Review Article Drug Repositioning for Gynecologic Tumors ...downloads.hindawi.com/journals/tswj/2015/341362.pdf · drug repositioning, human safety is already established, and therefore

Review ArticleDrug Repositioning for Gynecologic TumorsA New Therapeutic Strategy for Cancer

Kouji Banno Miho Iida Megumi Yanokura Haruko Irie Kenta MasudaYusuke Kobayashi Eiichiro Tominaga and Daisuke Aoki

Department of Obstetrics and Gynecology School of Medicine Keio University Tokyo 160-0016 Japan

Correspondence should be addressed to Kouji Banno kbannoz7keiojp

Received 26 September 2014 Accepted 13 January 2015

Academic Editor Anish Bali

Copyright copy 2015 Kouji Banno et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokineticsare established and to expand the therapeutic range of the drug to another disease Such drug discovery can be performed at lowcost and in the short term based on the results of previous clinical trials New drugs for gynecologic tumors may be found bydrug repositioning For example PPAR ligands may be effective against ovarian cancer since PPAR activation eliminates COX-2 expression arrests the cell cycle and induces apoptosis Metformin an antidiabetic drug is effective for endometrial cancerthrough inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growthfactor-1 due to AMPK activation COX-2 inhibitors for cervical cancermay also be examples of drug repositioning PGE2 is inducedin the arachidonate cascade by COX-2 PGE2maintains high expression of COX-2 and induces angiogenic factors including VEGFand bFGF causing carcinogenesis COX-2 inhibitors suppress these actions and inhibit carcinogenesis Combination therapy usingdrugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions Thusdrug repositioning may become a key approach for gynecologic cancer in drug discovery

1 Introduction

The goals of drug repositioning are to find a new pharma-cological effect for a drug for which human safety and phar-macokinetics are established and to expand the therapeuticrange of the drug to another disease The concept of drugrepositioning is well known in Europe and the United Statesbut uncommon in Asia Drugs for which indications havebeen expanded by drug repositioning include thalidomideaspirin metformin and digoxin Thalidomide is a sedativehypnotic agent that has serious teratogenic effects in admin-istration to pregnant women [1] However thalidomide iseffective against multiple myeloma and leprosy and is nowused for these diseases [2ndash4] Aspirin a nonsteroidal anti-inflammatory drug (NSAID) with antiplatelet effects hasalso been shown to be effective against colorectal cancer [5]metformin a drug for type 2 diabetes is effective againstmany cancers [6] and digoxin a cardiac glycoside hasefficacy against prostate cancer [7]

In this paper we discuss potential drug repositioning as anew therapeutic strategy for gynecologic tumors includingperoxisome proliferator-activated receptor (PPAR) ligandsand ritonavir for treatment of ovarian cancer metforminfor treatment of endometrial cancer and cyclooxygenase-2(COX-2) inhibitors for cervical cancer

2 Drug Repositioning as Drug Development

In the 1990s the drug discovery process was improvedby developments in genome-based drug discovery high-throughput screening and combinatorial chemistry withthe anticipation that many new drugs would be developedin the 21st century However the number of new drugslaunched on the market has decreased year after year duemainly to unexpected adverse reactions in clinical trials andpoor human pharmacokinetics Since drugs with safety andgood pharmacokinetics have already been developed drug

Hindawi Publishing Corporatione Scientific World JournalVolume 2015 Article ID 341362 10 pageshttpdxdoiorg1011552015341362

2 The Scientific World Journal

repositioning may be useful as a new approach to drugdiscovery [8ndash11]

The concept of drug repositioning is based on theidea that low molecular weight compounds are unlikely toact on only one target among the many proteins in cells[12] Drug repositioning is also facilitated by elucidationof molecular mechanisms involved in disease onset andprogression that is common pathologies of different diseasesthat were considered to be unrelated to each other Drugrepositioning also takes advantages of new approaches suchas DNA chips to facilitate a comprehensive investigationof the molecular pharmacology of existing drugs with thegoal of expanding the range of indications based on newlydiscovered pharmacological effects [12]

Drug repositioning has attracted attention due to sig-nificant advantages over traditional drug development Ittargets not only drugs that are on the current market but alsothose that have been withdrawn because of adverse effectsor those that have passed the safety issues in clinical trialsbut efficacy was insufficient and resulted in developmentfailure The available clinical trial data of suspended drugsreduces the time and costs of drug development Since thehuman safety and pharmacokinetics of these drugs havealready been evaluated unexpected adverse reactions andabnormal pharmacokinetics are unlikely to occur in clinicaltrials The reason behind the slow progress in new drugdevelopment is partly due to potential drugs showing efficacyand safety in animal studies but not in humans However indrug repositioning human safety is already established andtherefore candidate drugs from animal studies can be safelyprovisionally administered to humans to examine efficacywhich allows full-fledged development if efficacy is shown

In Japan drug repositioning was introduced around2012 Drug repositioning in Europe and the United Statesis better established and this approach produced six drugsapproved by the US Food and Drug Administration (FDA)in 2009 compared to only one drug in 2001 New indicationsintroduced by drug repositioning include thalidomide asedative hypnotic agent for multiple myeloma and leprosy[2ndash4] a COX-2 inhibitor for pancreatic cancer and colorectalcancer [13 14] aspirin an NSAID for colorectal cancer [5]and metformin an antidiabetic drug for endometrial cancer[6] In this paper we examine potential drug repositioningof PPAR ligands and ritonavir for ovarian cancer metforminfor endometrial cancer and a COX-2 inhibitor for cervicalcancer

3 PPARs and Ovarian Cancer

Peroxisome proliferator-activated receptors (PPARs) arenuclear receptor proteins that were discovered in 1990 [15]Three subtypes of PPARs 120572 120575 and 120574 have been identifiedwhich are expressed in different tissues [16] PPAR120572 isexpressed mainly in skeletal muscle liver kidney and heartand plays an important role in fatty acid metabolism PPAR120575is distributed in many tissues and regulates intracranial lipidmetabolism high-density lipoprotein (HDL) metabolismadipogenesis and preadipocyte differentiation PPAR120574

consists of three subtypes PPAR1205741 is expressed in manytissues including heart muscle colon kidney spleen andpancreas PPAR1205742 is found in adipose tissues and PPAR1205743is found in macrophages colon and white adipose tissuesPPAR120574 is involved in cell differentiation adipose depotsand modification of insulin action PPARs are activated byspecific ligands and bind to regulatory regions of target genesto regulate gene expression PPARs are targets in treatmentof diabetes dyslipidemia and arteriosclerosis due to thisgene regulation mechanism PPARs are also expressed invarious cancer cells and are implicated in oncogenesis

PPARs play a direct role in ovarian physiology throughregulation of expression and activation of proteases influ-encing tissue reconstruction and angiogenesis in folliculardevelopment ovulation and luteinization [17ndash20] Komar etal showed expression and localization of PPARs in normalrat ovarian tissues using in situ hybridization and specificroles of PPARs during follicular development [21] withlocalization of PPAR120574 in granulosa cells and PPAR120572 andPPAR120575 in the capsule and stroma PPAR120574 was shown tobe regulated by luteinizing hormone which is maintainedat a high level during follicular development and decreaseswith ovulation Furthermore progesterone and estrogenwere markedly increased by administration of ligands forPPAR120574 However PPAR120572 and PPAR120575 were expressed at highlevels regardless of the estrous cycle indicating that PPAR120572and PPAR120575 are involved in fundamental aspects of ovarianfunction the details of which are unknown Thus ligandsspecific to PPARs have certain effects on ovarian function butthe mechanisms are unclear

In 2004 Nicol et al found that PPAR120574 inhibited ovariancarcinogenesis induced by the carcinogen dimethyl benzan-thracene (DMBA) in mice [22] Following administration ofDMBA the incidences of cancer and metastasis in PPAR120574heterogenous knockout mice were ge3-fold and 46-fold thosein PPAR120574 wild mice respectively This suggests that PPAR120574reduces ovarian carcinogenesis Also in 2004 Sakamoto et alshowed that overexpression of COX-2 and underexpressionof PPAR120574 in ovarian epithelial cells were strongly implicatedin ovarian carcinogenesis and that PPAR120574 activation inovarian cancer cells inhibited COX-2 expression via thenuclear factor-kappa B (NF120581B) pathway [23] COX-2 isinvolved in carcinogenesis of colorectal and breast cancerand activation of PPAR120574 by specific ligands eliminates COX-2 expression induced by tumor necrosis factor (TNF)-120572 [23]Therefore PPAR120574 expression is inversely correlated withCOX-2 expression

These results suggest that ligands activating PPAR120574 mayinhibit ovarian carcinogenesis and serve as a therapeuticstrategy for ovarian cancer Several studies have found rela-tionships between PPAR120574 ligands and ovarian cancer Theseligands include ciglitazone which inhibits cell growth bycausing cell cycle arrest and apoptosis in ovarian cancer cells[24 25] (Figure 1) andDIM-C-pPhtBu which arrests the cellcycle by inducing PPAR120574-dependent p21 DIM-C-pPhtBualso reduces the activity of PPAR120574-independent cyclinD1 andinduces apoptosis which consequently inhibits cell growth[26] In an in vivo study in mice with subcutaneous ovariantumors and cancerous peritonitis Xin et al found that direct

The Scientific World Journal 3

O

N O

NHS

O

Ciglitazone

O

S NH

O

O

Pioglitazone (Actos)

Figure 1 Structures of ciglitazone and pioglitazone [25]

injection of ciglitazone significantly prolonged the survivalof mice with cancerous peritonitis [27] PPAR120574 in subcuta-neous tumors of mice treated with ciglitazone significantlyincreased in comparison with that before administrationApoptosis was induced and angiogenesis was inhibited intumors treated with ciglitazone Ciglitazone did not changeCOX-2 levels in tumors but microsomal prostaglandin Esynthase (mPGES) markedly decreased Thus ciglitazonereduced prostaglandin E2 (PGE2) in a COX-2-independentmanner induced apoptosis reduced angiogenesis and inhib-ited tumor progression

Pioglitazone another PPAR120574 ligand has similarinhibitory effects on tumor progression [28] However aclinical trial showed that the incidence of bladder cancerwith pioglitazone was higher than that with placebo [29]The relationship of bladder cancer and pioglitazone has beenexamined in the Kaiser Permanente Northern California(KPNC) study and in various meta-analyses with differentresults In 2014 the European Medicines Agency (EMA) rec-ommended that pioglitazone should not be given to patientswith bladder cancer or a history of bladder cancer The FDAalso instructed avoidance of pioglitazone for patients duringtreatment of bladder cancer because pioglitazone for one yearor more increased the risk of onset of bladder cancer Themechanism of action of pioglitazone is unclear and the risksassociated with bladder cancer require further evaluation

Fibrates are lipid-lowering drugs that activate PPAR120572 andpromote lipid metabolism which increases HDL cholesteroland has a preventive effect on arteriosclerosis An in vitrostudy in 2006 showed that PPAR120572 ligands inhibit cancercell growth [30] and several subsequent studies have shownthat PPAR120572 activation inhibits tumor growth [31ndash33] Theseresults confirm a relationship of PPAR120572 with tumor growthGrau et al found that ligand-based PPAR120572 activation incolorectal cancer cells inhibited transcriptional inductionof COX-2 and vascular endothelial growth factor (VEGF)

[30] with the mechanism thought to involve inhibition ofinduction of activator protein-1- (AP-1-) dependent geneswhich are involved in tumor progression AP-1 expression isregulated by the oncogene c-Jun In tumor growth inhibitionactivated PPAR120572 may bind directly to consensus DNAsequences which inhibits c-Jun transcriptional activity andattenuates AP-1 expression A subsequent study using PPAR120572ligands showed downregulated AP-1 expression in ovariancancer cells and inhibition of development of ovarian cancerproviding support for this mechanism [28]

Inhibition of solid tumor growth in vivo by PPAR120572activation was first shown in 2007 [31] Cancer-bearing miceandmice with cancerous peritonitis were produced using twotypes of human ovarian cancer cells and treated with clofibricacid a PPAR120572 ligand Clofibric acid reduced the tumor sizeand prolonged survival equally or more effectively comparedto cisplatin which is used for chemotherapy of ovariancancer The main mechanism of action may involve carbonylreductase which is induced in tumors by clofibric acidCarbonyl reductase is an enzyme that metabolizes carbonylcompounds with use of nicotinamide adenine dinucleotidephosphate (NADPH) [34] Clofibric acid also converts PGE2to prostaglandin F2120572 (PGF2120572) [35] and PGE2 inducesinflammation promotes angiogenesis and inhibits apoptosisand consequently is implicated in tumor growth [36 37]Clofibric acid also directly decreases the level of mPGES aPGE2 synthaseThus clofibric acid may reduce PGE2 activityin ovarian cancer by increasing carbonyl reductase anddecreasing mPGES with resultant inhibition of angiogenesisand induction of apoptosis Inflammation occurs aroundtumors and inflammatory cells release angiogenic factorsand cytokines which serve as nutrients for tumor cells [3233] PGE2 induces inflammation and ligand-induced PPAR120572activation inhibits this inflammation around tumor cells

Few studies have evaluated the relationship of PPAR120575withmalignant tumors PPAR120575 activation inhibits cell growthin breast cancer lung cancer and melanoma cells in vivo [3839] but the mechanisms of action are inconsistent Daikokuet al neutralized PPAR120575 in ovarian cancer cells overexpress-ing PPAR120575 in vivo and found tumor growth inhibitory effects[40] Aspirin a COX-1 selective inhibitor inhibits growth ofovarian cancer and attenuates PPAR120575 function implicatingPPAR120575 inactivation in growth inhibition of ovarian cancer[40] However another study showed that aspirin did notinhibit ovarian cancer growth [41] and further studies arerequired to examine the role of PPAR120575 in malignant tumors

4 Ritonavir and Ovarian Cancer

Ovarian cancer is a gynecological malignant tumor with ahighmortality because it is difficult to detect at an early stageMore than half of patients with ovarian cancer who undergochemotherapy with a first line platinum agent do not achieveclinical remission completely [42]

Treatment of HIV infection has the goal of prevention orcontrol of acquired immune deficiency syndrome (AIDS) Inantiretroviral therapy for inhibition of HIV growth anti-HIVdrugs targeting all viral life cycle stages are used There are


five types of currently approved anti-HIV drugs nucleosideanalogue reverse transcriptase inhibitors (NRTI) nonnu-cleoside analogue reverse transcriptase inhibitors (NNRTI)protease inhibitors (PI) integrase inhibitors (INI) and inva-sion inhibitors Monotherapy with these drugs producesresistant viruses resulting in failure of treatment thereforeit is common to use three or four drugs such as in highlyactive antiretroviral therapy (HAART) Typical HAART isa combination of NRTIs and PIs HAART reduces onset ofAIDS and opportunistic infection and risks for hospitaliza-tion and death [43] Interestingly the incidence of tumorlesions also decreases in patients treated with HAART [44ndash46] Clifford et al conducted a cohort study ofHIV and foundthat the standardized incidence ratio of Kaposirsquos sarcoma wassignificantly lower in patients treatedwithHAART (253 95CI 108ndash501) compared to those treated without HAART(239 95CI 211ndash270) [47] Other studies have shown similarresults for the antitumor effect of HAART [45 48 49]

Ritonavir a PI used for HAART induces apoptosis oflymphoblastic tumor cells including lymphoma myeloidleukemia fibrosarcoma andmastocytoma as well as Kaposirsquossarcoma [50 51] Ritonavir has an antitumor effect onMDH-2774 and SKOV-3 ovarian cancer cells through dose-dependent inhibition of the cell cycle and induction ofapoptosis After administration of ritonavir at a dose of 20120583Mfor 3 days cell death was induced in more than 60 ofMDH-2774 cells and 55 of SKOV-3 cells Ritonavir arreststhe G1 phase of the cell cycle in ovarian cancer cells bydepleting retinoblastoma (RB) phosphorylation G1 cyclinand cyclin dependent kinase The phosphatidylinositol-3kinase- (PI3K-) protein kinase- B(Akt-) mammalian targetof rapamycin (mTOR) signaling pathway is required forcell growth and plays an important role in progressionand metastasis of various cancers [52 53] Ritonavir dose-dependently decreases the amount of phosphorylated Aktwhich inhibits the PI3K-Akt pathway and has an antitumoreffect Akt inhibition by siRNA increases the apoptotic effectsynergistically with ritonavir These results suggest that useof ritonavir in combination with an Akt inhibitor mayenhance the antitumor effect The efficacy of this approachcompared to conventional chemotherapy requires furtherevaluation

5 Metformin and Endometrial Cancer

Patients with type 2 diabetes have risks of cancer includinghepatic endometrial pancreatic colon bladder and breastcancer [54 55] Most cases of endometrial cancer are ade-nocarcinoma and have low radiosensitivity thus the firsttreatment option is surgical therapy since there is little effec-tive chemotherapy Progestin therapy provides an option forfertility preservation and has a relatively high response rateand few adverse reactions however recurrence is high andthe therapeutic effect is limitedTheNational ComprehensiveCancer Network (NCCN) Clinical Practice Guidelines inOncology [56] recommend indications of progestin therapyfor young patients with atypical endometrial hyperplasia(AEH) or Grade 1 endometrioid adenocarcinoma who want

fertility preservation and for patients ineligible for surgery[57ndash59] The response rate of hormone therapy is high ifpatients meet these criteria If an appropriate response isnot obtained many patients who undergo hysterectomy asa change of therapeutic strategy achieve complete remission(CR) Conserving therapy uses three types of progesteronedrugs hydroxyprogesterone caproate (HPC) medroxypro-gesterone acetate (MPA) and megestrol acetate (MA) A lev-onorgestrel intrauterine device (LNG-IUS) has also recentlybeen used

In a meta-analysis published in 2012 Gallos et al showedthat the response to conservative therapy using progesteronewas 76 in endometrial cancer and 86 in AEH whichare relatively high [60] However the recurrence rates afterremission were 41 in endometrial cancer and 26 in AEHwhich are also high [60] The median disease-free survivaluntil recurrence was 24 months [61] and most cases recurredone to three years after treatment Consequently only 32of patients with endometrial cancer had long-term remission[62] The high recurrence rate after conservative therapyusing progesterone indicates that a new therapeutic strategyis required These may include LNG-IUS+GnRH therapy[63] and photodynamic therapy a procedure for irradiatingred light at 630 nm in the uterine cavity after intravenousinjection of photosensitizers [64] However outcomes arecurrently insufficient and these approaches are not an alter-native to progestin therapy

Metformin a drug for type 2 diabetes is of interest in drugrepositioning for endometrial cancer In an epidemiologicalstudy Evans et al found that the incidence of endometrialcancer in diabetic patients treated with metformin was lowerthan that in patients who were not given metformin [65]Metformin is an oral drug of the biguanide class that iscommonly used in patients with diabetes in addition to exer-cise and diet therapy Metformin inhibits gluconeogenesisenhances insulin sensitivity by inducing glucose transportersnormalizes blood glucose by increasing glucose uptake inskeletal muscles and decreases serum insulin Sulfonylureasstimulate insulin secretion and decrease blood glucose whilemetformin decreases insulin secretion and blood glucose

As described above endometrial cancer is stronglyrelated to obesity andmany patients with endometrial cancerhave hyperalimentation and high blood insulin [66] Thefunction of phosphatase and tensin homolog (PTEN) is fre-quently disturbed in endometrial cancer cells Consequentlythe PI3K-Akt-mTOR signaling pathway is activated in manypatients with endometrial cancer Several mechanisms ofaction for the antitumor effect of metformin have beenproposed activation of LKB1-AMP-activated protein kinase(LKB1-AMPK) which inhibits the mTOR pathway withresultant induction of progesterone receptor (PR) expressionand recovery of progesterone sensitivity [67 68] directreduction of insulin and insulin-like growth factor-1 (IGF-1) due to AMPK activation angiogenetic inhibition byreducing VEGF cell cycle arrest by inhibiting expressionof mitogen-activated protein kinase (MAPK) and cyclinD1 and inhibition of expression of epithelial growth factorreceptor 2 (HER2) and HER2 protein kinase and inhibitionof downstream signaling [69]


In 2014 Mitsuhashi et al conducted a study in 31patients with endometrial cancer who were scheduled toundergo surgery and were given metformin prior to surgeryGrowth of tumor cells in the endometrium was comparedhistologically before administration to after hysterectomy[70] There was a significant decrease of 442 (95 CI354ndash530 119875 lt 001) in the positive rate for Ki-67 a cellcycle protein that is correlated with the tumor grade AMPKincreased by 1132 (95 CI 136ndash2128 119875 = 003) andAMPK activation inhibits the mTOR pathway resulting indecreased activity of downstream substrate ribosomal proteinS6 (rpS6) Inhibition of MAPK and p27 expression increasedby 590 (95 CI 125ndash1055 119875 = 002) These results showthat metformin inhibits malignant growth of endometrialcancer in vivo

Mitsuhashi et al evaluated the effect of a combinationof metformin with MPA which is used in conventional pro-gestin therapy [70]Metformin at a dose of 1500ndash2250mgdaywas administered to patients with AEH or juvenile endome-trial cancer (FIGO stage IA G1 endometrioid adenocar-cinoma) who wanted fertility preservation simultaneouslywith MPA at a dose of 400mgday MPA was administeredfor 6 to 9 months and 91 of patients had CR Metforminwas administered continuously after completion of MPAadministration An interim analysis conducted after amedianobservation period of 26 months showed a recurrence rate ofonly 5 Given that the recurrence rate after MPA therapyis 40ndash50 metformin appears to be effective for preventionof cancer recurrence Diarrhea and nausea (Grade 2 orhigher) were observed in 13 of patients during the studyhowever these symptoms were relieved by decreasing themetformin dose and did not require suspension ofmetforminadministration Metabolic acidosis is also a known adversereaction of metformin when used as an antidiabetic drugHowever metformin is considered to be relatively safe foryoung women without renal dysfunction and no seriousadverse reactions were observed Body weight gain is alsoan adverse reaction of MPA but this was suppressed bymetformin and body weight was reduced after completionof MPA administration Administration of metformin alsoimproved insulin resistance and reduced IGF-1 Based onthese resultsMPA+metformin therapy resolves several prob-lems of MPA monotherapy including a high recurrence rateand has favorable effects on inhibition of body weight gainan adverse reaction ofMPA and improved insulin resistanceTherefore metformin may be a new therapy for youngerpatients with endometrial cancer although further clinicaltrials are required

6 COX-2 and Cervical Cancer

COX is a kinase enzyme that converts arachidonic acidreleased from phospholipids of cell membranes by phos-pholipase A2 (PLA2) to prostaglandins (PGs) and othereicosanoids (Figure 2) COX-2 is an inducible enzyme that istransiently produced in the nucleus by stimulation of inter-leukin 1 (IL-1) the primary inflammatory cytokine and TNF-120572 when inflammatory cells are activated COX-2 is expressed

Tissue injury

Arachidonic acids

Physiologic function

PGE2

InflammationNeoplasia

COX-2COX-1COX-2

inhibitor

Figure 2 Cyclooxygenase pathways

in inflammatory cells including macrophages neutrophilsfibroblasts and synoviocytes and at least 1 to 2 hours isrequired for onset of the enzyme activity Two transcriptionfactors AP-1 and NF-120581B play major roles in inducingCOX-2 expression following stimulation by growth factorscytokines hormones and endotoxins COX-2 is involved ininflammation vasodilation bone resorption cancer growthangiogenesis gastric ulcer repair and granulation [71 72]An increase in PGE2 the main product of COX-2 increasesvascular permeability and the vascular effusion response inearly inflammation COX-2 is expressed at extremely lowlevels in most tissues under normal physiological conditionsand is induced by response of inflammatory stimulationThus COX-2 is mainly expressed in inflammatory andimmunocompetent cells and the amount of PG productionby COX-2 is greater than that of COX-1 Therefore COX-2is involved in pathogenic malignancies and possible roles ofCOX-2 in carcinogenesis are of interest

Tumor and normal tissues have no significant differencein COX-1 expression but COX-2 has significantly higherexpression in tumor tissues including digestive cancers suchas colon gastric esophageal and pancreatic cancer and inlung breast bladder cervical and head and neck cancer andbrain tumors [73] High COX-2 expression is found in earlyto advanced cancer and upregulation is particularly strongin patients with metastasis and a poor prognosis [74] Incolorectal tumor COX-2 overexpression occurs in 40ndash50of cases of adenomatous polyposis and 80ndash90 of colorec-tal cancers [75] COX-2 is highly expressed in interstitialfibroblasts and invasive inflammatory cells in adenomatouspolyposis and in tumor epithelial cells and stromal cells incolorectal cancer [76] COX-2 expression is also increasedin lung cancer and particularly in lung adenocarcinomaRarely expressed in normal alveolar epithelial cells COX-2 is overexpressed in 30 of cases of atypical adenomatoushyperplasia a precancerous lesion and in 70 of lungadenocarcinomas [77] Among patients with stage I lungcancer who underwent radical surgery the five-year survivalrate was significantly higher in COX-2-negative cases (88)compared to cases with COX-2 overexpression (66) [78]

The incidence of COX-2 expression in breast cancerranges from 5 to 90 with high expression in patients


with a poor prognosis [79] highly malignant breast cancer[80] and HER2neu-positive tumor [81] Thun et al alsofound a significantly lower incidence of colorectal and gastriccancer in patients treated with long-term aspirin an NSAIDthat inhibits COX [82 83] The high COX-2 expression incancer tissues and epidemiological data on the effect of COXinhibitors on carcinogenesis suggest that COX-2 inhibitorsmay have an effect on carcinogenesis The role of COX-2 expression in carcinogenesis has also been studied indigestive cancer including colorectal cancer mPGES-1 anenzyme that converts PGH2 produced via COX-2 into PGE2is strongly expressed in many tumor tissues together withinduced COX-2 expression [84] Therefore coupled actionof COX-2 and mPGES-1 may increase PGE2 production intumor tissues The incidence of intestinal polyp is markedlyreduced in ApcΔ716 mice with a defective EP2 gene a PGEreceptor Therefore signaling pathways involving PGE2 andother prostanoids downstream of COX-2may play importantroles in intestinal tumors [85]

Involvement of PGE2 in carcinogenesis occurs throughseveral mechanisms In tumor tissues of ApcΔ716 mice COX-2 expression is significantly decreased which indicates thatPGE2 signaling via EP2 induces expression of COX-2 PGE2produced downstreamofCOX-2maintains overexpression ofCOX-2 by positive feedback [85] Expression of an angiogenicfactor VEGF and basic fibroblast growth factor (bFGF)is also induced via EP2 thus induced COX-2 expressionenhances PGE2 production and activates signals via EP2resulting in enhanced angiogenesis [86 87] PGE2 signalingalso induces activation ofmatrixmetalloproteinases (MMPs)which release transforming growth factor-120572 (TGF-120572) anepidermal growth factor receptor (EGFR) ligand from cellmembranes TGF-120572 induces proliferative signals by bindingto EGFR in tumor cells [88] PGE2 stimulation also inducesexpression of amphiregulin anEGFR ligand and the proteaseADAM17 which releases EGFR ligands from cell membranes[89] PGE2 signals can also activate peroxisome PPAR120575

Activation of Wnt a secretory glycoprotein inducesexpression of PPAR120575 and PGE2 signals induce PPAR120575 tran-scriptional activity via activation of the PI3KAkt pathwayand inhibit apoptosis in tumor cells [90] G proteins boundto ER2 receptors bind to axin with PGE2 stimulation andformation of a complex between APC and 120573-catenin isinhibited 120573-catenin is not phosphorylated becomes stabi-lized migrates to the nucleus and induces transcription ofWnt-target genes PGE2 also directly activates Wnt signalsinvolved in carcinogenesis [91] Thus the COX-2PGE2pathway may be involved in carcinogenesis through vari-ous mechanisms Prevention of carcinogenesis by COX-2selective inhibitors has been attempted but monotherapy isdifficult because these inhibitors cause heart-related adversereactions For this reason a combination of COX-2 inhibitorswith current anticancer drugs may be the best approach toimprove the therapeutic effect

High expression ofCOX-2 is also found in cervical cancerand COX-2 is found in cervical intraepithelial neoplasia(CIN) in addition to invasive cancer Epidermal growthfactor (EGF) activates mRNA and promoters of COX-2

Table 1 Drug repositioning for treatment of gynecologic tumors

Drug Original target New target

PPAR120574 ligand Type 2 diabetesatherosclerosis Ovarian cancer

Ritonavir AIDS Ovarian cancerMetformin Type 2 diabetes Endometrial cancerCOX-2 inhibitor Inflammation pain Cervical cancer

in cancer tissues [92] and COX-2 induction by EGF issuppressed by inhibition of kinases including PI3K mitogen-activated protein kinase (MAP2K) and p38 MAPK COX-2expression is also markedly increased in patients with lymphnodemetastases and invasion in the parametrium [93]Manypatients with cervical cancer particularly adenocarcinomahave COX-2 overexpression and the effects of neoadjuvantchemotherapy were poorer and survival was shorter inpatients with higher COX-2 levels [94] Thus COX-2 has animportant role in carcinogenesis and COX-2 inhibitors maybe effective as cancer therapy In this context clinical trialsof tegafur-uracil (UFT) + cyclophosphamide + celecoxibare underway in patients with advanced recurrent cervicalcancer

COX-2 inhibitors also increase the sensitivity of cancercells to drugs and radiotherapy in addition to having adirect anticancer effect In vitro administration of anticancertaxanes was found to stabilize mRNA of COX-2 [95] Ifthis occurs in vivo COX-2 may be implicated in acquisitionof resistance to taxanes In another in vitro study COX-2inhibitors were found to enhance the antitumor effects ofcisplatin and paclitaxel [96] while COX-2 overexpressiondecreases radiosensitivity by inhibiting apoptosis inducedby radiation regardless of overexpression and induction ofp53 protein prior to treatment [93] These results suggestthat COX-2 inhibitors may increase radiosensitivity andthis effect has been shown in tumor cells however COX-2inhibitors also damaged normal proliferating cells includingthe intestinal tract Drugs such as celecoxib inhibit PG pro-duction by COX-2 in cancer tissues and specifically increasethe sensitivity of tumor cells to radiotherapy [97 98] but theefficacy is uncertain [99] In general these studies indicatethat a combination of current therapy and COX-2 inhibitorsmay improve outcomes and result in fewer adverse reactionsin treatment of cervical cancer Clinical studies are requiredto examine these issues further

7 Conclusion

New drug development is currently occurring slowly anddiscovery of new antitumor drugs may be facilitated by drugrepositioning In this process it is important to analyzevarious pharmacological actions of existing drugs and toshow a low incidence of a certain cancer epidemiologicallyin patients treated with these drugs PPAR ligands riton-avir metformin and COX-2 inhibitors may be effective forgynecologic tumors but these drugs have yet to be used inclinical practice (Table 1) Use of these drugs in combinationwith current anticancer drugs may improve efficacy reduce


adverse reactions and improve patient QOL Further clinicaland epidemiological studies are required to examine theseissues

Conflict of Interests

The authors declare that they have no conflict of interests

References

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[2] A K Stewart ldquoHow thalidomide works against cancerrdquo Sciencevol 343 no 6168 pp 256ndash257 2014

[3] C Schwab and S Jagannath ldquoThe role of thalidomide inmultiple myelomardquoClinical Lymphoma andMyeloma vol 7 no1 pp 26ndash29 2006

[4] S L Walker M F R Waters and D N J Lockwood ldquoTherole of thalidomide in the management of erythema nodosumleprosumrdquo Leprosy Review vol 78 no 3 pp 197ndash215 2007

[5] A Chan ldquoThe role of aspirin in colorectal cancer preventionand treatmentrdquo Oncology vol 27 no 10 pp 1012ndash1042 2013

[6] E M Ko P Walter A Jackson et al ldquoMetformin is associatedwith improved survival in endometrial cancerrdquo GynecologicOncology vol 132 no 2 pp 438ndash442 2014

[7] EM Flahavan L Sharp K Bennett and T I Barron ldquoA cohortstudy of digoxin exposure and mortality in men with prostatecancerrdquo BJU International vol 113 no 2 pp 236ndash245 2014

[8] Roundtable on Translating Genomic-Based Research forHealth Board on Health Sciences Policy Institute of Medicine(US)Drug Repurposing and RepositioningWorkshop SummaryNational Academies Press Washington DC USA 2014

[9] Z-Y Wang and H-Y Zhang ldquoCorrigendum rational drugrepositioning by medical geneticsrdquo Nature Biotechnology vol32 no 6 article 592 2014

[10] G Temesi B Bolgar A Arany C Szalai P Antal and PMatyusldquoEarly repositioning through compound set enrichment anal-ysis a knowledge-recycling strategyrdquo Future Medicinal Chem-istry vol 6 no 5 pp 563ndash575 2014

[11] T Mizushima ldquoIdentification of molecular mechanism foractions of existing medicines and its application for drugdevelopmentrdquo Yakugaku Zasshi vol 132 no 6 pp 713ndash7202012

[12] A Power A C Berger and G S Ginsburg ldquoGenomics-enabled drug repositioning and repurposing insights froman IOM roundtable activityrdquo Journal of the American MedicalAssociation vol 311 no 20 pp 2063ndash2064 2014

[13] E Pomianowska A R Schjoslashlberg O P F Clausen and I PGladhaug ldquoCOX-2 overexpression in resected pancreatic headadenocarcinomas correlates with favourable prognosisrdquo BMCCancer vol 14 no 1 article 458 2014

[14] A Altun N H Turgut and T T Kaya ldquoAnticancer effectof COX-2 inhibitor DuP-697 alone and in combination withtyrosine kinase inhibitor (E7080) on colon cancer cell linesrdquoAsian Pacific Journal of Cancer Prevention vol 15 no 7 pp 3113ndash3121 2014

[15] I Issemann and S Green ldquoActivation of amember of the steroidhormone receptor superfamily by peroxisome proliferatorsrdquoNature vol 347 no 6294 pp 645ndash650 1990

[16] T Lemberger B Desvergne and W Wahli ldquoPeroxisomeproliferator-activated receptors a nuclear receptor signalingpathway in lipid physiologyrdquo Annual Review of Cell and Devel-opmental Biology vol 12 pp 335ndash363 1996

[17] N Marx P Libby M A Lazar and J Plutzky ldquoPeroxisomeproliferator-activated receptor 120574 activators inhibit gene expres-sion and migration in human vascular smooth muscle cellsrdquoCirculation Research vol 83 no 11 pp 1097ndash1103 1999

[18] M Ricote A C Li T M Willson C J Kelly and C K GlassldquoThe peroxisome proliferator-activated receptor-120574 is a negativeregulator of macrophage activationrdquo Nature vol 391 no 6662pp 79ndash82 1998

[19] N Marx G K Sukhova C Murphy P Libby and J PlutzkyldquoMacrophages in human atheroma contain PPAR 120574rdquoTheAmer-ican Journal of Pathology vol 274 pp 17ndash23 1998

[20] X Xin S Yang J Kowalski and M E Gerritsen ldquoPeroxisomeproliferator-activated receptor 120574 ligands are potent inhibitorsof angiogenesis in vitro and in vivordquo Journal of BiologicalChemistry vol 274 no 13 pp 9116ndash9121 1999

[21] C M Komar O Braissant W Wahli and T E CurryJr ldquoExpression and localization of PPARs in the rat ovaryduring follicular development and the periovulatory periodrdquoEndocrinology vol 142 pp 4831ndash4838 2001

[22] C J Nicol M Yoon J M Ward et al ldquoPPAR120574 influencessusceptibility to DMBA-induced mammary ovarian and skincarcinogenesisrdquo Carcinogenesis vol 25 no 9 pp 1747ndash17552004

[23] A Sakamoto Y Yokoyama M Umemoto et al ldquoClinicalimplication of expression of cyclooxygenase-2 and peroxisomeproliferator activated-receptor 120574 in epithelial ovarian tumoursrdquoBritish Journal of Cancer vol 91 no 4 pp 633ndash638 2004

[24] S Vignati V Albertini A Rinaldi et al ldquoCellular andmolecularconsequences of peroxisome proliferator-activated receptor-120574activation in ovarian cancer cellsrdquo Neoplasia vol 8 no 10 pp851ndash861 2006

[25] X Zhang and H A Young ldquoPPAR and immune systemmdashwhatdo we knowrdquo International Immunopharmacology vol 2 no 8pp 1029ndash1044 2002

[26] P Lei M Abdelrahim and S Safe ldquo11-Bis(31015840-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growththrough peroxisome proliferator-activated receptor-dependentand independent pathwaysrdquoMolecular CancerTherapeutics vol5 no 9 pp 2324ndash2336 2006

[27] B Xin Y Yokoyama T Shigeto M Futagami and HMizunuma ldquoInhibitory effect of meloxicam a selectivecyclooxygenase-2 inhibitor and ciglitazone a peroxisomeproliferator-activated receptor gamma ligand on the growth ofhuman ovarian cancersrdquo Cancer vol 110 no 4 pp 791ndash8002007

[28] T Shigeto Y Yokoyama B Xin and H Mizunuma ldquoPeroxi-some proliferator-activated receptor alpha and gamma ligandsinhibit the growth of human ovarian cancerrdquoOncology Reportsvol 18 no 4 pp 833ndash840 2007

[29] J A Dormandy B Charbonnel D J A Eckland et alldquoSecondary prevention ofmacrovascular events in patients withtype 2 diabetes in the PROactive Study (PROspective piogli-tAzone Clinical Trial in macroVascular Events) a randomisedcontrolled trialrdquo The Lancet vol 366 no 9493 pp 1279ndash12892005

[30] R Grau C Punzon M Fresno and M A IniguezldquoPeroxisome-proliferator-activated receptor 120572 agonists inhibit


cyclo-oxygenase 2 and vascular endothelial growth factortranscriptional activation in human colorectal carcinoma cellsvia inhibition of activator protein-1rdquo Biochemical Journal vol395 no 1 pp 81ndash88 2006

[31] Y Yokoyama B Xin T Shigeto et al ldquoClofibric acid a perox-isome proliferator-activated receptor 120572 ligand inhibits growthof human ovarian cancerrdquo Molecular Cancer Therapeutics vol6 no 4 pp 1379ndash1386 2007

[32] A Pozzi M R Ibanez A E Gatica et al ldquoPeroxiso-mal proliferator-activated receptor-120572-dependent inhibition ofendothelial cell proliferation and tumorigenesisrdquoThe Journal ofBiological Chemistry vol 282 no 24 pp 17685ndash17695 2007

[33] D Panigrahy A Kaipainen S Huang et al ldquoPPAR120572 ago-nist fenofibrate suppresses tumor growth through direct andindirect angiogenesis inhibitionrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 105 no3 pp 985ndash990 2008

[34] B Wermuth ldquoPurification and properties of an NADPH-dependent carbonyl reductase from human brain Relationshipto prostaglandin 9-ketoreductase and xenobiotic ketone reduc-taserdquo The Journal of Biological Chemistry vol 256 no 3 pp1206ndash1213 1981

[35] A Schieber R W Frank and S Ghisla ldquoPurification and prop-erties of prostaglandin 9-ketoreductase from pig and humankidney Identity with human carbonyl reductaserdquo EuropeanJournal of Biochemistry vol 206 no 2 pp 491ndash502 1992

[36] M Tsujii S Kawano S Tsuji H Sawaoka M Hori and RN DuBois ldquoCyclooxygenase regulates angiogenesis induced bycolon cancer cellsrdquo Cell vol 93 no 5 pp 705ndash716 1998

[37] H Sheng J Shao J D Morrow R D Beauchamp and RN DuBois ldquoModulation of apoptosis and Bcl-2 expression byprostaglandin E

2in human colon cancer cellsrdquoCancer Research

vol 58 no 2 pp 362ndash366 1998[38] E E Girroir H E Hollingshead A N Billin et al ldquoPeroxisome

proliferator-activated receptor-betadelta (PPARbetadelta) lig-ands inhibit growth of UACC903 andMCF7 human cancer celllinesrdquo Toxicology vol 243 no 1-2 pp 236ndash243 2008

[39] P Sertznig T Dunlop M Seifert W Tilgen and J ReichrathldquoCross-talk between Vitamin D Receptor (VDR)- and Per-oxisome Proliferator-activated Receptor (PPAR)-signaling inmelanoma cellsrdquo Anticancer Research vol 29 no 9 pp 3647ndash3658 2009

[40] T Daikoku S Tranguch A Chakrabarty et al ldquoExtracellularsignal-regulated kinase is a target of cyclooxygenase-1- perox-isome proliferator-activated receptor-120575 signaling in epithelialovarian cancerrdquo Cancer Research vol 67 no 11 pp 5285ndash52922007

[41] B Xin Y Yokoyama T Shigeto andHMizunuma ldquoAnti-tumoreffect of non-steroidal anti-inflammatory drugs on humanovarian cancersrdquo Pathology and Oncology Research vol 13 no4 pp 365ndash369 2007

[42] A Desai J Xu K Aysola et al ldquoEpithelial ovarian cancer anoverviewrdquoWorld Journal of Translational Medicine vol 3 no 1pp 1ndash8 2014

[43] G Panos G Samonis V G Alexiou G A Kavarnou GCharatsis and M E Falagas ldquoMortality and morbidity of HIVinfected patients receiving HAART a cohort studyrdquo CurrentHIV Research vol 6 no 3 pp 257ndash260 2008

[44] T W Cheung ldquoAIDS-related cancer in the era of highly activeantiretroviral therapy (HAART) a model of the interplay of theimmune system virus and cancer lsquoOn the offensivemdashthe trojan

horse is being destroyedrsquo Part A Kaposirsquos sarcomardquo CancerInvestigation vol 22 no 5 pp 774ndash786 2004

[45] J Laurence ldquoImpact of HAART on HIV-linked malignanciesrdquoAIDS Reader vol 13 no 5 pp 202ndash205 2003

[46] P Monini E Toschi C Sgadari et al ldquoThe use of HAART forbiological tumour therapyrdquo Journal of HIV Therapy vol 11 no3 pp 53ndash56 2006

[47] G M Clifford J Polesel M Rickenbach et al ldquoCancer riskin the Swiss HIV cohort study associations with immunod-eficiency smoking and highly active antiretroviral therapyrdquoJournal of the National Cancer Institute vol 97 no 6 pp 425ndash432 2005

[48] L Kincaid ldquoModernHAARTdecreases cancers in childrenwithHIVrdquoThe Lancet Oncology vol 8 no 2 p 103 2007

[49] J L Long E A Engels R DMoore andK A Gebo ldquoIncidenceand outcomes of malignancy in the HAART era in an urbancohort of HIV-infected individualsrdquo AIDS vol 22 no 4 pp489ndash496 2008

[50] M Z Dewan J-N Uchihara K Terashima et al ldquoEfficientintervention of growth and infiltration of primary adult T-cellleukemia cells by an HIV protease inhibitor ritonavirrdquo Bloodvol 107 no 2 pp 716ndash724 2006

[51] T Ikezoe E S Daar J-I Hisatake H Taguchi and H PKoeffler ldquoHIV-1 protease inhibitors decrease proliferation andinduce differentiation of human myelocytic leukemia cellsrdquoBlood vol 96 no 10 pp 3553ndash3559 2000

[52] J R Testa and A Bellacosa ldquoAKT plays a central role intumorigenesisrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 98 no 20 pp 10983ndash109852001

[53] I Vivanco and C L Sawyers ldquoThe phosphatidylinositol 3-kinase-AKT pathway in human cancerrdquoNature Reviews Cancervol 2 no 7 pp 489ndash501 2002

[54] H Noto T Tsujimoto T Sasazuki and M Noda ldquoSignificantlyincreased risk of cancer in patients with diabetes mellitus asystematic review and meta-analysisrdquo Endocrine Practice vol17 no 4 pp 616ndash628 2011

[55] H Noto T Tsujimoto and M Noda ldquoSignificantly increasedrisk of cancer in diabetes mellitus patients a meta-analysis ofepidemiological evidence in Asians and non-Asiansrdquo Journal ofDiabetes Investigation vol 3 no 1 pp 24ndash33 2012

[56] National Comprehensive Cancer Network NCCN ClinicalPractice Guidelines in Oncology (NCCN Guidelines) NationalComprehensive Cancer Network 2008

[57] American College of Obstetricians and GynecologistsldquoACOG practice bulletin clinical management guidelinesfor obstetrician-gynecologists number 65 August 2005management of endometrial cancerrdquo Obstetrics amp Gynecologyvol 106 no 2 pp 413ndash425 2005

[58] W H Gotlieb M E Beiner B Shalmon et al ldquoOutcome offertility-sparing treatment with progestins in young patientswith endometrial cancerrdquo Obstetrics amp Gynecology vol 102 no4 pp 718ndash725 2003

[59] P T Ramirez M Frumovitz D C Bodurka C C Sun and CLevenback ldquoHormonal therapy for the management of grade 1endometrial adenocarcinoma a literature reviewrdquo GynecologicOncology vol 95 no 1 pp 133ndash138 2004

[60] I D Gallos J Yap M Rajkhowa D M Luesley ACoomarasamy and J K Gupta ldquoRegression relapse and livebirth rates with fertility-sparing therapy for endometrial cancerand atypical complex endometrial hyperplasia a systematic


review and meta-analysisrdquo The American Journal of Obstetricsamp Gynecology vol 207 no 4 pp 266e1ndash266e12 2012

[61] C C Gunderson A N Fader K A Carson and R EBristow ldquoOncologic and reproductive outcomes with progestintherapy in women with endometrial hyperplasia and grade 1adenocarcinoma a systematic reviewrdquo Gynecologic Oncologyvol 125 no 2 pp 477ndash482 2012

[62] T Kaku H Yoshikawa H Tsuda et al ldquoConservative therapyfor adenocarcinoma and atypical endometrial hyperplasia ofthe endometrium in young women central pathologic reviewand treatment outcomerdquo Cancer Letters vol 167 no 1 pp 39ndash48 2001

[63] L Minig D Franchi S Boveri C Casadio L Boccioloneand M Sideri ldquoProgestin intrauterine device and GnRH ana-logue for uterus-sparing treatment of endometrial precancersand well-differentiated early endometrial carcinoma in youngwomenrdquo Annals of Oncology vol 22 no 3 pp 643ndash649 2011

[64] M C Choi S G Jung H Park Y H Cho C Lee and S JKim ldquoFertility preservation via photodynamic therapy in youngpatients with early-stage uterine endometrial cancer a long-term follow-up studyrdquo International Journal of GynecologicalCancer vol 23 no 4 pp 698ndash704 2013

[65] JMM Evans L A Donnelly AM Emslie-Smith D R Alessiand A D Morris ldquoMetformin and reduced risk of cancer indiabetic patientsrdquo BritishMedical Journal vol 330 no 7503 pp1304ndash1305 2005

[66] J K Burzawa K M Schmeler P T Soliman et al ldquoProspectiveevaluation of insulin resistance among endometrial cancerpatientsrdquo The American Journal of Obstetrics and Gynecologyvol 204 no 4 pp 355e1ndash355e7 2011

[67] J T Thigpen J A Blessing P J DiSaia E Yordan L F Carsonand C Evers ldquoA randomized comparison of doxorubicin aloneversus doxorubicin plus cyclophosphamide in the managementof advanced or recurrent endometrial carcinoma aGynecologicOncologyGroup Studyrdquo Journal of Clinical Oncology vol 12 no7 pp 1408ndash1414 1994

[68] J Tate Thigpen M F Brady H D Homesley et al ldquoPhaseIII trial of doxorubicin with or without cisplatin in advancedendometrial carcinoma a gynecologic oncology group studyrdquoJournal of Clinical Oncology vol 22 no 19 pp 3902ndash3908 2004

[69] H Noto A Goto T Tsujimoto and M Noda ldquoCancer risk indiabetic patients treated with metformin a systematic reviewand meta-analysisrdquo PLoS ONE vol 7 no 3 Article ID e334112012

[70] A Mitsuhashi T Kiyokawa Y Sato and M Shozu ldquoEffectsof metformin on endometrial cancer cell growth in vivo apreoperative prospective trialrdquoCancer vol 120 no 19 pp 2986ndash2995 2014

[71] R Salcedo X Zhang H A Young et al ldquoAngiogenic effects ofprostaglandin E

2are mediated by up-regulation of CXCR4 on

human microvascular endothelial cellsrdquo Blood vol 102 no 6pp 1966ndash1977 2003

[72] R Fukuda B Kelly and G L Semenza ldquoVascular endothelialgrowth factor gene expression in colon cancer cells exposedto prostaglandin E

2is mediated by hypoxia-inducible factor 1rdquo

Cancer Research vol 63 no 9 pp 2330ndash2334 2003[73] T Fujita M Matsui K Takaku et al ldquoSize- and invasion-

dependent increase in cyclooxygenase 2 levels in human col-orectal carcinomasrdquo Cancer Research vol 58 no 21 pp 4823ndash4826 1998

[74] D K Gaffney J Holden M Davis K Zempolich K J Murphyand M Dodson ldquoElevated cyclooxygenase-2 expression corre-lateswith diminished survival in carcinomaof the cervix treatedwith radiotherapyrdquo International Journal of Radiation OncologyBiology Physics vol 49 no 5 pp 1213ndash1217 2001

[75] C E Eberhart R J Coffey A Radhika F M Giardiello SFerrenbach and R N Dubois ldquoUp-regulation of cyclooxy-genase 2 gene expression in human colorectal adenomas andadenocarcinomasrdquo Gastroenterology vol 107 no 4 pp 1183ndash1188 1994

[76] H Sano Y Kawahito R L Wilder et al ldquoExpression ofcyclooxygenase-1 and -2 in human colorectal cancerrdquo CancerResearch vol 55 no 17 pp 3785ndash3789 1995

[77] T Hida Y Yatabe H Achiwa et al ldquoIncreased expression ofcyclooxygenase 2 occurs frequently in human lung cancersspecifically in adenocarcinomasrdquo Cancer Research vol 58 no17 pp 3761ndash3764 1998

[78] H Achiwa Y Yatabe T Hida et al ldquoPrognostic significance ofelevated cyclooxygenase 2 expression in primary resected lungadenocarcinomasrdquo Clinical Cancer Research vol 5 no 5 pp1001ndash1005 1999

[79] A Ristimaki A Sivula J Lundin et al ldquoPrognostic significanceof elevated cyclooxygenase-2 expression in breast cancerrdquoCancer Research vol 62 no 3 pp 632ndash635 2002

[80] M L Parkett R EHarris F S JoarderM S Ross K P Clausenand F M Robertson ldquoCyclooxygenase-2 gene expression inhuman breast cancerrdquo International Journal of Oncology vol 10no 3 pp 503ndash507 1997

[81] K Subbaramaiah L Norton W Gerald and A J DannenbergldquoCyclooxygenase-2 is overexpressed in HER-2neu-positivebreast cancer evidence for involvement of AP-1 and PEA3rdquoJournal of Biological Chemistry vol 277 no 21 pp 18649ndash186572002

[82] M JThunMMNamboodiri andCWHeath Jr ldquoAspirin useand reduced risk of fatal colon cancerrdquoTheNewEngland Journalof Medicine vol 325 no 23 pp 1593ndash1596 1991

[83] M J Thun M M Namboodiri E E Calle W D Flanders andC W Heath Jr ldquoAspirin use and risk of fatal cancerrdquo CancerResearch vol 53 no 6 pp 1322ndash1327 1993

[84] B P van Rees K Saukkonen A Ristimaki et al ldquoCycloox-ygenase-2 expression during carcinogenesis in the humanstomachrdquo The Journal of Pathology vol 196 no 2 pp 171ndash1792002

[85] M Sonoshita K Takaku N Sasaki et al ldquoAcceleration ofintestinal polyposis through prostaglandin receptor EP2 inApc(Δ716) knockout micerdquo Nature Medicine vol 7 no 9 pp1048ndash1051 2001

[86] H Seno M Oshima T-O Ishikawa et al ldquoCyclooxygenase 2-and prostaglandin E

2receptor EP

2-dependent angiogenesis in

ApcΔ716 mouse intestinal polypsrdquo Cancer Research vol 62 no2 pp 506ndash511 2002


[88] R Pai B Soreghan I L Szabo M Pavelka D Baatar and AS Tarnawski ldquoProstaglandin E

2 transactivates EGF receptor

a novel mechanism for promoting colon cancer growth andgastrointestinal hypertrophyrdquoNature Medicine vol 8 no 3 pp289ndash293 2002

[89] J Shao S B Lee H Guo B M Evers and H ShengldquoProstaglandin E2 stimulates the growth of colon cancer cells


via induction of amphiregulinrdquo Cancer Research vol 63 no 17pp 5218ndash5223 2003

[90] F G Buchanan D Wang F Bargiacchi and R N DuBoisldquoProstaglandin E

2regulates cell migration via the intracellular

activation of the epidermal growth factor receptorrdquoThe Journalof Biological Chemistry vol 278 no 37 pp 35451ndash35457 2003

[91] M D Castellone H Teramoto B O Williams K M Drueyand J S Gutkind ldquoProstaglandin E2 promotes colon cancer cellgrowth through a Gs-axin-120573-catenin signaling axisrdquo Sciencevol 310 no 5753 pp 1504ndash1510 2005

[92] S Kulkarni J S Rader F Zhang et al ldquoCyclooxygenase-2is overexpressed in human cervical cancerrdquo Clinical CancerResearch vol 7 no 2 pp 429ndash434 2001

[93] H S Ryu K H Chang HW YangM S Kim H C Kwon andK SOh ldquoHigh cyclooxygenase-2 expression in stage IB cervicalcancer with lymph node metastasis or parametrial invasionrdquoGynecologic Oncology vol 76 no 3 pp 320ndash325 2000

[94] G Ferrandina L Lauriola G F Zannoni et al ldquoIncreasedcyclooxygenase-2 (COX-2) expression is associated withchemotherapy resistance and outcome in ovarian cancerpatientsrdquo Annals of Oncology vol 13 no 8 pp 1205ndash1211 2002

[95] K Subbaramaiah T P Marmo D A Dixon and A J Dan-nenberg ldquoRegulation of cyclooxgenase-2 mRNA stability bytaxanes evidence for involvement of p38 MAPKAPK-2 andHuRrdquo Journal of Biological Chemistry vol 278 no 39 pp 37637ndash37647 2003

[96] A F Soriano B Helfrich D C Chan L E Heasley P A BunnJr and T-C Chou ldquoSynergistic effects of new chemopreventiveagents and conventional cytotoxic agents against human lungcancer cell linesrdquoCancer Research vol 59 no 24 pp 6178ndash61841999

[97] T W Davis J M OrsquoNeal M D Pagel et al ldquoSynergybetween celecoxib and radiotherapy results from inhibition ofcyclooxygenase-2-derived prostaglandin E

2 a survival factor

for tumor and associated vasculaturerdquo Cancer Research vol 64no 1 pp 279ndash285 2004

[98] T W Davis N Hunter O C Trifan L Milas and J LMasferrer ldquoCOX-2 inhibitors as radiosensitizing agents forcancer therapyrdquo The American Journal of Clinical OncologyCancer Clinical Trials vol 26 no 4 pp S58ndashS61 2003

[99] R Mutter B Lu D P Carbone et al ldquoA Phase II studyof celecoxib in combination with paclitaxel carboplatin andradiotherapy for patients with inoperable stage IIIAB non-small cell lung cancerrdquo Clinical Cancer Research vol 15 no 6pp 2158ndash2165 2009

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


repositioning may be useful as a new approach to drugdiscovery [8ndash11]

The concept of drug repositioning is based on theidea that low molecular weight compounds are unlikely toact on only one target among the many proteins in cells[12] Drug repositioning is also facilitated by elucidationof molecular mechanisms involved in disease onset andprogression that is common pathologies of different diseasesthat were considered to be unrelated to each other Drugrepositioning also takes advantages of new approaches suchas DNA chips to facilitate a comprehensive investigationof the molecular pharmacology of existing drugs with thegoal of expanding the range of indications based on newlydiscovered pharmacological effects [12]

Drug repositioning has attracted attention due to sig-nificant advantages over traditional drug development Ittargets not only drugs that are on the current market but alsothose that have been withdrawn because of adverse effectsor those that have passed the safety issues in clinical trialsbut efficacy was insufficient and resulted in developmentfailure The available clinical trial data of suspended drugsreduces the time and costs of drug development Since thehuman safety and pharmacokinetics of these drugs havealready been evaluated unexpected adverse reactions andabnormal pharmacokinetics are unlikely to occur in clinicaltrials The reason behind the slow progress in new drugdevelopment is partly due to potential drugs showing efficacyand safety in animal studies but not in humans However indrug repositioning human safety is already established andtherefore candidate drugs from animal studies can be safelyprovisionally administered to humans to examine efficacywhich allows full-fledged development if efficacy is shown

In Japan drug repositioning was introduced around2012 Drug repositioning in Europe and the United Statesis better established and this approach produced six drugsapproved by the US Food and Drug Administration (FDA)in 2009 compared to only one drug in 2001 New indicationsintroduced by drug repositioning include thalidomide asedative hypnotic agent for multiple myeloma and leprosy[2ndash4] a COX-2 inhibitor for pancreatic cancer and colorectalcancer [13 14] aspirin an NSAID for colorectal cancer [5]and metformin an antidiabetic drug for endometrial cancer[6] In this paper we examine potential drug repositioningof PPAR ligands and ritonavir for ovarian cancer metforminfor endometrial cancer and a COX-2 inhibitor for cervicalcancer

3 PPARs and Ovarian Cancer

Peroxisome proliferator-activated receptors (PPARs) arenuclear receptor proteins that were discovered in 1990 [15]Three subtypes of PPARs 120572 120575 and 120574 have been identifiedwhich are expressed in different tissues [16] PPAR120572 isexpressed mainly in skeletal muscle liver kidney and heartand plays an important role in fatty acid metabolism PPAR120575is distributed in many tissues and regulates intracranial lipidmetabolism high-density lipoprotein (HDL) metabolismadipogenesis and preadipocyte differentiation PPAR120574

consists of three subtypes PPAR1205741 is expressed in manytissues including heart muscle colon kidney spleen andpancreas PPAR1205742 is found in adipose tissues and PPAR1205743is found in macrophages colon and white adipose tissuesPPAR120574 is involved in cell differentiation adipose depotsand modification of insulin action PPARs are activated byspecific ligands and bind to regulatory regions of target genesto regulate gene expression PPARs are targets in treatmentof diabetes dyslipidemia and arteriosclerosis due to thisgene regulation mechanism PPARs are also expressed invarious cancer cells and are implicated in oncogenesis

PPARs play a direct role in ovarian physiology throughregulation of expression and activation of proteases influ-encing tissue reconstruction and angiogenesis in folliculardevelopment ovulation and luteinization [17ndash20] Komar etal showed expression and localization of PPARs in normalrat ovarian tissues using in situ hybridization and specificroles of PPARs during follicular development [21] withlocalization of PPAR120574 in granulosa cells and PPAR120572 andPPAR120575 in the capsule and stroma PPAR120574 was shown tobe regulated by luteinizing hormone which is maintainedat a high level during follicular development and decreaseswith ovulation Furthermore progesterone and estrogenwere markedly increased by administration of ligands forPPAR120574 However PPAR120572 and PPAR120575 were expressed at highlevels regardless of the estrous cycle indicating that PPAR120572and PPAR120575 are involved in fundamental aspects of ovarianfunction the details of which are unknown Thus ligandsspecific to PPARs have certain effects on ovarian function butthe mechanisms are unclear

In 2004 Nicol et al found that PPAR120574 inhibited ovariancarcinogenesis induced by the carcinogen dimethyl benzan-thracene (DMBA) in mice [22] Following administration ofDMBA the incidences of cancer and metastasis in PPAR120574heterogenous knockout mice were ge3-fold and 46-fold thosein PPAR120574 wild mice respectively This suggests that PPAR120574reduces ovarian carcinogenesis Also in 2004 Sakamoto et alshowed that overexpression of COX-2 and underexpressionof PPAR120574 in ovarian epithelial cells were strongly implicatedin ovarian carcinogenesis and that PPAR120574 activation inovarian cancer cells inhibited COX-2 expression via thenuclear factor-kappa B (NF120581B) pathway [23] COX-2 isinvolved in carcinogenesis of colorectal and breast cancerand activation of PPAR120574 by specific ligands eliminates COX-2 expression induced by tumor necrosis factor (TNF)-120572 [23]Therefore PPAR120574 expression is inversely correlated withCOX-2 expression

These results suggest that ligands activating PPAR120574 mayinhibit ovarian carcinogenesis and serve as a therapeuticstrategy for ovarian cancer Several studies have found rela-tionships between PPAR120574 ligands and ovarian cancer Theseligands include ciglitazone which inhibits cell growth bycausing cell cycle arrest and apoptosis in ovarian cancer cells[24 25] (Figure 1) andDIM-C-pPhtBu which arrests the cellcycle by inducing PPAR120574-dependent p21 DIM-C-pPhtBualso reduces the activity of PPAR120574-independent cyclinD1 andinduces apoptosis which consequently inhibits cell growth[26] In an in vivo study in mice with subcutaneous ovariantumors and cancerous peritonitis Xin et al found that direct


O

N O

NHS

O

Ciglitazone

O

S NH

O

O


























Tissue injury

Arachidonic acids


PGE2


COX-2COX-1COX-2

inhibitor
















7 Conclusion






References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

N O

NHS

O

Ciglitazone

O

S NH

O

O


























Tissue injury

Arachidonic acids


PGE2


COX-2COX-1COX-2

inhibitor
















7 Conclusion






References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























Tissue injury

Arachidonic acids


PGE2


COX-2COX-1COX-2

inhibitor
















7 Conclusion






References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Tissue injury

Arachidonic acids


PGE2


COX-2COX-1COX-2

inhibitor
















7 Conclusion






References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























7 Conclusion






References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References


































































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































2receptor EP




















2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























2 a survival factor









of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Drug Repositioning for Gynecologic Tumors ...downloads.hindawi.com/journals/tswj/2015/341362.pdf · drug repositioning, human safety is already established, and therefore