review article bladder cancer and urothelial impairment...

Review ArticleBladder Cancer and Urothelial ImpairmentThe Role of TRPV1 as Potential Drug Target

Francesco Mistretta Nicolograve Maria Buffi Giovanni Lughezzani Giuliana ListaAlessandro Larcher Nicola Fossati Alberto AbratePaolo DellrsquoOglio Francesco Montorsi Giorgio Guazzoni and Massimo Lazzeri

Department of Urology Ospedale San Raffaele Vita-Salute San Raffaele University Via Stamira DrsquoAncona 20 20127 Milan Italy

Correspondence should be addressed to Francesco Mistretta mistrettafrancescoagmailcom

Received 27 January 2014 Revised 23 March 2014 Accepted 19 April 2014 Published 8 May 2014

Academic Editor Rok Romih

Copyright copy 2014 Francesco Mistretta et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Urothelium in addition to its primary function of barrier is now understood to act as a complex system of cell communicationthat exhibits specialized sensory properties in the regulation of physiological or pathological stimuli Furthermore it has beenhypothesized that bladder inflammation and neoplastic cell growth the two most representative pathological conditions of thelower urinary tract may arise from a primary defective urothelial lining Transient receptor potential vanilloid channel 1 (TRPV1)a receptor widely distributed in lower urinary tract structures and involved in the physiological micturition reflex was describedto have a pathophysiological role in inflammatory conditions and in the genesis and development of urothelial cancer In ouropinion new compounds such as curcumin the major component of turmeric Curcuma longa reported to potentiate the effectsof the chemotherapeutic agents used in the management of recurrent urothelial cancer in vitro and also identified as one of severalcompounds to own the vanillyl structure required to work like a TRPV1 agonist could be thought as complementary in the clinicalmanagement of both the recurrences and the inflammatory effects caused by the endoscopic resection or intravesical chemotherapyadministration or could be combined with adjuvant agents to potentiate their antitumoral effect

1 Introduction

Inflammation and neoplastic cell growth represent the maintwo pathologies of the bladder and they have a huge impacton patientrsquos quantity and life-span

The urothelium has been recognized to be more than asimple barrier separating the luminal contents from the innerlayers of the urinary tract It works with suburothelium as afunctional unit which responds to external stresses by therelease of modulator agents that regulate the activity of notonly the nearby afferent nerves but also of the underlyingsmooth muscle and urothelial stem cells In particular itmay act as an efficient chemomechanosensor the ldquoafferentfunctionrdquo and at the same time it is able to synthesizeand release into suburothelium layer molecules involved inthe bladder storagevoiding activity the ldquoefferent functionrdquoFurthermore urothelium may protect the basal cells from

toxins or other substances capable of activating a pathologicalcell growth

Since the early 90s investigators focused their basicscience and clinical research on the expression function andclinical application of a subset of capsaicin-sensitive primarysensory afferents of the lower urinary tract (LUT) [1ndash7]

Both the upper and LUT are densely innervated bycapsaicin-sensitive primary afferent neurons in a number ofspecies including humans [8] Early pharmacological studiesrevealed that capsaicin-sensitive C type bladder fibers play arole inmicturition reflex and it was shown that capsaicin sen-sitive nerves exhibit both a sensory (afferent) and an ldquoefferentrdquofunction which is determined by the release of peptidesincluding tachykinins substance P (SP) and calcitonin gene-related peptide (CGRP) [9] The sensory function includesthe regulation of the micturition threshold and the percep-tion of pain from the urinary bladder while the efferent

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 987149 10 pageshttpdxdoiorg1011552014987149

2 BioMed Research International

function controls nervous tissue excitability smooth musclecontractility and plasma protein extravasation (neurogenicinflammation) The discovery of specific binding sites forcapsaicin in several tissues and organs including the raturinary bladder [9] initiated a rush that ended up with thecloning of the vanilloid receptor [10] presently known asTRPV1 (transient receptor potential vanilloid subfamily 1)

In the lower urinary tract TRPV1 expression is nowfirmly documented not only in a large subpopulation ofnerve fibers but also in nonneuronal tissues Knowledgeabout the presumable function of TRPV1 also evolved rapidlyFrom a receptor initially considered as an integrator ofthermal and chemical noxious stimuli TRPV1 is emergingas a possible regulator of bladder reflex activity and celldifferentiation These findings together with the promisingclinical applications of TRPV1 targeting in the LUT justifiedour interest in the distribution and function of capsaicinoidsand their receptors in normal and pathological conditionsRecently it has been demonstrated that capsaicin and othervanilloids which are linked to TRP receptors may promotecellular death [11] and inhibit the growth of normal andneoplastic cells by apoptosis induction [12ndash15]

In this paper we report the documented role of TRPV1in the transitional cell carcinoma (TCC) of human bladderin presence of urothelium impairment and explore theopportunity of considering TRPV1 as a drug target

2 Bladder Cancer

Bladder cancer is the second most common genitourinarycancer in the United States overall the fourth most frequentcancer inmen and the ninth in women with 72570 new cases(54610 men and 17960 women) and 15210 deaths both inmen and women predicted to occur in 2013 [16]

Usually bladder cancer is distinguished in muscle inva-sive and non-muscle-invasive urothelial carcinoma of thebladder (NMIBC) Due to its pathophysiological charac-teristics and the worldwide assessed management workupNMIBChas a high probability to recurwith a low progressionand metastasis rate For the management of the noninvasivebladder cancer EAU FICBT NCCN and AUA guidelinesagree about the importance of endoscopic resection in allpatients and the benefit of adjuvant intravesical therapy [17]

The benefits of a single early intravesical instillationof mitomycin C after transurethral bladder resection inpatientswith low riskNMIBChave been investigated In 1999Solsona et al showed how mitomycin C instillation at 24-month follow-up significantly increased the recurrence freeinterval but the result could not be reproduced at long-termfollow-up More recently a single center study described asignificant reduction in risk of both early and late recurrences[18] In 2013 an updatedmeta-analysis confirmed that intrav-esical administration of chemotherapy after transurethral ofNMIBC prolongs recurrence free interval and reduces earlyrecurrences [19]

However mitomycin C was seen to own several sideeffects and in particular after transurethral resection it has

been described to delay the healing of themucosa at resectionsites both in animal and human [20 21] Urologists remainedunconvinced that the benefits ofMMC (immediate +mainte-nance) including a 30 relative reduction in the recurrenceof a nonlethal disease outweigh the potential harms forexample cystitis which can occasionally be severe andirreversible [22 23]

In our opinion to delay the recurrence time fromthe endoscopic treatment procedure of patients affected byNMIBC is of outstanding importance In 2004 Sylvester et aldemonstrated with a meta-analysis of seven randomizedclinical trials that single intravesical chemotherapy (IVC)following transurethral resection reduces recurrences [23]Despite this the adoption of this practice has been modestand a recent analysis described the rate of perioperativelyintravesical administration of chemotherapy in as few as 03to 32 cases [24]

Recently the consideration that an urothelial disfunc-tion could be the basis of benign bladder pathology bar-rier disfunction in pathological bacteria urinary infectionsincreased permeability decreased E-cadherin content and anincreased number of apoptotic urothelial cells in interstitialcystitis (painful bladder syndrome) has grown up Sensoryfunction impairment due to stones or neoplasms can causechanges to the urothelium resulting in bladder overactivityand urge incontinence or in underactive bladder in case ofoutlet obstruction [25] Similarly an urothelial disfunctioncould be supposed to be linked with the development ofbladder cancer Based on such observation some compoundsthat are able to repair the urothelium defect are nowentering the clinical practice for the treatment of urothelialdysfunction We could point out hyaluronic acid for thetherapy of not malignant bladder conditions such as bladderpain syndrome interstitial cystitis or recurrent urinary tractinfections [26] or in combination with paclitaxel for thetreatment of bladder bacillus Calmette-Guerin refractorycarcinoma in situ [27]

3 Urothelium Impairment

The urothelium is the most superficial layer of the urinarytract that separates the lumen from underlying tissues ofthe wall Formed by three layers a basal an intermediateand a superficial or apical layer was composed of largehexagonal cells known as ldquoumbrella cellsrdquo [28] there are nowstrong evidences that the urinary bladder urothelium exhibitsspecialized sensory properties and plays a role in the detec-tion and transmission of both physiological and mechanicalstimuli such as luminal pressure urine composition andnociceptive stimuli beyond acting as an effective barrier[29] Bladderrsquos barrier function is conferred by a mucinlayer formed by sulphated polysaccharide glycosaminoglycan(GAG) which covers the cellular apical surface The mucinlayer acts as a nonspecific antiadherence factor and as adefence mechanism against infection and irritants [30] butseveral agents such as chronic bacterial infections autoim-mune diseases chemotherapeutic agents or external sources

BioMed Research International 3

(eg radiation exposure) can lead to urothelial damage andloss of the GAG function [31]

There is a wide consensus that many clinical conditionsmay arise from a primary defective urothelial lining [32] andin particular from a GAG injury This injury induces a lossof the watertight function and leads to an infiltration of nor-mal and abnormal constituents of urine through the lesioncausing a failure in the healing process and producing chronicbladder epithelial damage and neurogenic inflammation [33]In a randomised placebo-controlled trial it has been shownthat restoring theGAG layer with intravesical administrationof a combination of hyaluronic acid and chondroitin sulphatein women with a recurrent urinary tract infection (UTI) theUTIs rate could be reducedwithout causing severe side effectswhile improving quality of life over a period of a year [34]

As mentioned previously bladder urothelium acts asa specialized sensory tissue mediating both afferent andefferent signals through a flourishing subset of receptorsand mediators Receptors for purines [35] noradrenaline[36] bradykinin [37] and acetylcholine [38 39] and severaltransient receptor potential (TRP) channels (TRPV1 TRPV2TRPV4 TRPM8 TRPA1) [40ndash43] are expressed on themembranes of urothelial cells From a neural point of viewan urothelial damage and the loss of the GAG functionlead in the suburothelium to the activation of a subsetof unmyelinated C fibres selectively sensitive to capsaicinThese unmyelinated C fibres serve as primary afferents in theregulation of micturition reflex and pain sensation and acti-vation of visceral reflex but are even involved through theirefferent function in the regulation of the lower urinary tractinfluencing the smooth muscle contraction [44] immunecell migration mast cells degranulation and neurogenicinflammation thus playing a role in bladder inflammation[45]

These notions added to the description of a decreasein both rate of contraction and bladder hyperreflexiain cyclophosphamide-inflamed rat urinary bladders afteradministration of Capsazepine a selective antagonist forTRPV1 [46] lead to speculation about a role of this familyof sensory receptor in the treatment of cystitis-inducedhyperalgesia through targeting their activity on C fibres

Furthermore the prolongedGAGdefect persistence leadsto a chronic stimulation of suburothelial tissues which resultsin the allodynia caused by a visceral hypersensitivity ofbladder C-fibre nociceptors and in molecular changes suchas altered expression of transcription factors or activationof cellular inflammatory pathways (eg NF-120581B related)producing an increase in frequency urgency nocturia andchronic pain characteristic symptoms of cystitis [47 48]

According to these basics and to the more recent studies[26 49] the early repair of the mucin layer by intravesicaladministration of mucopolysaccarides should be obtainedto avoid the chronic evolution of the bladder inflammatorypathologies A chronic defect of GAGs might allow irritantsto reach the basal cells and to determine an anomalous cellgrowth

4 Transient Receptor Potential Vanilloid 1

Transient receptor potential (TRP) superfamily of ion chan-nels was first cloned from the visual system of Drosophila atthe end of the 1980s [50]

In mammalian the 28 TRP superfamily members areexpressed in the plasma membrane of several cell typesprincipallymediating calciumand sodium inwardmembranecurrents [51]

TRP proteins were first divided into three main sub-families the canonical or classical TRP proteins (TRPC)the vanilloid receptor related TRP proteins (TRPV) and themelastatin-related TRP proteins (TRPM) Later the mucol-ipins (TRPML) the olycystins (TRPP) and the ankyrin trans-membrane protein 1 (TRPA1) subfamilies have been included[40]

Numerous members of TRP superfamily of ion channelsare expressed in the LUT TRP expression in the mousebladder was described showing the presence of 27 TRP familymembers mRNA in whole bladder tissue [52] A pivotal roleof the thermosensitive TRPs TRPV1 TRPM8 and TRPA1and of TRPV2 and TRPV4 in normal and pathological LUTfunction has been established mainly as sensors of stretchor chemical irritation [53 54] but information regarding thefunctional significance of others TRP proteins in the LUT stillremains limited

In 1993 Szallasi et al characterized binding sites for cap-saicin in rat urinary bladder [55] while in 1997 Caterina et alcloned the vanilloid receptor presently known as TRPV1 [10]a nonselective highly Ca2+-permeable cationic channel

This channel is widely distributed in LUT structures[15] and although there are few solid data it has beenreported that in some species for examplemouse the TRPV1channel is expressed not only in bladder neurones but also inurothelial cellsrsquo membranes [56 57]

Firstly TRPV1 used to be considered as an integrator ofthermal and chemical noxious stimuli but evidences led it tobe thought as a possible regulator of bladder reflex activityand cell differentiation [58]

The role of TRPV1 in bladder function is well establishedand basic scientific evidence supports TRPV1 action in theregulation of the frequency of bladder reflex contractionseven in chronically inflamed rat urinary bladders [46]

TRPV1 channels in the suburothelium are needed for nor-mal excitability of low-threshold bladder fibres In TRPV1-knockout mice low-threshold response has been seen atten-uated compared with their wild type TRPV1 littermateswhereas high-threshold sensitivity was unchanged [59] Fur-thermore the knockout of TRPV1 in mice led to intermic-turition spotting suggested by an increase in the frequencyof nonvoiding contractions in cystometrograms but it doesnot affect normal micturition [53]

Maggi et al described in humans a functionalmodulationof capsaicin sensitive C-fibers on the micturition reflexMoreover after the intravesical administration of capsaicinauthors observed a reduction of the first desire to voidbladder capacity and pressure threshold for micturitionand an attenuation of symptoms of hypersensitive LUTdisorders Moreover TRPV1 activation generates a burning


pain sensation similar to that reported by CPCPPS patientsduring micturition and ejaculation [60]

Although both capsaicin and resiniferatoxin (RTX) havebeen tested by intravesical administration to reduce pain inpatients with painful bladder syndromes including intersti-tial cystitis [6 60 61] the first large randomized clinicaltrial testing several concentrations of RTX compared againstplacebo did not detect any advantage in the use of thecompound [62]

Moreover the expression of TRPV1 in terminal nervesending near to the mucosa and to the smooth muscle cellscould indicate its involvement in maintaining the tone ofthe muscular layer [51] and the relationship between thecapsaicin selective activation of bladder TRPV1 and theincrease of dieresis and natriuresis supported the hypothesisof a TRPV1 involvement in fluid homeostasis [2]

It is well described how malignant cell transformationis often accompanied by changes in ion channel expression[63] and among them several members of the TRP familyCa2+ and Na+-permeable channels show altered expressionin cancer cells

To date most changes involving TRP proteins do notinvolve mutations in the TRP gene but rather an increase ora decrease in the wild type TRP protein levels of expressiondepending on the stage of the cancer It is not yet possibleto say whether these changes in TRP expression are centralsteps in the progression of the cancer or are secondary toother cellular modifications Irrespective of the answer to thisquestion several TRP proteins have been shown in the lastyears to be valuable markers in predicting the progress ofurological cancers and have been considered potential targetsfor pharmaceutical treatment [64ndash66]

Recently the expression of TRPV1 has been describedassociated with urothelial cancers of human bladder [67]

Capsaicin the major TRPV1 agonist has been shown toinhibit in vivo and in vitro cancer growth andprogression andto induce apoptosis of different cancer cells [68ndash70]

An antimigration activity of capsaicin on highly meta-static B16-F10 melanoma cells was investigated A significantinhibition in the migration of melanoma neoplastic cellseffect correlated with the downregulation of phosphatidyli-nositol 3-kinase (PI3-K) and ofAkt PI3-K downstream targetwere described Moreover in the same study capsaicin wasfound to significantly inhibit Rac1 activity in a pull-downassay [71]

The genetic deficiency of TRPV1 was described to inducea higher incidence and number of tumors in the distal colonand an accentuated development of colonic adenomas inmice affected by colitis-associated cancer and in APCMinminus+model of spontaneous colon cancer respectively [72]

In bladder urothelium Lazzeri et al firstly demonstratedhow the expression of TRPV1 decreases from normal urothe-lium to transitional cell carcinoma (TCC) of human bladderFrom specimens obtained by multiple cold cup and full-thickness biopsy during open surgery they showed a reducedlabelling intensity after immunohistochemistry in superficialTCC a very light labelling was occasionally detected in themuscle invasive TCC from scattered superficial cells and no

labeling was present in the basal cells and in those that hadinvaded the adventitia Similarly in the Western Blot whichin the controls recognized two thick stained bands in allsuperficial TCCs the two bands were similar to control oneswhereas they were very thin in muscle invasive and no bandwas detected in the patients staged as pT4 [73]

More recently Amantini et al displayed a markeddecrease or absence of TRPV1 labelling in urothelial cancerspecimens proportionally to differentiation levels decreaseafter a quantitative real-time PCR and that TRPV1 mRNAlevel was highly expressed in low-grade cancers whereas itsexpression confirming the previous results was reduced inhigh-grade tumors or in advanced stage invasive pathologiesIn the same study the treatment of low-grade RT4 humanurothelial cell carcinoma with capsaicin at 100120583M doseinduced a TRPV1-dependent G0G1 cell cycle arrest andapoptosis effect that was seen associated with the transcrip-tion of proapoptotic genes including FasCD95 Bcl-2 andcaspases and the activation of the DNA damage responsepathway [74]

On the other hand attention has to be paid to theCapsaicin property to exhibit tumor-promoting effects in areceptor-dependent manner in particular in cancer straincells lacking TRPV1 receptor where the transfection withthe TRPV1 cDNA leads to an increase in capsaicin-mediatedcalcium level growth inhibition apoptosis and capsaicin-induced migration regression suggesting that the TRPV1plays an inhibitory role in urothelial cancer invasion andmetastasis [75]

However it is necessary to recognize that the mechanismof action of agonists such as capsaicinmay be independent byTRPV1 activation An example is the aforementioned workof Shin et al on B16-F10 melanoma cells where the authorsdescribed how capsaicin could have a role in the regulationof intracellular pathways independently from TRPV1 activity[71] Other studies suggested an inhibition of migrationinduced by capsaicin without an involvement of TRPV1

In 2002 Surh indicated that capsaicin could mediateapoptosis in human skin cancer cells through the inhibitionof mitochondrial and plasma membrane electron transportsystems inducing an excessive generation of reactive oxygenspecies [76] In the same way an increase in the reactiveoxygen species after capsaicin administration was confirmedin 2005 by Qiao et al [77]

Recently Gonzales et al demonstrated that in vitroand in mouse xenografts the local delivery of capsazepinedecreases cellular duplication rate and reverses the growth oforal squamous carcinoma cells inducing the production ofreactive oxygen species and apoptosis and mediating theseactions independently from TRPV1 activation This data wasconfirmed by calcium imaging technique which showed howTRPV1 even if present did not respond to capsaicin (alone orin combination with capsazepine) activation at noncytotoxicconcentrations in all cancer cell lines whereas a significantcalcium influx was described in positive controls afterionomycin (nonselective cation channel agonist) administra-tion Moreover they described that at equal concentrationcapsazepine is more effective at inhibiting cell viability thancapsaicin without adverse effects on nonmalignant tissues


after in vitro and in vivo administration of the TRPV1antagonist [78]

All the data showed lead to speculation about a possibleclinical involvement for the TRPV1 not only for the treat-ment of bladder urothelial inflammatory condition or in painreduction in patients with painful bladder syndromes buteven in the management of tumoral conditions

The in vivo and in vitro cancer growth and progressioninhibition the induction of apoptosis and the antimigrationactivity of capsaicin in tumor of other tissues such as gastriccancer and glioma and the studies of Lazzeri and Amantinirsquosgroups suggest a theoretical role of targeting the TRPV1 forclinical management of urothelial cancer

In particular a modulation of TRPV1 activity could beinterestingly investigated in themanagement of NMIBC aftera transurethral resection for both the anti-inflammatory andcancer recurrence rate decreasing possible features

5 Curcumin

Curcumin [diferuloylmethane 17-bis-(4-hydroxy-3-methox-yphenyl)-16-heptadiene-35-dione] is an active principleheld inside in the rhizome of Curcuma species widely usedas a yellow coloring and flavoring agent in food [79]

Its pharmacological benefits have been appreciated sinceancient times in particular for the antioxidant and anti-inflammatory properties

Curcuminrsquos metabolism is explicated by the endogenousreductase system that reduces it to dihydrocurcumin tetrahy-drocurcumin (THC) and trace of hexahydrocurcumin in astepwise manner to be lately glucuronidated by the uridine51015840-diphospho (UDP)-glucuronosyltransferase [80] Further-more some studies have described a higher antioxidantactivity [81 82] and in somemodels a higher preventive effecton carcinogenesis [83] of tetrahydrocurcumin was comparedto curcumin

Several studies have shown that curcumin induces apop-tosis via deactivation of nuclear factor-kappa B (NF-120581B) andits regulated gene products in addition to suppression of cellproliferation invasion and angiogenesis Curcumin was alsofound to suppress several inflammatory cytokines such astumor necrosis factor-alpha (TNF-120572) interleukins (IL-1 -1b-6 and -8) and cyclooxygenase- 2 (COX-2) [84]

Shehzad et al described the main roles that curcuminmay perform in inflammatory pathways (the most importantof them are summarized in Table 1) and in the managementof the related chronic inflammatory diseases [85]

Cheng et al demonstrated in urinary bladder isolatedfromWistar rats that curcumin has an ability to activate M1-mAChR for increase of glucose uptake in muscle Believed asthe most common subtype of muscarinic receptor in skeletalmuscle mAChR has been introduced as an important factorin the regulation of muscle tone

In the same study Chengrsquos group found that curcumincaused a concentration-dependent increase of muscle tonein urinary bladder isolated fromWistar rats This action wasinhibited by pirenzepine at concentration high enough toblock M1-mAChR [86]

Table 1 Main inflammatory pathways influenced by curcuminactivity

Chronic disease Major mediators involvedArthritis COX MMPs STAT3 NF-120581BScleroderma MAP kinase NF-120581B TGIFPsoriasis STAT3 NF-120581B Bcl-xL IAPsAllergies and asthma MAP kinase NF-120581BDiabetes PPAR-120574 NOSObesity TNF-120572 IL-6 Wint120573-cateninNeuropathies IL-1120573 VEGF NF-120581B TNF-120572 NO LRRK2Cardiopathies Bcl-2 IL-6 Caspase NF-120581B TNF-120572Renal ischemia HSP-70 MAP kinase NF-120581B TNF-120572

Due to the pleiotropic beneficial effects of curcumin ininflammatory disease its role in urothelial pathologies hasbeen speculated

Though not well established the main field investigatedis the curcumin preventive effect in the development ofhemorrhagic cystitis after cyclophosphamide administration

The prior administration of curcumin before cyclophos-phamide challenge possibly through modulating the releaseof inflammatory endocoids was shown to improve allthe biochemical and histologic alterations induced by thecytotoxicity ameliorates the energy status and restores theoxidantantioxidant balance [87]

Feasibility and curative effects of an intravesical treat-ment for cystitis glandularis a metaplastic alteration of theurothelium in the urinary bladder due to persistent infectioncalculi bladder exstrophy outlet obstruction or even tumorwere respectively explored and displayed administratingcurcumin in 14 patients diagnosed with the pathology whichremained symptomatic after the state-of-the-art designedprimary treatments [88]

Curcumin controls cell proliferation and cycle progres-sion via the modulation of enzymes growth factors and theirreceptors cytokines and various kinase proteins activitiesA potential therapeutic involvement has been discussed forpulmonary digestive system reproductive system breasthematological thymic bone and brain tumors

Furthermore studies have shown how not only cur-cumin but also its analogues 35-Bis(2-fluorobenzylidene)-4-piperidone (EF24) and 35-Bis(2-pyridinyl-methylidene)-4-piperidone (EF31) a more potent inhibitor of NF-120581B activ-ity than either EF24 or curcumin exhibit both anti-inflam-matory and anticancer activities [89]

In the urological field curcumin seems to have a role inthe management of prostate kidney and urothelial bladdercancer regulating cell survival proliferation invasion andangiogenesis (Table 2)

In prostate curcumin induces apoptosis in androgen-dependent (LNCap) and androgen-independent (DU15)prostate cancer cell lines [90] downregulating antiapoptoticgenes such as Bcl2 and Bcl-xL and inducing procaspase-3and 8 Curcumin also inhibits the prostate specific antigenand decreases the expression of AP-1 cyclin D1 NF-120581BcAMP response element-binding (CREB) EGFR tyrosine


Table 2 Cancer regulator factors influenced by curcumin activityin urological neoplasia

Urological cancers Major mediators involvedProstate cancer EGFR AP-1 cyclin D1 NF-120581B CREBKidney cancer Bcl2 Bcl-xL ROS Akt TRAIL IAPBladder cancer Bcl2 AP-1 cyclin D1 VEGF NF-120581B

kinase and the activities of androgen receptor-dependentNKX31 [91] Furthermore a decrease of cell proliferationcolony formation and cell motility and an enhancement ofcell aggregation through the activation of protein kinase D1have been described which in turn inhibits nuclear b-catenintranscription activity [92] Herbal preparations based uponcurcumin extracts were given to the HGPIN patients threetimes per day for 18monthsThe 18-month biopsy revealed nomarkers of HGPIN and a reduction in NF-120581B and C-reactiveprotein [93]

In human bladder cancer cells studies have shownthat curcumin induces apoptosis downregulating Bcl2 andincreasing the levels of Bax and p53 and moreover itinhibits the development of urothelial tumors in a rat bladdercarcinogenesis model [94] Other effects described are thedownregulation of VEGF and VEGF receptor 1 (VEGFR1)and the inhibition of NF-120581B and cyclin D1 [95] Furthermoreit has been described that intravesical injection of curcumincan inhibit bladder cancer in female C57BL6mice implantedwith MB49 bladder cancer cells [96]

Tharakan et al described that curcumin potentiatesthe apoptotic effects of gemcitabine against human bladdercancer where curcumin also suppresses the cell survivaltranscription factor NF-120581B activated by gemcitabine More-over in orthotopic mouse model curcumin alone signifi-cantly reduced the bladder tumor volume and decreasedthe proliferation marker Ki-67 and microvessel density butmaximum reduction was observed when curcumin was usedin combination with gemcitabine At least as just describedin other studies they confirmed how curcumin abolishesthe constitutive activation of NF-120581B in the tumor tissuedecreases cyclin D1 VEGF COX-2 c-myc and Bcl-2 expres-sion in the bladder cancer tissue and induces apoptosis [97]

At least curcumin has the same vanilloid ring as cap-saicin a particular structure considered necessary for theactivation of the TRPV1 receptor [98] suggesting that TRPV1is a plausible target for the pharmacological action of cur-cumin

Several studies have investigated the role of curcuminin the thermal and pain regulatory patterns involving theTRPV1 It was shown that curcumin attenuates thermalhyperalgesia in diabetic neuropathic pain [99] produces anantihyperalgesic effect in a formalin-induced orofacial painmodel in rats [100] and ameliorates the severity of damagein dinitrobenzene sulphonic-acid-induced colitis possibly byacting as a TRPV1 agonist [98] At least curcumin reducedcapsaicin-induced currents in a dose-dependent manner inboth trigeminal ganglion neurons thus the antagonism ofTRPV1 may provide a potential mechanism underlying theantihyperalgesic effect of curcumin [101]

6 Clinical Perspectives

The genesis of neoplastic lesions of urothelial epitheliumin particular of bladder urothelium recognizes differentcauses and the major risk factors could be divided intoinherited or acquired The most important risk factor isundoubtedly the habit of smoking but even the work-relatedand environmental conditions play an important role

Among medical conditions chronic inflammationchronic urinary retention and upper tract dilation whichcause the increase of urothelial exposure to carcinogens arethemost pathological features involved in the carcinogenesis

It has been hypothesized that the inflammatory conditionlinked to the disruption of the urothelial layer could beinvolved in the processes of cancer development as seen inother tumoral conditions (eg colorectal cancer [102])

In this context agents like TRP channel ligands involvedin functional and pathological pathways could play animportant role

The vanilloid receptor TRPV1 owning a role in themodulation of urothelial inflammatory condition could bethought as an interesting factor in the management or in theprevention of neoplastic pathologies

In particular its targeting could be conjectured in caseof NMIBC after a transurethral resection where its charac-teristic of anti-inflammatory agent could be helpful for theepithelium healing or in the management of patients duringthe postoperative time

Moreover the property of inducing apoptosis and theantimigration activity makes TRPV1 an interesting target inthe handling of recurrences

Curcumin the major component of turmeric Curcumalonga has been described to own benefic effects in pathologi-cal pathways common of both inflammation and carcinogen-esis

Its applications for pathologies involving urotheliumdisruption such as cystitis glandularis or hemorrhagic cystitiscyclophosphamide-induced have been successfully investi-gated In a like manner its intrinsic property in cell survivaland angiogenesis regulation has been shown in several tumortissues including bladder cancer where in particular anincrease of apoptotic effect has been described after itsassociation with Gemcitabine

Moreover owning a vanilloid ring curcumin might beable to activate the TRPV1 receptor The combination ofthe intrinsic properties of curcumin in association with thecapacity of acting on TRPV1 could make this compounda very interesting agent in the management of urothelialdysfunctions However this hypothesis needs further studiesto be confirmed

In this context new compounds such as curcumincould be complementarily used in the clinical practiceto manage the recurrences and soothe the inflammatoryeffect of transurethral resection or intravesical chemotherapyadministration or in combination with the chemotherapiesto potentiate the antitumor effect


Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] A Lecci S Giuliani M Lazzeri G Benaim D Turini andC A Maggi ldquoThe behavioral response induced by intravesicalinstillation of capsaicin in rats is mediated by pudendal urethralsensory fibersrdquo Life Sciences vol 55 no 6 pp 429ndash436 1994

[2] M Lazzeri G Barbanti P Beneforti et al ldquoVesical-renal reflexdiuresis and natriuresis activated by intravesical capsaicinrdquoScandinavian Journal of Urology and Nephrology vol 29 no 1pp 39ndash43 1995

[3] M Lazzeri P Beneforti G Benaim C A Maggi A Lecciand D Turini ldquoIntravesical capsaicin for treatment of severebladder pain a randomized placebo controlled studyrdquo Journalof Urology vol 156 no 3 pp 947ndash952 1996

[4] S Giuliani R Patacchini M Lazzeri et al ldquoEffect of severalbicyclic peptide and cyclic pseudopeptide tachykinin NK2receptor antagonists in the human isolated urinary bladderrdquoJournal of Autonomic Pharmacology vol 16 no 5 pp 251ndash2591996

[5] M Lazzeri P Beneforti and D Turini ldquoUrodynamic effects ofintravesical resiniferatoxin in humans preliminary results instable and unstable detrusorrdquo Journal of Urology vol 158 no6 pp 2093ndash2096 1997

[6] M Lazzeri P Beneforti M Spinelli A Zanollo G Barbagliand D Turini ldquoIntravesical resiniferatoxin for the treatmentof hypersensitive disorder a randomized placebo controlledstudyrdquo Journal of Urology vol 164 no 3 part 1 pp 676ndash6792000

[7] M Lazzeri M Spinelli A Zanollo and D Turini ldquoIntravesicalvanilloids and neurogenic incontinence ten years experiencerdquoUrologia Internationalis vol 72 no 2 pp 145ndash149 2004

[8] A Lecci and C A Maggi ldquoTachykinins as modulators of themicturition reflex in the central and peripheral nervous systemrdquoRegulatory Peptides vol 101 no 1ndash3 pp 1ndash18 2001

[9] C A Maggi ldquoThe dual function of capsaicin-sensitive sensorynerves in the bladder and urethrardquoCiba Foundation symposiumvol 151 pp 77ndash83 1990

[10] M J Caterina M A Schumacher M Tominaga T A RosenJ D Levine and D Julius ldquoThe capsaicin receptor a heat-activated ion channel in the pain pathwayrdquoNature vol 389 no6653 pp 816ndash824 1997

[11] A Hiura Y Nakae and H Nakagawa ldquoCell death of primaryafferent nerve cells in neonatal mice treated with capsaicinrdquoAnatomical Science International vol 77 no 1 pp 47ndash50 2002

[12] Y S Lee D H Nam and J-A Kim ldquoInduction of apoptosis bycapsaicin inA172 human glioblastoma cellsrdquoCancer Letters vol161 no 1 pp 121ndash130 2000

[13] A Macho M A Calzado J Munoz-Blanco et al ldquoSelectiveinduction of apoptosis by capsaicin in transformed cells therole of reactive oxygen species and calciumrdquo Cell Death andDifferentiation vol 6 no 2 pp 155ndash165 1999

[14] M-Y Jung H-J Kang and A Moon ldquoCapsaicin-inducedapoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2downregulation and caspase-3 activationrdquo Cancer Letters vol165 no 2 pp 139ndash145 2001

[15] E Jambrina R Alonso M Alcalde et al ldquoCalcium influxthrough receptor-operated channel induces mitochondria-triggered paraptotic cell deathrdquo Journal of Biological Chemistryvol 278 no 16 pp 14134ndash14145 2003

[16] R Siegel DNaishadham andA Jemal ldquoCancer statistics 2013rdquoCA Cancer Journal for Clinicians vol 63 no 1 pp 11ndash30 2013

[17] M Brausi J A Witjes D Lamm et al ldquoA review of currentguidelines and best practice recommendations for the manage-ment of nonmuscle invasive bladder cancer by the internationalbladder cancer grouprdquo Journal of Urology vol 186 no 6 pp2158ndash2167 2011

[18] C de Nunzio A Carbone S Albisinni et al ldquoLong-term expe-rience with early single Mitomycin C instillations in patientswith low-risk non-muscle-invasive bladder cancer prospectivesingle-centre randomised trialrdquo World Journal of Urology vol29 no 4 pp 517ndash521 2011

[19] N Perlis A R Zlotta J Beyene A Finelli N E Fleshnerand G S Kulkarni ldquoImmediate post-transurethral resectionof bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences an updated meta-analysis on 2548 patients and quality-of-evidence reviewrdquoEuropean Urology vol 64 no 3 pp 421ndash430 2013

[20] J C-T Hou S Landas C YWang and O Shapiro ldquoInstillationof mitomycin C after transurethral resection of bladder cancerimpairs wound healing an animal modelrdquo Anticancer Researchvol 31 no 3 pp 929ndash932 2011

[21] M F Aagaard K Mogensen and G G Hermann ldquoDelayedhealing at transurethral resection of bladder tumour sites afterimmediate postoperative mitomycin C instillationrdquo Scandina-vian Journal of Urology vol 48 no 2 pp 222ndash224 2013

[22] D A Tolley M K B Parmar K M Grigor et al ldquoThe effectof intravesical mitomycin C on recurrence of newly diagnosedsuperficial bladder cancer a further report with 7 years offollowuprdquo Journal of Urology vol 155 no 4 pp 1233ndash1238 1996

[23] R J Sylvester W Oosterlinck and A P M van Der MeijdenldquoA single immediate postoperative instillation of chemotherapydecreases the risk of recurrence in patients with stage TaT1 bladder cancer a meta-analysis of published results ofrandomized clinical trialsrdquo Journal of Urology vol 171 no 6part 1 pp 2186ndash2190 2004

[24] D A Barocas A Liu F N Burks et al ldquoPractice basedcollaboration to improve the use of immediate intravesicaltherapy after resection of nonmuscle invasive bladder cancerrdquoThe Journal of Urology vol 190 no 6 pp 2011ndash2016 2013

[25] L A Birder M Ruggieri M Takeda et al ldquoHow does theurothelium affect bladder function in health and disease ICI-RS 2011rdquoNeurourology and Urodynamics vol 31 no 3 pp 293ndash299 2012

[26] E Costantini M Lazzeri D Pistolesi et al ldquoMorphologicalchanges of bladder mucosa in patients who underwent instil-lation with combined sodium hyaluronic Acid-chondroitinsulphate (ialuril(R))rdquo Urologia Internationalis vol 91 no 1 pp81ndash88 2013

[27] P F Bassi A Volpe D DrsquoAgostino et al ldquoPaclitaxel-hyaluronicacid for intravesical therapy of bacillus calmette-gurin refrac-tory carcinoma in situ of the bladder results of a phase i studyrdquoJournal of Urology vol 185 no 2 pp 445ndash449 2011

[28] G Apodaca ldquoThe uroepithelium not just a passive barrierrdquoTraffic vol 5 no 3 pp 117ndash128 2004

[29] L A Birder A S Wolf-Johnston M K Chib C A BuffingtonJ R Roppolo and A T Hanna-Mitchell ldquoBeyond neurons


involvement of urothelial and glial cells in bladder functionrdquoNeurourology and Urodynamics vol 29 no 1 pp 88ndash96 2010

[30] D A Janssen XM vanWijk K C Jansen T H vanKuppeveltJ P Heesakkers and J A Schalken ldquoThe distribution andfunction of chondroitin sulfate and other sulfated glycosamino-glycans in the human bladder and their contribution to theprotective bladder barrierrdquoThe Journal of Urology vol 189 no1 pp 336ndash342 2013

[31] R E Hurst J B Roy K W Min et al ldquoA deficit of chondroitinsulfate proteoglycans on the bladder uroepithelium in intersti-tial cystitisrdquo Urology vol 48 no 5 pp 817ndash821 1996

[32] K Ananthasubramaniam R Weiss B McNutt B KlaukeK Feaheny and S Bukofzer ldquoA randomized double-blindplacebo-controlled study of the safety and tolerance ofregadenoson in subjects with stage 3 or 4 chronic kidneydiseaserdquo Journal of Nuclear Cardiology vol 19 no 2 pp 319ndash329 2012

[33] P Geppetti R Nassini S Materazzi and S Benemei ldquoTheconcept of neurogenic inflammationrdquo BJU International Sup-plement vol 101 no 3 pp 2ndash6 2008

[34] R Damiano G Quarto I Bava et al ldquoPrevention of recur-rent urinary tract infections by intravesical administration ofhyaluronic acid and chondroitin sulphate a placebo-controlledrandomised trialrdquo European Urology vol 59 no 4 pp 645ndash6512011

[35] L A Birder H Z Ruan B Chopra et al ldquoAlterations in P2XandP2Ypurinergic receptor expression in urinary bladder fromnormal cats and cats with interstitial cystitisrdquo The AmericanJournal of PhysiologymdashRenal Physiology vol 287 no 5 ppF1084ndashF1091 2004

[36] L A Birder G Apodaca W C De Groat and A J KanaildquoAdrenergic- and capsaicin-evoked nitric oxide release fromurothelium and afferent nerves in urinary bladderrdquoThe Ameri-can Journal of PhysiologymdashRenal Physiology vol 275 no 2 part2 pp F226ndashF229 1998

[37] B Chopra S R Barrick S Meyers et al ldquoExpression andfunction of bradykinin B1 and B2 receptors in normal andinflamed rat urinary bladder urotheliumrdquo Journal of Physiologyvol 562 no 3 pp 859ndash871 2005

[38] D Giglio and G Tobin ldquoMuscarinic receptor subtypes in thelower urinary tractrdquo Pharmacology vol 83 no 5 pp 259ndash2692009

[39] L A Birder ldquoUrothelial signalingrdquo Autonomic NeuroscienceBasic and Clinical vol 153 no 1-2 pp 33ndash40 2010

[40] M Lazzeri E Costantini and M Porena ldquoTRP family proteinsin the lower urinary tract translating basic science into newclinical prospectiverdquoTherapeutic Advances in Urology vol 1 no1 pp 33ndash42 2009

[41] R J Stein S Santos J Nagatomi et al ldquoCool (TRPM8) andhot (TRPV1) receptors in the bladder and male genital tractrdquoJournal of Urology vol 172 no 3 pp 1175ndash1178 2004

[42] T Streng H E Axelsson P Hedlund et al ldquoDistribution andfunction of the hydrogen sulfide-sensitive TRPA1 ion channelin rat urinary bladderrdquo European Urology vol 53 no 2 pp 391ndash399 2008

[43] K-E Andersson C Gratzke and P Hedlund ldquoThe role ofthe transient receptor potential (TRP) superfamily of cation-selective channels in themanagement of the overactive bladderrdquoBJU International vol 106 no 8 pp 1114ndash1127 2010

[44] C A Maggi P Santicioli and P Geppetti ldquoThe contributionof capsaicin-sensitive innervation to activation of the spinal

vesico-vesical reflex in rats relationship between substance Plevels in the urinary bladder and the sensory-efferent functionof capsaicin-sensitive sensory neuronsrdquoBrain Research vol 415no 1 pp 1ndash13 1987

[45] A Sculptoreanu W C De Groat C A Tony Buffington and LA Birder ldquoAbnormal excitability in capsaicin-responsive DRGneurons from cats with feline interstitial cystitisrdquo ExperimentalNeurology vol 193 no 2 pp 437ndash443 2005

[46] P Dinis A Charrua A Avelino et al ldquoAnandamide-evokedactivation of vanilloid receptor 1 contributes to the developmentof bladder hyperreflexia and nociceptive transmission to spinaldorsal horn neurons in cystitisrdquo Journal of Neuroscience vol 24no 50 pp 11253ndash11263 2004

[47] M Lazzeri and F Montorsi ldquoThe therapeutic challenge ofldquochronic cystitisrdquo search well work together and gain resultsrdquoEuropean Urology vol 60 no 1 pp 78ndash80 2011

[48] B D Carter C Kaltschmidt B Kaltschmidt et al ldquoSelectiveactivation of NF-120581B by nerve growth factor through the neu-rotrophin receptor p75rdquo Science vol 272 no 5261 pp 542ndash5451996

[49] C Iavazzo S Athanasiou E Pitsouni and M E FalagasldquoHyaluronic acid an effective alternative treatment of intersti-tial cystitis recurrent urinary tract infections and hemorrhagiccystitisrdquo European Urology vol 51 no 6 pp 1534ndash1541 2007

[50] C Montell and G M Rubin ldquoMolecular characterization ofthe drosophila trp locus a putative integral membrane proteinrequired for phototransductionrdquoNeuron vol 2 no 4 pp 1313ndash1323 1989

[51] R Skryma N Prevarskaya D Gkika and Y Shuba ldquoFromurgency to frequency facts and controversies of TRPs in thelower urinary tractrdquo Nature Reviews Urology vol 8 no 11 pp617ndash630 2011

[52] W Yu W G Hill G Apodaca and M L Zeidel ldquoExpressionand distribution of transient receptor potential (TRP) channelsin bladder epitheliumrdquo The American Journal of PhysiologymdashRenal Physiology vol 300 no 1 pp F49ndashF59 2011

[53] W Everaerts T Gevaert B Nilius and D De Ridder ldquoOn theorigin of bladder sensing Tr(i)ps in urologyrdquoNeurourology andUrodynamics vol 27 no 4 pp 264ndash273 2008

[54] L Birder andK E Andersson ldquoUrothelial signalingrdquo Physiolog-ical Reviews vol 93 no 2 pp 653ndash680 2013

[55] A Szallasi B Conte C Goso P M Blumberg and S ManzinildquoCharacterization of a peripheral vanilloid (capsaicin) receptorin the urinary bladder of the ratrdquo Life Sciences vol 52 no 20pp L-221ndashL-226 1993

[56] M Lazzeri M G Vannucchi C Zardo et al ldquoImmunohis-tochemical evidence of vanilloid receptor 1 in normal humanurinary bladderrdquo European Urology vol 46 no 6 pp 792ndash7982004

[57] L A Birder Y Nakamura S Kiss et al ldquoAltered urinary bladderfunction in mice lacking the vanilloid receptor TRPV1rdquo NatureNeuroscience vol 5 no 9 pp 856ndash860 2002

[58] A Avelino and F Cruz ldquoTRPV1 (vanilloid receptor) in theurinary tract expression function and clinical applicationsrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 373 no4 pp 287ndash299 2006

[59] D Daly W Rong R Chess-Williams C Chapple and DGrundy ldquoBladder afferent sensitivity in wild-type and TRPV1knockout micerdquo Journal of Physiology vol 583 no 2 pp 663ndash674 2007


[60] C A Maggi G Barbanti P Santicioli et al ldquoCystometricevidence that capsaicin-sensitive nerves modulate the afferentbranch of micturition reflex in humansrdquo Journal of Urology vol142 no 1 pp 150ndash154 1989

[61] F Cruz M Guimaraes C Silva M E Rio A Coimbraand M Reis ldquoDesensitization of bladder sensory fibers byintravesical capsaicin has long lasting clinical and urodynamiceffects in patients with hyperactive or hypersensitive bladderdysfunctionrdquo Journal of Urology vol 157 no 2 pp 585ndash5891997

[62] C K Payne P G Mosbaugh J B Forrest et al ldquoIntraves-ical resiniferatoxin for the treatment of interstitial cystitis arandomized double-blind placebo controlled trialrdquo Journal ofUrology vol 173 no 5 pp 1590ndash1594 2005

[63] K Kunzelmann ldquoIon channels and cancerrdquo Journal of Mem-brane Biology vol 205 no 3 pp 159ndash173 2005

[64] L Tsavaler M H Shapero S Morkowski and R Laus ldquoTrp-p8 a novel prostate-specific gene is up-regulated in prostatecancer and other malignancies and shares high homology withtransient receptor potential calcium channel proteinsrdquo CancerResearch vol 61 no 9 pp 3760ndash3769 2001

[65] S Fuessel D Sickert A Meye et al ldquoMultiple tumor markeranalyses (PSA hK2 PSCA trp-p8) in primary prostate cancersusing quantitative RT-PCRrdquo International Journal of Oncologyvol 23 no 1 pp 221ndash228 2003

[66] T Fixemer U Wissenbach V Flockerzi and H BonkhoffldquoExpression of the Ca2+-selective cation channel TRPV6 inhuman prostate cancer a novel prognostic marker for tumorprogressionrdquo Oncogene vol 22 no 49 pp 7858ndash7861 2003

[67] C Kalogris S Caprodossi C Amantini et al ldquoExpression oftransient receptor potential vanilloid-1 (TRPV1) in urothelialcancers of human bladder relation to clinicopathological andmolecular parametersrdquo Histopathology vol 57 no 5 pp 744ndash752 2010

[68] L Lopez-Carrillo M H Avila and R Dubrow ldquoChili pepperconsumption and gastric cancer in Mexico a case-controlstudyrdquoTheAmerican Journal of Epidemiology vol 139 no 3 pp263ndash271 1994

[69] S R Kim S U Kim U Oh and B K Jin ldquoTransient receptorpotential vanilloid subtype 1 mediates microglial cell death invivo and in vitro via Ca2+-mediated mitochondrial damage andcytochrome c releaserdquo Journal of Immunology vol 177 no 7 pp4322ndash4329 2006

[70] C Amantini M Mosca M Nabissi et al ldquoCapsaicin-inducedapoptosis of glioma cells is mediated by TRPV1 vanilloidreceptor and requires p38 MAPK activationrdquo Journal of Neu-rochemistry vol 102 no 3 pp 977ndash990 2007

[71] D-H Shin O-H Kim H-S Jun and M-K Kang ldquoInhibitoryeffect of capsaicin on B16-F10 melanoma cell migration viathe phosphatidylinositol 3-kinaseAktRac1 signal pathwayrdquoExperimental and Molecular Medicine vol 40 no 5 pp 486ndash494 2008

[72] A G Vinuesa R Sancho C Garcıa-Limones et al ldquoVanilloidreceptor-1 regulates neurogenic inflammation in colon andprotects mice from colon cancerrdquo Cancer Research vol 72 no7 pp 1705ndash1716 2012

[73] M Lazzeri M G Vannucchi M Spinelli et al ldquoTransientreceptor potential vanilloid type 1 (TRPV1) expression changesfrom normal urothelium to transitional cell carcinoma ofhuman bladderrdquo European Urology vol 48 no 4 pp 691ndash6982005

[74] C Amantini P Ballarini S Caprodossi et al ldquoTriggeringof transient receptor potential vanilloid type 1 (TRPV1) bycapsaicin induces FasCD95-mediated apoptosis of urothelialcancer cells in anATM-dependentmannerrdquoCarcinogenesis vol30 no 8 pp 1320ndash1329 2009

[75] S Caprodossi C Amantini M Nabissi et al ldquoCapsaicinpromotes a more aggressive gene expression phenotype andinvasiveness in null-TRPV1 urothelial cancer cellsrdquoCarcinogen-esis vol 32 no 5 pp 686ndash694 2011

[76] Y-J Surh ldquoMore than spice capsaicin in hot chili peppersmakes tumor cells commit suiciderdquo Journal of the NationalCancer Institute vol 94 no 17 pp 1263ndash1265 2002

[77] S Qiao W Li R Tsubouchi M Haneda K Murakami andMYoshino ldquoInvolvement of peroxynitrite in capsaicin-inducedapoptosis of C6 glioma cellsrdquoNeuroscience Research vol 51 no2 pp 175ndash183 2005

[78] C B Gonzales N B Kirma J J De La Chapa et al ldquoVanilloidsinduce oral cancer apoptosis independent of TRPV1rdquo OralOncology vol 50 no 5 pp 437ndash447 2014

[79] H Itokawa Q Shi T Akiyama S L Morris-Natschke and K-H Lee ldquoRecent advances in the investigation of curcuminoidsrdquoChinese Medicine vol 3 article 11 2008

[80] M-H Pan T-M Huang and J-K Lin ldquoBiotransformationof curcumin through reduction and glucuronidation in micerdquoDrug Metabolism and Disposition vol 27 no 4 pp 486ndash4941999

[81] T Osawa Y Sugiyama M Inayoshi and S Kawakishi ldquoAntiox-idative activity of tetrahydrocurcuminoidsrdquo Bioscience Biotech-nology and Biochemistry vol 59 no 9 pp 1609ndash1612 1995

[82] Y Sugiyama S Kawakishi and T Osawa ldquoInvolvement ofthe 120573-diketone moiety in the antioxidative mechanism oftetrahydrocurcuminrdquo Biochemical Pharmacology vol 52 no 4pp 519ndash525 1996

[83] C-S Lai J-C Wu S-F Yu et al ldquoTetrahydrocurcumin is moreeffective than curcumin in preventing azoxymethane-inducedcolon carcinogenesisrdquo Molecular Nutrition and Food Researchvol 55 no 12 pp 1819ndash1828 2011

[84] A Shehzad F Wahid and Y S Lee ldquoCurcumin in can-cer chemoprevention molecular targets pharmacokineticsbioavailability and clinical trialsrdquo Archiv der Pharmazie vol343 no 9 pp 489ndash499 2010

[85] A Shehzad G Rehman and Y S Lee ldquoCurcumin in inflamma-tory diseasesrdquo Biofactors vol 39 no 1 pp 69ndash77 2013

[86] T-C Cheng C-C Lu H-H Chung et al ldquoActivation of mus-carinic M-1 cholinoceptors by curcumin to increase contractil-ity in urinary bladder isolated from Wistar ratsrdquo NeuroscienceLetters vol 473 no 2 pp 107ndash109 2010

[87] H M M Arafa ldquoUroprotective effects of curcumin incyclophosphamide-induced haemorrhagic cystitis paradigmrdquoBasic and Clinical Pharmacology and Toxicology vol 104 no 5pp 393ndash399 2009

[88] Q Lu F Jiang R Xu et al ldquoA pilot study on intravesicaladministration of curcumin for cystitis glandularisrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 269745 5 pages 2013

[89] A Olivera T W Moore F Hu et al ldquoInhibition of theNF-120581B signaling pathway by the curcumin analog 35-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) anti-inflam-matory and anti-cancer propertiesrdquo International Immunophar-macology vol 12 no 2 pp 368ndash377 2012


[90] T Dorai N Gehani and A Katz ldquoTherapeutic potential of cur-cumin in human prostate cancer - I Curcumin induces apop-tosis in both androgen-dependent and androgen-independentprostate cancer cellsrdquo Prostate Cancer and Prostatic Diseasesvol 3 no 2 pp 84ndash93 2000

[91] S Cimino G Sortino V Favilla et al ldquoPolyphenols key issuesinvolved in chemoprevention of prostate cancerrdquo OxidativeMedicine and Cellular Longevity vol 2012 Article ID 6329598 pages 2012

[92] V Sundram S C Chauhan M Ebeling and M Jaggi ldquoCur-cumin attenuates 120573-catenin signaling in prostate cancer cellsthrough activation of protein kinase D1rdquo PLoS ONE vol 7 no4 Article ID e35368 2012

[93] J L Capodice P Gorroochurn A S Cammack et al ldquoZyfla-mend in men with high-grade prostatic intraepithelial neopla-sia results of a phase I clinical trialrdquo Journal of the Society forIntegrative Oncology vol 7 no 2 pp 43ndash51 2009

[94] B Tian ZWang Y Zhao et al ldquoEffects of curcumin on bladdercancer cells and development of urothelial tumors in a ratbladder carcinogenesis modelrdquo Cancer Letters vol 264 no 2pp 299ndash308 2008

[95] G Chadalapaka I Jutooru S Chintharlapalli et al ldquoCurcumindecreases specificity protein expression in bladder cancer cellsrdquoCancer Research vol 68 no 13 pp 5345ndash5354 2008

[96] F T Watanabe D C Chade S T Reis et al ldquoCurcumin butnot Prima-1 decreased tumor cell proliferation in the syngeneicmurine orthotopic bladder tumormodelrdquoClinics vol 66 no 12pp 2121ndash2124 2011

[97] S T Tharakan T Inamoto B Sung B B Aggarwal andA M Kamat ldquoCurcumin potentiates the antitumor effectsof gemcitabine in an orthotopic model of human bladdercancer through suppression of proliferative and angiogenicbiomarkersrdquo Biochemical Pharmacology vol 79 no 2 pp 218ndash228 2010

[98] L Martelli E Ragazzi F Di Mario et al ldquoA potential rolefor the vanilloid receptor TRPV1 in the therapeutic effect ofcurcumin in dinitrobenzene sulphonic acid-induced colitis inmicerdquo Neurogastroenterology and Motility vol 19 no 8 pp668ndash674 2007

[99] S Sharma S K Kulkarni J N Agrewala and K ChopraldquoCurcumin attenuates thermal hyperalgesia in a diabetic mousemodel of neuropathic painrdquo European Journal of Pharmacologyvol 536 no 3 pp 256ndash261 2006

[100] N Mittal R Joshi D Hota and A Chakrabarti ldquoEvaluationof antihyperalgesic effect of curcumin on formalin-inducedorofacial pain in ratrdquo Phytotherapy Research vol 23 no 4 pp507ndash512 2009

[101] K Y Yeon S A Kim Y H Kim et al ldquoCurcumin producesan antihyperalgesic effect via antagonism of TRPV1rdquo Journal ofDental Research vol 89 no 2 pp 170ndash174 2010

[102] A M Gallimore and A Godkin ldquoEpithelial barriers micro-biota and colorectal cancerrdquo The New England Journal ofMedicine vol 368 no 3 pp 282ndash284 2013

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


function controls nervous tissue excitability smooth musclecontractility and plasma protein extravasation (neurogenicinflammation) The discovery of specific binding sites forcapsaicin in several tissues and organs including the raturinary bladder [9] initiated a rush that ended up with thecloning of the vanilloid receptor [10] presently known asTRPV1 (transient receptor potential vanilloid subfamily 1)

In the lower urinary tract TRPV1 expression is nowfirmly documented not only in a large subpopulation ofnerve fibers but also in nonneuronal tissues Knowledgeabout the presumable function of TRPV1 also evolved rapidlyFrom a receptor initially considered as an integrator ofthermal and chemical noxious stimuli TRPV1 is emergingas a possible regulator of bladder reflex activity and celldifferentiation These findings together with the promisingclinical applications of TRPV1 targeting in the LUT justifiedour interest in the distribution and function of capsaicinoidsand their receptors in normal and pathological conditionsRecently it has been demonstrated that capsaicin and othervanilloids which are linked to TRP receptors may promotecellular death [11] and inhibit the growth of normal andneoplastic cells by apoptosis induction [12ndash15]

In this paper we report the documented role of TRPV1in the transitional cell carcinoma (TCC) of human bladderin presence of urothelium impairment and explore theopportunity of considering TRPV1 as a drug target

2 Bladder Cancer

Bladder cancer is the second most common genitourinarycancer in the United States overall the fourth most frequentcancer inmen and the ninth in women with 72570 new cases(54610 men and 17960 women) and 15210 deaths both inmen and women predicted to occur in 2013 [16]

Usually bladder cancer is distinguished in muscle inva-sive and non-muscle-invasive urothelial carcinoma of thebladder (NMIBC) Due to its pathophysiological charac-teristics and the worldwide assessed management workupNMIBChas a high probability to recurwith a low progressionand metastasis rate For the management of the noninvasivebladder cancer EAU FICBT NCCN and AUA guidelinesagree about the importance of endoscopic resection in allpatients and the benefit of adjuvant intravesical therapy [17]

The benefits of a single early intravesical instillationof mitomycin C after transurethral bladder resection inpatientswith low riskNMIBChave been investigated In 1999Solsona et al showed how mitomycin C instillation at 24-month follow-up significantly increased the recurrence freeinterval but the result could not be reproduced at long-termfollow-up More recently a single center study described asignificant reduction in risk of both early and late recurrences[18] In 2013 an updatedmeta-analysis confirmed that intrav-esical administration of chemotherapy after transurethral ofNMIBC prolongs recurrence free interval and reduces earlyrecurrences [19]

However mitomycin C was seen to own several sideeffects and in particular after transurethral resection it has

been described to delay the healing of themucosa at resectionsites both in animal and human [20 21] Urologists remainedunconvinced that the benefits ofMMC (immediate +mainte-nance) including a 30 relative reduction in the recurrenceof a nonlethal disease outweigh the potential harms forexample cystitis which can occasionally be severe andirreversible [22 23]

In our opinion to delay the recurrence time fromthe endoscopic treatment procedure of patients affected byNMIBC is of outstanding importance In 2004 Sylvester et aldemonstrated with a meta-analysis of seven randomizedclinical trials that single intravesical chemotherapy (IVC)following transurethral resection reduces recurrences [23]Despite this the adoption of this practice has been modestand a recent analysis described the rate of perioperativelyintravesical administration of chemotherapy in as few as 03to 32 cases [24]

Recently the consideration that an urothelial disfunc-tion could be the basis of benign bladder pathology bar-rier disfunction in pathological bacteria urinary infectionsincreased permeability decreased E-cadherin content and anincreased number of apoptotic urothelial cells in interstitialcystitis (painful bladder syndrome) has grown up Sensoryfunction impairment due to stones or neoplasms can causechanges to the urothelium resulting in bladder overactivityand urge incontinence or in underactive bladder in case ofoutlet obstruction [25] Similarly an urothelial disfunctioncould be supposed to be linked with the development ofbladder cancer Based on such observation some compoundsthat are able to repair the urothelium defect are nowentering the clinical practice for the treatment of urothelialdysfunction We could point out hyaluronic acid for thetherapy of not malignant bladder conditions such as bladderpain syndrome interstitial cystitis or recurrent urinary tractinfections [26] or in combination with paclitaxel for thetreatment of bladder bacillus Calmette-Guerin refractorycarcinoma in situ [27]

3 Urothelium Impairment

The urothelium is the most superficial layer of the urinarytract that separates the lumen from underlying tissues ofthe wall Formed by three layers a basal an intermediateand a superficial or apical layer was composed of largehexagonal cells known as ldquoumbrella cellsrdquo [28] there are nowstrong evidences that the urinary bladder urothelium exhibitsspecialized sensory properties and plays a role in the detec-tion and transmission of both physiological and mechanicalstimuli such as luminal pressure urine composition andnociceptive stimuli beyond acting as an effective barrier[29] Bladderrsquos barrier function is conferred by a mucinlayer formed by sulphated polysaccharide glycosaminoglycan(GAG) which covers the cellular apical surface The mucinlayer acts as a nonspecific antiadherence factor and as adefence mechanism against infection and irritants [30] butseveral agents such as chronic bacterial infections autoim-mune diseases chemotherapeutic agents or external sources









































5 Curcumin









































References

















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































5 Curcumin









































References

















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































References

















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article bladder cancer and urothelial impairment...

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