Nutraceuticals as new treatment approaches for oral cancer – i

Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i Nutraceuticals as new treatment approaches for oral cancer – i

Nutraceuticals as new treatment approaches for oral cancer – I: Curcumin

Ayelet Zlotogorskia, Aliza Dayanb, Dan Dayanf,⇑, Gavriel Chaushua,c, Tuula Salod,e, Marilena Veredf,g

a

Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

b Tiltan College, Natural Health Science, Tel Aviv, Israel

c

Department of Oral and Maxillofacial Surgery, School of Dentistry, Tel Aviv University, Tel Aviv, Israel

d

Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland

e

Institute of Dentistry, University of Helsinki, Helsinki, Finland

f

Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv, Israel

g

Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Israel

a r t i c l e i n f o

Article history:

Received 16 August 2012

Accepted 22 September 2012

Available online 30 October 2012

Keywords:

Oral cancer

Curcumin

Nutraceuticals

Anti-cancer activity

Nuclear Factor-jB (NF-jB)

Bioavailability

Radiotherapy

Chemotherapy

s u m m a r y

Oral squamous cell carcinoma (OSCC) is a growing global public health problem for which standard ther-apeutic strategies have failed to contribute significantly to improve the survival rates that have remained around 50% over the past three decades Therefore, there is a pressing need for new therapeutic strate-gies Curcumin is a natural dietary compound with known anti-neoplastic activities, hence its classifica-tion as a nutraceutical agent This review presents the current in vitro and in vivo studies in which curcumin has been examined for its anti-cancer potential in treating OSCC Its mechanisms of action are also beginning to become unveiled The available studies have been focusing on the impact of curcu-min on epithelial malignant cells, but overlooking the components of the tumor microenvironment Cur-cumin has been emerging as a promising therapeutic agent in oral cancer, either alone or in combination with standard therapeutic agents, and will probably become of practical use once its route of administra-tion has overcome its poor bioavailability

Ó 2012 Elsevier Ltd All rights reserved

Introduction

Oral and oropharyngeal cancers, the vast majority of which are

comprised of squamous cell carcinomas (SCCs), are among the 10

most common cancers worldwide.1The American Cancer Society

estimated 40,250 new cases of these cancers for 2012 in the United

States alone, with oral SCC (OSCC) constituting more than half of

them.2Tobacco use and alcohol consumption are regarded as the

main risk factors for OSCC, while human papilloma virus (HPV)

infection is emerging as the leading risk factor in cancers of the

oropharynx.3 In view of the difference in etiopathogenesis, there

are also different trends in morbidity and mortality between OSCC

and oropharyngeal cancers.3

In spite of extensive treatment (surgery, radiotherapy and/or

chemotherapy), OSCC is associated with recurrence and second

pri-mary tumors that are responsible for poor overall survival rates

(50%) that have not improved significantly over the past three

decades.4This can be attributed, in part, to genetic predisposition,

which can be a key issue in oral cancer pathogenesis, since tumors

often develop within pre-neoplastic fields of genetically altered cells.5In addition, components of the tumor microenvironment that are in continuous molecular crosstalk with the cancer cells have been shown to further facilitate the invasion and spread of the tu-mor and, therefore, they play a crucial role in the poor prognosis

of OSCC patients.6–8OSCC patients who have been apparently suc-cessfully treated have to contend with serious side effects, especially following radiotherapy.9As a consequence, there have been con-certed efforts to find alternative therapies which encompass more favorable clinical results and less morbidity among those patients

‘‘Nutraceutical’’ (a combination of the words ‘‘nutrition’’ and

‘‘pharmaceutical’’) refers to any substance considered to be a food

or a food ingredient that provides medical and health benefits A number of nutraceuticals have been identified during the past decade.10The present review will focus on one of the more prom-ising and more extensively investigated nutraceuticals, curcumin Curcumin is one of the components of curry and a popular dietary spice worldwide It is the primary active constituent of turmeric, a botanical agent derived from the rhizome (root) of the Curcuma longa, a perennial herb belonging to the ginger family that is broadly cultivated in south and south-east Asia Turmeric is com-prised of a group of three curcuminoids, i.e., curcumin (difer-uloylmethane), demethoxycurcumin, and bisdemethoxycurcumin,

as well as volatile oils, sugars, proteins and resins Curcumin is a 1368-8375/$ - see front matter Ó 2012 Elsevier Ltd All rights reserved.

⇑ Corresponding author Address: Department of Oral Pathology and Oral

Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978, Israel Tel.:

+972 3 6409305; fax: +972 3 6409250.

E-mail address: ddayan@post.tau.ac.il (D Dayan).

Contents lists available atSciVerse ScienceDirect

Oral Oncology

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / o r a l o n c o l o g y

hydrophobic polyphenol that is nearly insoluble in water

Impor-tantly, it has limited systemic bioavailability due to its rapid

metabolism, largely through conjugation to sulfates and

glucuron-ides.11,12 In humans, this metabolism presumably occurs in the

gastrointestinal tract rather than in the liver.13

Curcumin has been used for thousands of years in traditional

oriental medicine as a healing agent for a variety of illnesses, such

as biliary disorders, anorexia, cough, diabetic wounds, hepatic

dis-orders, rheumatism, and sinusitis.12Epidemiologic data have

sug-gested a correlation between the widespread use of dietary

curcumin and the low incidence of gastrointestinal mucosal

can-cers in south-east Asia.14Paradoxically, OSCC has the highest

inci-dence rates in the same geographical areas, with apparently no

benefit from the popular consumption of curcumin.4These results

may be attributed to the concomitant excessive habitual use of

to-bacco, alcohol and other carcinogenic substances Curcumin has

been considered pharmacologically safe, based on the fact that it

has been consumed for centuries as a dietary spice at doses up to

100 mg/day.15Moreover, its safety and tolerability became evident

in phase I studies when it was administered at doses as high as 8 g

per day.16

Curcumin has been studied in various in vitro and in vivo models

of OSCC with encouraging results The present paper summarizes

the current literature on the potential therapeutic and

chemopre-ventive qualities of this nutraceutical in the treatment of OSCC

The focus of this review is on the in vitro studies that employed

cancer cell lines from the oral cavity per se as well as on the

in vivo animal studies in which tumors were induced in the oral

cavity or oral tumors were implanted subcutaneously Some of

these studies were performed some years ago, before oral cancer

had been differentiated from oropharyngeal cancer We are aware

that some of the reviewed studies included cells or tumors from

both locations and that clear-cut separation between them was

not always feasible Therefore, whenever the cell line origin was

specifically mentioned as being from the oral cavity, it will be

re-ferred to as an OSCC cell line, and the rest will be rere-ferred to as

head and neck squamous carcinoma (HNSCC) cell lines

In vitro studies

Extensive in vitro and in vivo studies have indicated that nuclear

factor-jB (NF-jB) activation, one of the ‘‘masters’’ of inflammation,

has a promoting role in most cancers It is involved in most aspects

of tumorigenesis, and many of its important activities are exerted

through components of the tumor microenvironment.17NF-jB is

activated by a broad range of agents, including various carcinogens,

inflammatory cytokines (e.g., interleukin-1 [IL-1] and tumor

necro-sis factor [TNF]), and extracellular stress (e.g., ultraviolet light and

cigarette smoke), most of which play an important role in OSCC.17,18

Activation of NF-jB has been implicated in cellular transformation,

tumor promotion, angiogenesis, and tumor invasion and

metasta-sis.17One mechanism that may play a role in the anticancer

proper-ties of curcumin may be related to the down-regulation of NF-jB

Aggarwal et al.18 demonstrated that HNSCC cell lines expressed

constitutively active NF-jB and IjBakinase (IKK), and that

treat-ment with curcumin inhibited NF-jB activation through abrogation

of IKK This led to the suppression of expression of various cell

sur-vival and cell proliferative gene products, i.e., Bcl-2, cyclin D1, IL-6,

COX-2, and MMP-9, cell cycle arrest in the G1/S phase, and to the

activation of upstream- and downstream-caspases and PARP

cleav-age It has been demonstrated that curcumin down-regulates

smokeless tobacco-induced NF-jB activation and COX-2 expression

in oral premalignant and malignant cells.19Furthermore, exposure

to curcumin led to reduced nuclear expression of NF-jB and

conse-quently to a dose-dependent growth inhibition of HNSCC cell

lines,20which was followed by a dose-dependent inhibition of

IL-6 and IL-8.21Compared to other HNSCC cell lines, OSCC cells had significantly higher IjB kinase levels and required considerably higher doses of curcumin for the inhibition of IL-6 and IL-8.21Wang

et al.22showed that curcumin was able to inhibit NF-jB through an AKT-independent mechanism in an UM-SCC1 cell line Kim et al.23 collected saliva before and after subjects chewed curcumin tablets: treatment of an UM-SCC1 cell line with curcumin as well as with a post-curcumin salivary supernatant showed a reduction of their IKKb kinase activity It has also been suggested that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of Notch-1 and NF-jB signaling pathways,24 since curcumin treatment in CAL-27 cell lines significantly reduced cell viability in association with down-regulation of Notch-1 and NF-jB In addition, it was proposed that the inhibitory effect of cur-cumin on the motility of the highly invasive human YD-10B OSCC cell line could result from its potential to inhibit the activation

of MAP kinases (especially ERK) and NF-jB that consequently down-regulate the mRNA expressions and activities of proteolytic enzymes, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-2/9.25

The oncogenic significance of activated signal-transducer-and-activator-of-transcription-3 (STAT3) molecules stems from their ef-fects on the development and progression of malignancy.26Studies have shown that STAT3 is often constitutively activated in HNSCC27 and mediated by IL-6.28It has been implicated in the induction of resistance to apoptosis.29Chakravarti et al.30demonstrated that cur-cumin is a potent inhibitor of constitutive and IL-6-induced STAT3 phosphorylation and, as a result, it has the ability to suppress prolif-eration of HNSCC cell lines Abuzeid et al.31recently demonstrated that a novel curcumin analog (FLLL32) inhibited the active form of STAT3 in HNSCC cells and induced a potent antitumor effect Chak-ravarti et al.32showed that curcumin inhibited the growth of immor-talized oral mucosa epithelial cells, leukoplakia cells and HNSCC cell lines, but had only a minimal effect on the growth of normal oral epi-thelial cells In the abnormal and cancerous cells, however, curcumin inhibited cap-dependent translation by suppressing the phosphory-lation and/or total levels of mTOR-related factors (4E-BP1, eIF4G, eIF4B, eIF4E and Mnk1) The inhibition of p4E-BP1 and eIF4E was associated with a reduction in cyclin D1, which could explain the inhibitory effect of curcumin on cell proliferation

Rinaldi et al.33reported that curcumin increased the expression and function of cytochrome P450 (CYP) 1A1 and/or CYP1B1 in OSCC of the tongue cells, indicating that it has chemopreventive properties mediated by the inhibition of carcinogen bioactivation

A more recent study also revealed that curcumin is a potent inhib-itor of CYP 1B1in OSCC.34

Insulin-like growth factors (IGFs) that bind high affinity IGF receptors (IGFRs) play important roles in regulating cell pheno-types, including proliferation, differentiation, migration and apop-tosis The binding of IGF binding proteins (IGFBPs) to IGF prolongs the half-life of the latter and limits the bioavailability of free IGF to bind to IGFRs Down-regulation of IGFBP-5 was recently shown to increase tumorigenesis of OSCC cells.35The results of another cur-rent study further indicated that the inhibitory effects of curcumin

on the tumorigenesis of an SAS cell line of OSCC origin were prob-ably exerted by up-regulating IGFBP-5.36That latter study also re-vealed that up-regulation by curcumin of CCAAT/enhancer-binding proteina(C/EBPa), another tumor suppressor for HNSCC, underlies the up-regulation of IGFBP-5

In vivo studies Curcumin as a single therapeutic agent or combined with others has been currently tested in OSCC models in rats and hamsters

Tanaka et al.37found that curcumin inhibited rat oral

carcinogen-esis initiated with 4-nitroquinoline 1-oxide (4-NQO) Azuine and

Bhide38showed inhibition of oral mucosa tumors in hamsters

fol-lowing the administration of dietary turmeric In another study,

curcumin administered both alone and in combination with green

tea had inhibitory effects against oral carcinogenesis in hamsters,

which the authors described as being related to the suppression

of cell proliferation, induction of apoptosis and inhibition of

angi-ogenesis.39Inhibition of tumor growth was observed in nude mice

xenografts from a HNSCC cell line following the application of

cur-cumin as a topical paste.20Manoharan et al.40induced OSCC in the

buccal pouch of hamsters by painting them with

7,12-dimethyl-benz[a]anthracene (DMBA) Oral administration of curcumin and

piperine to the DMBA-painted hamsters on alternate days to DMBA

painting completely prevented the formation of oral tumors,

prably due to their antioxidant properties It has been previously

ob-served that the combination of curcumin with piperine (an

inhibitor of hepatic and intestinal glucuronidation) resulted in

higher curcumin concentrations in serum and substantially

im-proved the bioavailability of curcumin in healthy human

volun-teers.41 Lin et al.42 showed significant inhibitory effects of

curcumin on the proliferation and the growth of a human OSCC cell

line (SAS) inoculated subcutaneously to mice The cytotoxic effect

of curcumin was mainly at the G2/M phase of the cell cycle

Intravenous liposomal curcumin has been studied in xenograft

tumors of an HNSCC cell line in nude mice and it was found to

be both nontoxic as well as effective at suppressing tumor growth;

in addition, it was found that curcumin’s growth suppressive

ef-fects are related to the suppression of NF-jB in an AKT-indepen-dent pathway, thus supporting the in vitro findings.22 Clark

et al.43showed that curcumin was highly effective in suppressing the growth of HNSCC cell xenografts in mice, and that its activity was associated with modulation of the MTOR downstream target pS6 In addition, the authors showed that curcumin suppressed carcinogenesis via inhibition of the AKT/MTOR pathway In another study, Chang et al.36demonstrated that curcumin-induced IGFBP-5 expression was associated with the suppression of xenograft tumorigenesis in mice Those authors suggested that curcumin activates p38, which, in turn, activates the C/EBPa transactivator

by interacting with binding elements in the IGFBP-5 promoter The consequent up-regulation of C/EBPa and IGFBP-5 by curcumin

is crucial to the suppression of oral carcinogenesis

In vitro and in vivo therapeutic potential of curcumin combined with standard anti-neoplastic treatment modalities

In addition to its holding considerable therapeutic promise as a single agent, much interest has been shown in the administration

of curcumin as an adjuvant agent combined with different thera-peutic modalities Elattar and Virji44 concluded that curcumin has a significant dose-dependent inhibitory effect on growth and proliferation of OSCC cells, but that it was 5-fold less potent than cisplatin Duarte et al.45showed enhanced growth suppression of HNSCC cell lines in vitro and in vivo, using combinations of these two agents According to their report, the suppressive effect of

Figure 1 Curcumin acts on oral squamous cell carcinoma (OSCC) cells through multiple pathways Curcumin’s anti-cancer effect consists of inhibiting the NF-jB pathway, thereby holding back the downstream NF-jB-related factors (e.g., cyclin D1, Bcl-2, IL-6, IL-8, MMP-9 and COX2) Curcumin also acts through epithelial growth factor receptors (EGFRs) to inhibit two downstream pathways, STAT3 and AKT-mTOR These pathways participate in cancer cell proliferation, have an anti-apoptotic effect, and are involved in cancer cell-tumor microenvironment crosstalk related to extra-cellular matrix degradation and angiogenesis Unlike these pathways, curcumin activates the C/EBPa transactivator by interacting with binding elements in the IGFBP-5 promoter The resultant up-regulation of C/EBPa and IGFBP-5 by curcumin is crucial to the suppression of

curcumin was mediated through the inhibition of cytoplasmic and

nuclear IKKb, resulting in the inhibition of NF-jB activity

Concom-itantly, they demonstrated that cisplatin acts through the nuclear

p53 protein to control NF-jB transactivation with the resultant

re-duced expression of NF-jB-regulated proteins As a result, the

anti-neoplastic cytotoxic effect of cisplatin should be enhanced by the

addition of curcumin, necessitating lower, less toxic doses of

cis-platin Furthermore, Abuzeid et al.31recently found that the novel

curcumin analog FLLL32 sensitized cisplatin-resistant cancer cells,

achieving an equivalent tumor kill with a 4-fold lower dose of

cisplatin

Recent studies have also investigated the radiosensitization

ef-fect of curcumin upon irradiated OSCC HNSCC cell lines and

ortho-topic mouse models of SCC-1 tumors were treated with curcumin,

irradiation, or their combination The combination of curcumin and

irradiation exerted an additive effect In one study, curcumin

treat-ment of SCC-1 cell lines resulted in diminished COX-2 expression

and inhibition of EGFR phosphorylation.46In another study,

curcu-min adcurcu-ministration to OSCC cells (PE/CA-PJ15), which were

ex-posed to different doses of irradiation (1, 2.5 and 5 Gy), resulted

in enhanced cytotoxic activity in the OSCC cells.47Javvadi et al.48

reported that an inhibitory activity of curcumin on the

anti-oxi-dant enzyme thioredoxin reductase-1 (TxnRd1) is required for

cur-cumin-mediated radiosensitization of squamous carcinoma cells

Tuttle et al.49examined curcumin-induced irradiation sensitization

in HNSCC cell lines with differing HPV status and expressing

differ-ent levels of TxnRd1 and found that all HPV ( ) cell lines expressed

high levels of TxnRd1 and exhibited higher intrinsic resistance to

irradiation While curcumin was effective in increasing the

irradi-ation response of the resistant HPV ( ) cell lines, it had no effect

on the HPV (+) cells.49

Bioavailability of curcumin in clinical trials

Although curcumin has multiple pathways of action that lead to

enhanced therapeutic effects, the main disadvantages associated

with its oral administration are the high metabolic instability and

poor aqueous solubility that limit its systemic bioavailability.11,12

In addition, significant side effects and low patient compliance

may preclude the use of oral curcumin at the high doses

(>8 g/day) needed to achieve a therapeutic effect.50In order to

over-come these difficulties, new strategies for effective delivery of

cur-cumin are being investigated.51Among these methods, there are

liposomal curcumin formulations and encapsulation in diverse

polymeric nanoparticles.14,22,51 Lin et al.52 tested the effect of

microemulsions carrying a concentration of curcumin as high as

15lM together with low-frequency ultrasound on two OSCC cell

lines (OSCC-4 and OSCC-25) The ultrasound-enhanced delivery of

curcumin as a cytotoxic agent for OSCC was found to be favorable:

the microemulsion could be ingested orally and the concentration

could be adjusted so as to have minimal effect on healthy tissues

in the absence of the ultrasound releasing trigger Those authors

found that the addition of ultrasound strongly enhanced the

cyto-toxic effect of curcumin-containing microemulsions, especially on

OSCC-25 cells

Role of curcumin in modulation of the tumor

microenvironment

Recent studies have shown that curcumin possesses anti-tumor

action through modulation of some essential components of the

tumor microenvironment that regulates tumor progression.53,54

There are emerging lines of evidence that curcumin alters

fibro-blast cell behavior, such as proliferation, migration and

apopto-sis.55 Furthermore, curcumin modifies immune cells and

inflammatory processes by enhancing the cytotoxicity of CD8(+)

T cells toward tumors.56Tumor suppression via regulation of the tumor microenvironment represents a new attractive way for the therapeutic usage of curcumin in malignant diseases More re-search is required to confirm those beneficial properties of curcu-min in OSCC as well The main routes of action of curcucurcu-min on the malignant cells as well as on the components of the tumor microenvironment are schematically illustrated inFig 1

Concluding remarks and future perspectives Various scientific investigations have confirmed that curcumin possesses diverse and multiple molecular pathways of action in-volved in carcinogenesis and tumor formation Experimental

in vitro and in vivo studies have demonstrated the anti-tumor ef-fects of curcumin on OSCC as a single agent as well as in combina-tion with currently available convencombina-tional therapies It should be noted that the in vitro studies are actually a mixture of oral and oropharyngeal cell lines and so future studies should take into con-sideration the essential differences between SCC of the oropharynx and SCC of the oral cavity in terms of etiopathogenesis, morbidity and mortality, and investigate each of them separately A variety of strategies and delivery systems have been developed to improve the bioavailability of curcumin and to refine its therapeutic effi-cacy, including liposomal formulations or encapsulation in poly-meric nanoparticles Further preclinical and clinical studies are required in order to establish their bioavailability and their chemo-preventive and therapeutic effects on OSCC Further research is also required to confirm the antitumor effect of curcumin in mod-ulating the tumor microenvironment in OSCC

Conflict of interest statement None declared

Acknowledgments The authors would like to thank Ms Esther Eshkol for editorial assistance

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