

tion as well as inhibition of apoptosis [140]. A recent study

by Ning and coworkers [141] showed that curcumin elicited

downregulation of the notch1 signaling pathway as well as

the notch intracellular domain in HEP3B, SK-Hep-1 and

222 Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 Darvesh et al.

SNU449 cells. Curcumin as well as its analogs have shown

anti-proliferative effects in various hepatoma cells [142-

144]. Simoni and colleagues [142] showed that curcumin and

its -diketone modified analogs stimulated apoptosis and

produced antiproliferative activity in HA22T/ VGH cells.

Tetrahydrocurcumin showed comparable results to curcumin

with regards to the attenuation of the proliferative activity of

HepG2 cells [143]. In an equivalent study, curcumin as well

as its novel analog GL63 produced an inhibitory effect on

HepG2 cells. The inhibitory effect was accompanied by in-

creased apoptosis and enhanced expression of C/EBP ho-

mologous protein, a pro-apoptotic activating protein [144].

The effects of curcumin in combination with standard che-

motherapeutic agents have also been investigated. In an in-

teresting study, Notarbartalo and colleagues [145] showed

that curcumin when combined with cisplatin and doxorubicin

caused a synergistic cell growth inhibition in HA22T/VGH

cells. The aforementioned effect was accompanied by an

increase in apoptosis and a decrease in NF- B activation as

well as a lowering of COX-2 levels.

CURCUMIN AND LIVER CANCER: IN VIVO STUD-

IES

The effects of curcumin and its analogous compounds

have been a subject of considerable investigation over more

than the past decade in several chemically-induced as well as

xenograft preclinical rodent models of HCC. These studies

document the potential role of curcumin as well as its ana-

logs in the prevention and treatment of HCC (Table 2).

Chemical Models of Hepatocarcinogenesis

Chemically-induced HCC remains one of the most exten-

sively used methods both of the study of the biological

mechanisms of HCC as well as the elucidation of the che-

mopreventive and therapeutic effects of potential anti-cancer

agents [146-148]. In one of the earliest studies, Soni and

colleagues [149] demonstrated that curcumin as well as tur-

meric extract reduced the number of gamma glutamyl

transpeptidase-positive foci in rats challenged with aflatoxin

B1. Nitrosoamines in general and diethylnitrosoamine

(DENA) in particular, either used alone or in presence of a

promoter such as phenobarbital (PB) have been a corner-

stone of pre-clinical liver cancer research [146, 147, 150].

Several studies have investigated the pharmacological effects

of curcumin and its analogs in DENA-induced HCC. Chuang

et al. [152, 153] have shown that curcumin protected against

DENA-induced hyperplasia and HCC in rodents. The

authors of the aforementioned studies also investigated the

underlying biochemical mechanisms of curcumin in DENA-

treated rodents. Curcumin strongly inhibited the DENA-

induced increase in the expression of the oncogenic p21ras

and tumor suppressor p53 protein as well as the elevated

levels of proliferating cell nuclear antigen as well as NF- B.

Thapliyal and coworkers [153] have also documented the

attenuation of DENA-induced hepatocarcinogenesis in rats

by dietary curcumin. The suppressive effects of curcumin in

the DENA-initiated and 2-acetylaminofluorene-promoted

alteration of hepatic foci in rats was accompanied by the

restoration of the normal levels of several hepatic metabolic

enzymes [154]. Sreepriya and Bali [155, 156] utilized the

well-characterized DENA-initiated and PB-promoted two-

stage model to investigate the potential anti-hepatocarcino-

genic properties of curcumin. In these studies, curcumin ad-

ministration prevented hepatocellular carcinogenesis in rats.

The investigators also reported that curcumin normalized the

elevated levels of several enzymes of liver function and bili-

rubin, increased glutathione content, elevated antioxidant

enzymes and attenuated lipid peroxidation. Curcumin has

also been shown to suppress the formation of hepatic ade-

nomas in mice treated with, 2,2'-dihydroxy-di-n-propylnitro-

samine (DHPN) [157].

In addition to aforementioned positive reports, several

studies have documented the failure of curcumin in protect-

ing against chemical hepatocarcinogenesis in rodents. Using

a multi-organ hepatocarcinogenesis rat model Takaba and

colleagues [158] reported the inability of curcumin to pre-

vent HCC in rats treated with DNPN, N-ethyl-N-hydroxy-

ethylnitrosamine and 3, 2'-methyl-4-aminobiphenyl. Curcu-

min also failed to attenuate both the DENA-induced increase

in formation of glutathione S-transferase (GST)-positive foci

as well as the DENA/2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline-induced hepatocarcinogenesis in rats [159, 160].

Curcumin treatment did not prevent the GST-positive foci

formation in rats treated with DENA and 3,3',4,4'-tetrachlo-

robiphenyl [161]. In an interesting study, chronic curcumin

administration did not prevent the copper-induced HCC in

rats [126]. A common feature of the aforementioned studies

which document the inability of curcumin to protect against

chemically-induced hepatocarcinogenesis is the administra-

tion of a relatively low dose of dietary curcumin which may

lead to its pro-oxidant effects. A low dietary dose may also

offer limited bioavailability of curcumin.

Xenograft Models of Hepatocarcinogenesis

A few investigators have studied the therapeutic effects

of curcumin in xenograft models of hepatocarcinogenesis.

Busquets et al. [162], demonstrated that curcumin treatment

blocked tumor growth in the Yoshida ascites hepatoma in

rats. Curcumin also suppressed the intrahepatic metastasis in

female mice implanted with CBO140C12 cells [132]. Subse-

quent studies have also demonstrated the curcumin-mediated

tumor inhibition in mice xenografted with several hepatoma

cells [135, 141]. Although the aforementioned xenograft

studies highlight the protective role of curcumin, the investi-

gators do not provide any mechanistic explanation to curcu-

min’s anti-tumor properties. Yoysungnoen and colleagues

[143, 163, 164] in a series of studies document the signifi-

cant antiangiogenic property of curcumin and its analog in

nude mice implanted with human HepG2 cells. Curcumin

treatment decreased both capillary density and vascularity

and also decreased expression of the pro-angiogenic vascular

endothelial growth factor.

CONCLUSION

The essential premise for the potential use of curcumin as

a chemopreventive and therapeutic agent in HCC rests on its

potent antioxidant and anti-inflammatory properties as well

as its ability to modulate a multitude of signaling mecha-

nisms. It is clearly evident from the in vitro as well as in vivo

pre-clinical models that curcumin, along with other curcumi-

noids, hold great promise as curative agents for HCC.

Curcumin and Liver Cancer Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 223

Table 2. Biological Effects of Curcumin in Preclinical In Vivo Models of Liver Cancer

Biological Effects Mechanisms of Action Dose/Duration Reference

Chemical models of hepatocarcinogenesis

Curcumin and turmeric extract reduced GGT+ foci in

AFB1-treated male Wistar rats.

Curcumin 0.005% and turmeric

0.05%, diet; 22 weeks Soni et al. [149]

Curcumin treatment protected against DENA-induced

hyperplasia in male Wistar rats. p21

ras, p53, NF- B 200, 600 mg/kg, p.o. Chuang et al. [151]

Curcumin suppressed the DENA-induced hepatocel-

lular carcinoma in male C3H/HeN mice. p21

ras, PCNA, Cdc2

0.2% diet;

38 weeks Chuang et al. [152]

Curcumin attenuated DENA-induced GGT+ foci and

hepatocellular carcinoma in female Wistar rats.

0.2, 1, 5%, diet;

10 weeks Thapliyal et al. [153]

Curcumin prevented the DENA-initiated and 2-AAF-

promoted development of altered GGT+/GST

+ hepatic

foci in male Wistar rats.

ATPase, ALP, G6Pase,

GGT, GST-P

200 mg/kg/day, p.o.;

5 days Shukla and Arora [154]

Curcumin significantly blocked the DENA-initiated

and PB-promoted nodule incidence in male Wistar rats. ALT, AST, ALP, BR

100 mg/kg/day, p.o.;

14 weeks Sreepriya and Bali [155]

Curcumin administration attenuated the DENA/PB-

induced hepatic oxidative stress in male Wistar rats. GSH, GST, GPX, MDA

100 mg/kg/day, p.o.;

14 weeks Sreepriya and Bali [156]

Curcumin suppressed the DHPN-induced liver ade-

noma formation in male BALB/c mice. 10, 100, 200 M, i.p.; 22 weeks Huang et al. [157]

Curcumin failed to protect against hepatocellular

carcinoma in male F344 rats treated with DHPN,

EHEN and DMAB.

1% diet;

36 weeks Takaba et al. [158]

Curcumin did not inhibit DENA-induced increase in

GST-P+ foci in male F344 rats.

0.5%, diet;

6 weeks Hirose et al. [159]

Curcumin did not prevent the DENA/MeIQx-induced

GST-P+ foci in male F344 rats.

0.5%, diet;

26 weeks Hirose et al. [160]

Curcumin did not decrease the preneoplastic GST-P+

foci in female Sprague-Dawley rats treated with

DENA and PCB-77.

0.5% diet;

80 days Tharappel et al. [161]

Curcumin did not protect against copper-induced

hepatocellular carcinoma in Long-Evans Cinnamon

rats.

0.5% diet;

100 weeks Frank et al. [126]

Xenograft models of hepatocarcinogenesis

Curcumin treatment restrained the tumor growth in

the Yoshida ascites hepatoma in male Wistar rats.

20 g/kg/day, i.p.;

6 days Busquets et al. [162]

Curcumin suppressed the intrahepatic metastasis in

female B6C3F1 mice implanted with CBO140C12

cells.

100, 200 mg/kg/day, p.o.;

20 days Ohasi et al. [133]

Curcumin significantly attenuated tumor growth in

female BALB/c athymic mice injected with Bel7402,

SGC7901 and HL60 cells.

50, 100, 200 mg/kg/day Cui et al. [135]

Curcumin treatment significantly attenuated tumor

growth in male nude athymic mice injected with SK-

Hep-1 cells.

100 mg/kg/day, i.p.;

16 days Ning et al. [141]

Curcumin produced antiangiogenic activity in male

BALB/c nude mice implanted with human HepG2

cells.

capillary density 3000 mg/kg/day, p.o.;

14 days Yoysungnoen et al. [163]

224 Current Pharmaceutical Biotechnology, 2012, Vol. 13, No. 1 Darvesh et al.

(Table 2) contd….

Biological Effects Mechanisms of Action Dose/Duration Reference

Xenograft models of hepatocarcinogenesis

Curcumin exerted antiangiogenic activity in HepG2

cell-implanted male BALB/c nude mice. COX-2, VEGF

300, 3000 mg/kg/day, p.o.;

14 days Yoysungnoen et al. [164]

Curcumin and tetrahydrocurcumin prevented tumor

angiogenesis in male BALB/c nude mice inoculated

with human HepG2 cells.

capillary vascularity 300, 3000 mg/kg/day, p.o.;

21 days Yoysungnoen et al. [143]

Abbreviations: 2-AAF, 2-acetylaminofluorene; AFB1, aflatoxin B1; ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartase transaminase;

ATPase, adenosine triphosphatase; BR, bilirubin; COX-2, cycloxygenase-2; DENA, diethylnitrososamine; DHPN, 2,2'-dihydroxy-di-n-propylnitrosamine;

DMAB, 3,2'-methyl-4-aminobiphenyl; EHEN, N-ethyl-N-hydroxyethylnitrosamine; G6Pase, glucose-6-phosphatase; GGT, gamma-glutamyl transpeptidase;

GPX, glutathione peroxidase; GSH, glutathione; GST, glutathione S-transferase; GST-P, glutathione S-transferase placental form; i.p., intaperitoneal; MDA,

malondialdehyde; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; NF- B, nuclear factor-kappaB; p.o., per os, PB, phenobarbital; PCB-77, 3,3',4,4'-

tetrachlorobiphenyl; PCNA, proliferating cell nuclear antigen; VEGF, vascular endothelial growth factor.

However, considerable amount of work and significant ef-

forts would be required before curcumin’s routine clinical

use for HCC. The key to success is translational research –

well designed clinical trials which systematically evaluate

the anti-cancer effects of curcumin against HCC. A major

problem which needs attention is the reduced bioavailability

of curcumin. Low therapeutic concentration of curcumin in

humans has been cited as a reason for lack of sufficient suc-

cess clinical trials. There exists a critical need to develop

novel dosage forms of curcumin to enhance its bioavailabil-

ity and investigate their anti-cancer effects in clinical studies.

Epidemiological studies, conducted in regions such as South

Asia where turmeric is an integral part of the diet, would

provide valuable clues to its potential effects against liver

cancer. Although curcumin is the most widely known and

effective curcuminoid present in turmeric, this spice also

contains at least three additional polyphenolic curcuminoids.

Hence, the role of the synergistic effects of curcuminoids

pleads further attention. Although, curcumin is a regular die-

tary component in various countries, and deemed safe and

nontoxic, its long term effects need to be investigated. The

high doses used clinically remain a source of concern and a

safe dosing regimen needs to be established. In conclusion,

although significant effort is essential prior to its successful

clinical application, curcumin remains a promising chemo-

preventive and therapeutic agent in the treatment of HCC.

ACKNOWLEDGEMENTS

The authors of this manuscript wish to express their sin-

cere thanks to Ms. Karishma A. Samtani for her kind help

with collection of primary literature reviewed in this article.

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Received: September 03, 2010 Revised: September 29, 2010 Accepted: October 01, 2010