Taurolidine and oxidative stress: a rationale for local treatment of mesothelioma

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1 Eur Repir J 29; 34: DOI: / CopyrightßERS Joura Ltd 29 Tauroidie ad oxidative tre: a ratioae for oca treatmet of meotheioma N. Aceto*,#, P. Bertio*, D. Barboe*,", G. Tai +, L. Mazo 1, C. Porta e, L. Mutti**,## ad G. Gaudio*,## ABSTRACT: Maigat meotheioma i a abeto-reated, aggreive tumour, reitat to mot aticacer therapie. i a key mediator of meotheioma ce urviva ad chemoreitace. Thi tudy aimed to carify the mechaim by which tauroidie (), a kow ythetic compoud with atimicrobia ad atieopatic propertie, ead to meotheioma ce death. Apoptoi wa tudied by aexi V bidig, ce cyce aayi, capae-8 activatio, poy(adp-riboe) poymerae (PARP) ceavage ad termia deoxyuceotidy traferaemediated deoxyuridie triphophate ick-ed abeig (TUNEL). Oxidative tre wa meaured by itrite productio ad DNA oxidative damage. Protei expreio ad phophoryatio were evauated by immuoprecipitatio ad immuobottig. iduce ce death of meotheioma ce, but ot of o-eopatic huma meotheia ce. After treatmet of meotheioma ce, but ot extraceuar iga-reguated kiae (Erk) 1/ 2 activity i ihibited a i time- ad doe-depedet maer. Protei phophatae (PP)1a ad PP2A are activated evera hour after drug additio. Apoptoi iduced by i drive by oxidative tre ad ce expoure to ufydry door, uch a gutathioe mooethyeter ad L-N-acetycyteie, igificaty reduced pro-apoptotic effect ad ihibitio. Coverey, expreio of cotitutivey activated did ot affect cytoxicity eicited by, which retaied it abiity to ihibit the kiae. iduce meotheioma ce death via oxidative tre, accompaied by ihibitio of igaig. Thi provide a promiig moecuar ratioae for a oca treatmet of maigat meotheioma. KEYWORDS:, apoptoi, maigat meotheioma, oxidative tre, tauroidie Maigat meotheioma i a abetoreated maigat tumour. Due to it bioogica aggreivee, thi cacer i cotaty fata, except i rare, e-advaced cae, with a media urviva of 12.6 moth [1]. The cotiuig icreae i meotheioma icidece ha bee aociated with the widepread ue of abeto i the pat cetury, eve if geetic predipoitio may reder ome idividua more uceptibe [2]. Moreover, SV4, preet i poio vaccie ditributed i may coutrie, behave a a co-carcioge, cauig maigat traformatio of huma meotheia ce (HMC) [3] through -depedet urviva igaig [4, 5]. Tauroidie (), or bi(1,1-dioxoperhydro-1,2,4- thiodiaziy-4)-methae, i a atibacteria drug origiay ytheied i 197 with activity agait a broad pectrum of microorgaim ad ha bee ued a a afe avage atibiotic to prevet bacteria ifectio i patiet after abdomia urgery [6]. Over recet year, i vitro evidece ha highighted the roe of a a pro-apoptotic ad atiagiogeic aget ad a a ihibitor of protei bioythei [7, 8]. Some of thee i vitro effect were ao oberved i brai tumour ce, wherea orma ce were uaffected [9]. Moreover, itraperitoea admiitratio of i experimeta rat ihibited the growth of ijected ovaria ad coo cacer ce [1]. Safety ad efficacy of itracavitary admiitratio of, aog with a prooged i.v. admiitratio ha bee propoed to treat huma tumour [11] ad idicate that thi drug i of potetia hep for therapy of tumour with prevaet oca preadig, uch a peritoea ad peura meotheioma. The importace of the pathway i maitaiig ati-apoptotic urviva iga, repoibe AFFILIATIONS *DISCAFF Dept ad DFB Ceter, Uiverity of Piemote Orietae A. Avogadro, Novara, + Chet Medicie Uit, Brecia Hopita, Brecia, 1 Dept of Toxicoogy, Uiverity of Pavia, e Medica Ocoogy, IRCCS Sa Matteo Uiverity Hopita, Pavia, **Loca Heath Uit 11, Piemote, Borgoeia, Itay. # Friedrich Mietcher Ititute, Bae, Switzerad. " Lug Bioogy Ceter, SFGH, UCSF, Sa Fracico, CA, USA. ## L. Mutti ad G. Gaudio cotributed equay to thi work. CORRESPONDENCE G. Gaudio Dept of Chemica, Food, Pharmaceutica ad Pharmacoogica Sciece ad Drug ad Food Biotechoogy Ceter Uiverity of Piemote Orietae A. Avogadro Via Bovio Novara Itay E-mai: Received: Juy 5 28 Accepted after reviio: May 6 29 Firt pubihed oie: May Europea Repiratory Joura Prit ISSN Oie ISSN c EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER

2 THORACIC ONCOLOGY N. ACETO ET AL. for oet ad progreio of meotheioma, ha bee demotrated [4, 12] ad very recety we howed that addreig with pharmacoogica aget i ao a promiig approach for meotheioma [13, 14]. Oxidative tre geerated by reactive oxyge pecie ha bee idicated both a a egative reguator of the urviva factor i huma eukaemia ce [15] ad a oe of the effect eicited by i gioma ce, eadig to uppreio of VEGF productio ad to ce death [16]. We how here that pecificay target meotheioma ce, but ot o-eopatic HMC, ad that it pro-apoptotic mechaim i moty drive by oxidative tre ad ihibitio of activity. METHODS Ce cuture We ued two huma meotheia o-eopatic ce ie (HMC ad MET5A) ad two etabihed huma maigat meotheioma ce ie (MMB ad MMP). A cotro we ued huma derma fibrobat (HDF) ad huma ug carcioma (A549). Primary HMC were obtaied from patiet with cogetive heart faiure ad cutured i Ham F12 medium (Sigma-Adrich, St. Loui, MO, USA) uppemeted with 1% feta bovie erum (FBS; Life Techoogie, Rockvie, MD, USA). MET5A were purchaed from the America Type Cuture Coectio (ATCC; Maaa, VA, USA), ad cutured i Medium 199 (Sigma-Adrich) uppemeted with 1% FBS. MMB ad MMP ce were derived from peura effuio of maigat meotheioma patiet ad cutured i Ham F12 medium uppemeted with 1% FBS. HDF were obtaied from a heathy door ad cutured i Ham F12 medium uppemeted with 1% FBS. A549 were purchaed from ATCC ad cutured i Ham F12 medium uppemeted with 1% FBS. Ce were grow at 37uC i a 5% CO 2 -humified atmophere. Myr-MMB were obtaied by trafectig MMB ce with Addgee pamid 98 (pcdna3 myr-ha- 1), uig ipofectamie 2. Trafectat were eected by G418 for 3 week. Chemica Gutathioe moo-ethyeter (GSH), N-acety-L-cyteie (L-NAC) ad rapamyci were purchaed from Sigma-Adrich. Cytofuorimetric aayi of apoptoi Subcofuet ce were expoed to 1 mm (Tauroi1; Geitich Pharma, Wohue, Switzerad) or CD95-activatig atibody 1 g?ml -1 (coe CH11; Uptate Biotechoogy, Lake Pacid, NY, USA). After 24-h icubatio, ce were harveted i bidig buffer (1 mm Hepe/NaOH ph 7.4, 14 mm NaC, 2.5 mm CaC 2 ), taied i the dark for 1 mi with 5 ml of fuorocei iothiocyaate-abeed aexi V (Aexi, Lauae, Switzerad), wahed with bidig buffer ad the taied with 1 mg?ml -1 propidium iodide (Sigma- Adrich). We aayed 5, evet per ampe. Apoptotic ce were poitive to aexi V taiig oy ad ate apoptotic ce were poitive to both aexi V ad propidium iodide taiig. Termia deoxyuceotidy traferae-mediated deoxyuridie triphophate ick-ed abeig aayi Apoptoi wa evauated by termia deoxyuceotidy traferae-mediated deoxyuridie triphophate ick-ed abeig (TUNEL) aayi (DeadEd TM Coorimetric TUNEL Sytem; Promega, Madio, WI, USA) foowig treatmet for 24 h with 1 mm aoe ad i the preece of 1 mm GSH or 1 mm L-NAC. I brief, ubcofuet ce cuture were expoed to medium uppemeted with 2% FBS accordig to differet treatmet for 24 h ad fixed i 1% buffered formai. Bioti-deoxyuridie (du)-poitive ucei were couted o 1 fied with at eat 1 ce i the ame ide. Ce cyce aayi Ce were ychroied by.1 mg?ml -1 cocemid (Sigma- Adrich) treatmet for 24 h, ad the kept i orma medium for 4 day before aayi. After treatmet with 1 mm for 6 h, ce were wahed i phophate-buffered aie, fixed i ethao ad taied for 3 mi at room temperature with 5 mg?ml -1 propidium iodide (Sigma-Adrich) i phophatebuffered aie cotaiig RNae. 1, evet per ampe were aayed by fow cytometry. Cytotoxicity ad DNA adduct Ce were treated for differet time ad at differet drug cocetratio i the preece of 2% FBS. Cytotoxicity wa aeed by MTT aay, uig 3-(4,5-dimethythiazo-2-y)-2,5- dipheytetrazoium bromide (Sigma-Adrich) ad performed i quadrupicate, a previouy decribed [17]. Normaied viabiity percetage were obtaied accordig to the ratio (A 57 mea vaue of extract from expoed ampe/a 57 mea vaue of extract from cotro ce ampe)61. DNA adduct were evauated by high-performace iquid chromatography o DNA extract from ce treated with 1 mm for 16 h ad are expreed a amout of 8-hydroxy-2- deoxyguaoie per 1 5 deoxyguaoie, a previouy decribed [18]. Nitrite productio Ce were cutured i medium cotaiig 2% FBS ad the timuated with 1 mm i medium cotaiig 2% FBS. Nitrite productio wa determied by the Grie Reaget Sytem (Promega). Immuobottig After drug treatmet, ubcofuet ce were yed i L-buffer (2.5% odium dodecy ufate (SDS), Tri-HC 25 mm ph 7.4) ad 4 mg of tota ce yate were oaded i reducig coditio. After eparatio o SDS-poyacryamide ge eectrophorei ad trafer to itroceuoe fiter (Protra; S&S, Dae, Germay), fiter were probed with phopho- (Ser 473 ), phopho-p7 S6 kiae (Thr 389 ), phopho-p38 MAPK (Thr 18 /Tyr 182 ), phopho- SAPK/c-Ju N-termia kiae (JNK) (Thr 183 /Tyr 185 ), phopho- PTEN (Ser 38 /Thr 382/383 ), phopho-protei phophatae (PP)1a (Thr 32 ),, p7 S6 kiae, p38, SAPK/JNK, PTEN, PP1a,PP2A ad capae-8 atibodie (a from Ce Sigaig Techoogy, Bevery, MA, USA), phopho-extraceuar iga-reguated kiae (Erk) 1/2 (Thr 183 /Tyr 185 )ada-tubui atibodie (both from Sigma-Adrich), phopho-pp2a (Tyr 37 ) ad poy(adpriboe) poymerae (PARP)-1 atibodie (from Sata Cruz Biotechoogy, Ic., Sata Cruz, CA, USA). The iga wa 14 VOLUME 34 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

3 N. ACETO ET AL. THORACIC ONCOLOGY a) Ce viabiity % mm a) Apoptotic ce % b) HMC 4 2 HMC MMB MMP Evet Evet b) 12 MMB Evet Evet Ce viabiity % MMP Evet PI Evet PI Time after treatmet h c) PARP HMC MMB MMP FIGURE 1. Tauroidie () iduce ce death i meotheioma ce i a timead doe-depedet maer. a) Viabiity (MTT) aay performed o huma derma fibrobat ($), huma meotheia ce (HMC; &), MET5A (m), maigat meotheioma ce ie MMB () admmp(h), ad A549 ce (#) treated with (25 15 mm), for 16 h i 2% feta bovie erum medium. Fied ymbo idicate o-eopatic ce ad empty ymbo idicate eopatic ce. The ieage of differet ce are reported i the Method ectio. b) Viabiity (MTT) aay performed at the idicated time o HMC (&), ad MMB () ad MMP (h) ce treated with 1 mm. TABLE 1 Ce cyce aayi of ychroied huma meotheia ce (HMC) ad maigat meotheioma (MMB ad MMP) ce upo treatmet with 1 mm tauroidie () for 6 h Ce cyce phae Sub-G1 G1 S G2-M HMC MMB MMP Data are preeted a average percetage of ce i ce cyce phae SE. Capae-8 p43/p41 p18 a-tubui FIGURE 2. Tauroidie () i pro-apoptotic i meotheioma ce. a) Fow cytometry aayi of apoptoi i huma meotheia ce (HMC), maigat meotheioma MMB ad MMP ce treated with 1 g?ml -1 CD95-activatig atibody (&) or with 1 mm for 24 h i 2% feta bovie erum (FBS) medium (&) after aexi V/propidium iodide (PI) abeig. h: utreated ce a compared with acd95 (CD95 activatig atibody)- ad -treated ce. b) Repreetative picture of fow cytometry ce cyce aayi, performed a reported i the Method ectio o HMC, ad MMB ad MMP ce either treated or ot treated with 1 mm for 6 h i 2% FBS. The percetage of ce i the differet phae of the ce cyce are give i tabe 1. c) Immuobottig aayi of poy(adp-riboe) poymerae (PARP) ceavage ad capae-8 activatio o tota ce yate of HMC, ad MMB ad MMP ce treated with 15 mm for 6 h i 2% FBS. c EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 6 141

4 THORACIC ONCOLOGY N. ACETO ET AL. a) HMC MMP MMB - RP - RP - RP P-p7S6 kiae p7s6 kiae a-tubui b) HMC MMP mm mm a-tubui c) HMC MMP Time h P-Erk 1/2 P-p38 P-JNK P-PP2A P-PP1a P-PTEN Erk 1/2 p38 JNK PP2A PP1a PTEN a-tubui 142 VOLUME 34 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

5 N. ACETO ET AL. THORACIC ONCOLOGY FIGURE 3. Tauroidie () pecificay ihibit the pathway i meotheioma ce. a) Immuobottig aayi of the phophoryatio of (, Ser 473 ), p7 S6 kiae (P-p7 S6 kiae, Thr 389 ) o o-eopatic huma meotheia ce (HMC), o eopatic maigat meotheioma MMP ad MMB ce treated with 2 M of the mtor ihibitor rapamyci (RA) or with 15 mm for 3 mi i 2% feta bovie erum (FBS) medium. The protei eve of the ige kiae ad of a-tubui are ao reported a cotro. b) Doe repoe immuobottig aay of (Ser 473 ) o HMC ad MMP ce treated with betwee 5 mm ad 5 mm of for 3 mi i 2% FBS medium. Expreio of ad a-tubui are ao reported a cotro. c) Time-coure immuobottig aayi of phophoryatio eve of (Ser 473 ), Erk 1/2 (Thr 183 /Tyr 185 ), p38 (Thr 18 /Tyr 182 ), JNK (Thr 183 /Tyr 185 ), PP2A (Tyr 37 ), PP1a (Thr 32 ) ad PTEN (Ser 38 /Thr 382/383 ) o HMC ad MMP ce treated with 15 mm for differet time ragig from 3 mi to 8 h i 2% FBS medium. The protei eve of the ige effector ad of a-tubui are ao reported a oadig cotro. detected by the ehaced SuperSiga Wet Pico Chemiumiecet Subtrate (Pierce, Rockford, IL, USA). Immuoprecipitatio For immuoprecipitatio, after drug treatmet, tota ceuar protei were extracted by RIPA buffer (5 mm Tri-HC ph 7.4, 15 mm NaC,.5% odium deoxychoate, 1% Trito X- 1,.1% SDS) cotaiig proteae ihibitor (1 mg?ml -1 aprotii, 1 mg?ml -1 eupepti, 1 mg?ml -1 peptati, 1 mm pheymethyufoy fuoride) ad phophatae ihibitor (1 mm Na 3 VO 4, 2 mm NaF). For co-immuoprecipitatio, after drug treatmet, ce were yed i oubiiatio buffer (2 mm Tri-HC ph 7.4, 5 mm EDTA, 15 mm NaC, 1% gycero, 1% Trito X-1) with proteae ad phophatae ihibitor. 5-mg aiquot of carified ce yate were icubated with 1 mg of atibody immobiied o protei-aepharoe 4B packed bead (GE Heathcare, Picataway, NY, USA) for 2 h at 4uC. After exteive wahe with yi buffer, precipitated protei were oaded i reducig coditio a decribed above. Fiter were probed with Met (hepatocyte growth factor receptor) ad pateet-derived growth factor receptor (PDGFR)-b atibodie (both from Sata Cruz Biotechoogy), phopho-tyroie, p85, p11a ad itrotyroie atibodie (a from Uptate Biotechoogy), Hp-9 (from BD Biociece, Sa Joe, CA, USA). Statitic Data from cytotoxicity, apoptoi ad ce cyce cytofuorimetric aayi, itrite productio ad DNA adduct are expreed a mea SE of at eat three idepedet experimet. Statitica differece were evauated by ANOVA, foowed by Tukey hoety igificat differece tet. Vaue from TUNEL aay are expreed a percetage of poitive ucei over tota couted. Statitica aayi wa performed by Fiher exact tet. I a tatitica evauatio, the igificace threhod wa pecified i the text. A tatitica tet were two-ided ad cacuated uig Origi oftware (Microca Software, Northampto, MA, USA). RESULTS i cytotoxic ad pro-apoptotic i meotheioma ce Primary meotheia (HMC), immortaied meotheia (Met- 5A) ad meotheioma ce (MMB ad MMP) were treated with differet cocetratio of, ragig from 25 mm to 15 mm, for 16 h i ow erum. Norma derma fibrobat ad ug carcioma ce were ao treated a cotro. A igificat cytotoxic effect wa oberved at cocetratio.5 mm i MMB, MMP ad A549 eopatic ce compared with oeopatic ce (p,.1). MMB ce were more eitive to, whie o-eopatic ce, whether meotheia or ot i origi, dipayed egigibe cytotoxicity upo the ame treatmet (fig. 1a). The cytotoxic effect iduced by 1 mm wa time-depedet, tartig after 5 h of treatmet (p,.1) (fig. 1b). -depedet programmed ce death wa ao examied. Meotheioma ce, abeed with propidium iodide ad aexi V, were aayed for apoptoi by fow cytometry i the preece of. Moreover, give that Fa take part i ce death pathway i meotheioma [19], apoptoi ha ao bee verified foowig agoitic CD95 atibodie (CH-11). A igificat umber of apoptotic ce wa oberved i meotheioma ce treated with 1 mm for 24 h (p,.1). However, apoptoi iduced i MMB ce wa far higher tha that iduced i MMP ce (fig. 2a). Thee reut were cofirmed by ce cyce aayi (fig. 2b), which reveaed a igificat icreae i the ub-g1 popuatio i MMB (p,.1) ad MMP (p,.5) ce treated with. Moreover, treatmet with iduced a igificat decreae i G2-M ubpopuatio i both meotheioma ce compared with utreated ce (p,.1) (tabe 1). To achieve a moecuar characteriatio of -iduced apoptoi, PARP ad capae-8 ceavage wa determied by Weter bottig o tota ce yate of HMC, ad MMB ad MMP ce after 6-h treatmet with 15 mm. Uder thee coditio, iduced a cear-cut ceavage of PARP ad of capae-8 protei i meotheioma ce, a how by the appearace of ower moecuar weight bad (fig. 2c). Apoptoi, PARP ad capae-8 ceavage or ce cyce ateratio were ot oberved i o-eopatic HMC (fig. 2). We cocude that pecificay iduce apoptoi of meotheioma ce i a time- ad doe-depedet maer. The ack of effect o o-traformed meotheia ce prompted u to verify the mechaim of targetig to meotheioma ce. iactivate ad activate PP2A i meotheioma ce ha bee reported to affect evera itraceuar pathway ad to ihibit protei ythei [7]. A we ad other have reported a payig a key roe i meotheioma urviva [4, 5, 12], we verified i meotheioma ce the effect of o the activity of ad it dowtream p7 S6 kiae (p7 S6K ) effector, a kow reguator of traatio. ihibited ad p7 S6K phophoryatio oy i meotheioma ce (MMP ad MMB), ad ot i o-eopatic HMC. O the cotrary, the pecific ihibitor of mtor, rapamyci, wa effective i bockig the dowtream p7 S6K i a ce examied (fig. 3a). To verify phophoryatio i ce reitat or eitive to treatmet, we compared o-eopatic -reitat HMC with -eitive MMP meotheioma ce dipayig comparabe eve of protei. The ihibitio of activity c EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 6 143

6 THORACIC ONCOLOGY N. ACETO ET AL. by wa doe-depedet, beig evidet at 5 mm ad reachig a maximum at 15 mm, wherea i HMC phophoryatio wa totay uaffected (fig. 3b). The ihibitory effect of o activity wa ao time-depedet, tartig at 3 mi ad atig for up to 8 h (fig. 3c). To verify the pecificity of igaig ihibitio, we ao compared the activitie of Erk 1/2, JNK ad p38 by immuobottig with phophopecific atibodie o yate of HMC ad MMP ce treated with with the ame kietic evauated for. Moreover, to get a better iight ito the ihibitory effect iduced by, we examied the activitie of two protei phophatae ad of oe ipid phophatae, which have bee reported to reguate [2]. Therefore, the phophoryatio of reidue critica for the activity of PP2A (Tyr37), PP1a (Thr32) ad PTEN (Ser38, Thr382/383) phophatae, a poitivey reguated by Ser/Thr or Tyr de-phophoryatio [21], wa evauated by immuobottig with phophopecific atibodie o o-eopatic HMC ad o MMP ce. Regardig Erk 1/2 activity, beide of a harp icreae iduced after 3 mi of treatmet i both ce type, o differece were oberved thereafter, eve upo prooged (8 h) ce expoure to the drug. Coverey, JNK ad p38 phophoryatio wa icreaed by treatmet both i HMC ad i MMP ce (fig. 3c). Aayi of the phophatae activitie reveaed that PP2A became de-phophoryated with a ower kietic to thoe of, with a igificat activatio from the ecod hour of treatmet, idicatig a progreive activatio i phophohydroae activity upo. O the cotrary, PP1a howed a very ate (8 h) ad weak activatio upo treatmet with, wherea PTEN activity did ot vary at a (fig. 3c). Simiar fidig were foud i the MMB ce ie (data ot how). Moreover, we teted cytotoxicity eicited by o MMB ce expreig a myritoyated form of (myr-mmb), which i permaety ocaied to the pama membrae ad therefore cotitutivey active [22]. Surpriigy, o differece were oberved betwee wid-type MMB ad the ame ce expreig active i ce viabiity ad i ihibitig phophoryatio i a doe-depedet maer (data ot how). Atogether, thee reut idicate that exert a pecific timead doe-depedet ihibitio o activity oy i meotheioma ce, ad ot i orma meotheia ce, ad that PP2A joity with PP1a might be additioay ivoved i utaiig thi proce. The icreae i JNK ad p38 activitie i ao iduced by treatmet, but it i ot pecific for eopatic ce. pro-apoptotic activity o meotheioma ce i mediated by oxidative tre pro-apoptotic effect o gioma ce reie upo the geeratio of reactive oxyge itermediate [16] ad oxidative tre ca caue ihibitio i huma eukaemia ce [15]. We verified whether the mechaim of pro-apoptotic activity i meotheioma ce might be the activatio of a oxidative pathway ad whether thi wa repoibe for bioogica effect. The rate of oxyge free radica geeratio i chaged by the productio of itric oxide. We evauated itrite productio by Grie aay, upo treatmet of HMC, a we a of MMB ad MMP meotheioma ce, with 1 mm for differet time ragig from 3 mi to 24 h. We oberved a time-depedet itrite productio occurrig eary ad oy i meotheioma ce, where the differece with meotheia ce became igificat (p,.1) at betwee 2 ad 4 h. I HMC, oy after 24 h wa a igificat eve of itrite productio oberved, which wa ower tha that of meotheioma ce (p,.1) (fig. 4a). To verify the oxidative-tre iduced by, we meaured the amout of 8-hydroxy-29 deoxyguaoie (8-OHdG) DNA adduct, a a coequece of itraceuar reactive oxyge pecie productio [23]. Upo treatmet, the fod icreae of DNA adduct, ormaied for deoxyguaoie moecue, wa igificaty higher i meotheioma ce a compared with o-eopatic meotheia ce (p,.1) (fig. 4b). Thee reut cofirm that meotheioma ce are more eitive to activity, which i mediated by oxidative tre. Atioxidat aget have bee widey ued to prevet the effect eicited by oxidative tre i ive ce [24]. We evauated phophoryatio i yate from MMP ce pre-treated with 1 mm GSH for 24 h before the additio of 15 mm for 3 mi. GSH did ot affect phophoryatio i the abece of, wherea GSH ce pre-treatmet competey preveted ihibitio by, uggetig that dephophoryatio by i mediated via a oxidative repoe (fig. 4c). Simiar reut were obtaied i a parae experimet coducted uig the atioxidat aget L-NAC (fig. 4c). Thee atioxidat aget did ot ater -iduced JNK ad p38 activatio (data ot how). Ce viabiity wa examied by MTT aay i ce treated for 24 h with icreaig cocetratio of, after 24 h of pretreatmet with 1 mm GSH or 1 mm L-NAC. Uder thee coditio, iduced a doe-depedet decreae i ce viabiity, which i more proouced tha that oberved after oy 16 h (ee fig. 1a). Pre-expoure of the ame ce to the atioxidat aget igificaty ihibited the cytotoxic effect of, eve at the highet cocetratio (p,.1) (fig. 4d). The effect of atioxidat o apoptoi wa ao evauated uig TUNEL aay o MMP ce. A higher umber (14.1%) of bioti-du-poitive ucei wa oberved upo ce expoure to 1 mm for 24 h tha i cotro otimuated ce (3.1%). The cocurret treatmet with 1 mm GSH or 1 mm L-NAC decreaed the percetage of apoptotic ucei to 2.6% ad 3.1%, repectivey (fig. 4e). Thee differece were tatiticay igificat (p,.1). We obtaied imiar reut for ce viabiity ad apoptoi, with both atioxidat aget actig o the meotheioma MMB ce (data ot how). We cocude that the cytotoxic, pro-apoptotic effect of o meotheioma ce, tem from oxidative tre, ivove itrite productio ad i revered by geera atioxidat aget. DISCUSSION Our reut provide a expaatio of the mechaim uderyig the aticacer effect exerted by o meotheioma ce. The eective aticacer effect of ha bee focued o [9, 25] ad it roe for meotheioma treatmet ha aready bee hypotheied [26, 27]. The mechaim by which may 144 VOLUME 34 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

7 N. ACETO ET AL. THORACIC ONCOLOGY a) 2. b) 1 Nitrite mm OHdG fod icreae Time after treatmet h 8 24 HMC MMP MMB c) - GSH + GSH d) 12 L-NAC+ 1 - L-NAC + L-NAC a-tubui Ce viabiity % GSH+ a-tubui 5 mm 1 15 e) 16 Apoptotic ucei % GSH + L-NAC FIGURE 4. Tauroidie () actio o meotheioma ce i mediated by oxidative tre. a) Grie aay for itrite micromoar determiatio i huma meotheia ce (HMC; h), ad maigat meotheioma MMP (&) ad MMB (&) ce treated with 1 mm at differet time, ragig from 3 mi to 24 h, i 2% feta bovie erum (FBS) medium. b) 8-Hydroxy-2-deoxyguaoie (8-OHdG) adduct determiatio i HMC ad MMP ad MMB ce treated with 1 mm for 16 h i 2% FBS. Data are reported a fod icreae over the repective utreated ampe. c) Immuobottig aayi of phophoryatio of (Ser 473 ) i MMP ce i 2% FBS medium pre-treated for 24 h with 1 mm gutathioe moo-ethyeter (GSH) or with 1 mm L-N-acety-cyteie (L-NAC), repectivey, ad expoed to 15 mm for 3 mi ad to both ad atioxidat (upper pae, +GSH ad ower pae, +L-NAC). Leve of ad a-tubui protei are reported a oadig cotro. d) Doe repoe viabiity (MTT) aay, performed o MMP ce i 2% FBS medium with ragig from 5 to 15 mm for 24 h or treated with at the ame cocetratio i preece of 1 mm GSH or L-NAC. e) termia deoxyuceotidy traferae-mediated deoxyuridie triphophate ick-ed abeig (TUNEL) aay performed o MMP ce i 2% FBS medium, with 1 mm for 24 h, i either the preece or abece of GSH 1 mm or L-NAC 1 mm. Percetage of apoptotic ucei are how, foowig cout o 1 fied with at eat 1 ce o the ame ide. c EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 6 145

8 THORACIC ONCOLOGY N. ACETO ET AL. provoke tumour ce death ha bee debated [8], but ot yet carified. We demotrate herei that eectivey iduce meotheioma ce death via oxidative tre ad by egativey affectig activity. Give the crucia roe payed by igaig i huma tumour ad i deveopmet, progreio ad chemo-reitace ofmeotheioma,apreviouyhowbyu[4,5]adbyother [12], we aeed whether coud iterfere with activity. Our reut ceary demotrate that ihibit igaig, a demotrated by the reevat reductio of ad of dowtream mtor-depedet p7 S6K activitie, but ot of Erk 1/2 activity. Foowig treatmet, we oberved i HMC ad i meotheioma ce a cear ad progreive icreae of p38 ad JNK activitie, moty ivoved i ce tre repoe [28]. Coverey, eitivity of meotheioma ce to oxidative tre ha bee propoed a a potetia therapeutic trategy [29], whie other have uggeted a cytotoxic effect of o gioma ce via oxyge itermediate-depedet apoptoi [16]. Other have demotrated that ao exert oxidative tre o meotheioma ce, with ubequet p53 activatio ad dowreguatio of urvivi, Bc-2 ad Mc1 urviva protei ad ce death [27]. I the preet tudy, we oberved the effect of pecific ad time-depedet itrite productio upo meotheioma ce treatmet with. Iteretigy, i both MMB ad MMP ce, the kietic of itrite reeae i cogruet with the time-coure of cytotoxicity caued by thi drug. Moreover, ihibitio ao occur after treatmet, foowig a imiar tred. Atogether, thee reut ead u to cocude that iduce oxidative tre ad thi ceario i cofirmed by the igificat icreae of 8-OHdG adduct productio iduced by i meotheioma ce compared with o-eopatic meotheia ce. Thi eectivity of actio o meotheioma ce wa the further aeed by retorig ce viabiity whe treatmet wa accompaied by either GSH or L-NAC. Both atioxidat recue activity ihibited by, highightig the coe aociatio betwee -iduced cytotoxicity ad de-phophoryatio. I MMB ce expreig a myritoyated, cotitutivey active [22], wa ti abe to ihibit phophoryatio ad iduce cytotoxicity, a i wid-type MMB ce. The fact that ihibited eve cotitutive activated (abeit at higher cocetratio) reiforce the pecific effect of o thi igaig. Iteretigy, PP2A activity wa eectivey icreaed upo treatmet oy i MMP but ot i HMC, with a peak tartig 2 h after drug expoure, wherea PP1a wa activated very ate ad PTEN activity wa ot modified at a. The roe of PP2A ha bee exteivey tudied a a moduator of igaig kiae ad a a key reguator i huma tumour [3]. Moreover, other tudie reiforced that PP2A ca be pecificay targeted by pharmacoogica aget [31] ad that thi phophatae pecificay ihibit activity [32]. Our reut revea a differece i timig of ihibitio ad PP2A activatio. We ca hypotheie either that very ow PP2A activity, beow the immuobottig detectio threhod, may be ufficiet to ihibit i the eary phae of ce repoe to or, more ikey, that PP2A ad poiby PP1a utai the ihibited tatu provoked by aother yet ukow effector. It ha recety bee uggeted that oxidative tre may ifuece activity by itratio of the p85 ubuit of phophoioitide 3-kiae, eadig to the impairmet of the p85/p11 compex [33]. We oberved o detectabe itratio of the p85 reguatory ubuit i meotheioma ce upo treatmet with (data ot how). Coverey, other tudie reported that itratio may timuate receptor tyroie kiae (RTK) eadig to icreae of activity i rat fibrobat [34]. However, we were ot abe to detect ay modificatio of tyroie phophoryatio eve of thoe RTK mot commoy expreed i meotheioma ce, uch a Met ad PDGFRb (data ot how). The dicrepacy with our reut may be due to ce ieage differece i repoivee to oxidat aget. Our reut trogy ugget that i actig o the mechaim of activatio/ihibitio more tha o the uptream igaig. The chaperoe heat-hock protei Hp9 preerve activity by prevetig PP2A-mediated dephophoryatio [35]. Uder the coditio of -iduced ihibitio of, we oberved o differece i Hp9 or PP2A aociatio with the kiae (data ot how). We cocude that aother a yet uidetified mechaim uderie the oberved effect of o, compriig at eat oe eary evet (aready occurrig after 3 mi of treatmet), which might cotribute to the oberved apoptoi due to oxidative tre. Locay ijected i mice with itra-peritoea meotheioma exerted atitumour effect [26], uggetig that meotheioma may be cured with via prooged itra-peura ifuio. Our tudy provide a ratioae for a a ove oca treatmet for maigat meotheioma. SUPPORT STATEMENT Fiacia upport wa provided by the Buzzi Uicem Foudatio for the tudy of Meotheioma, Caae M., Itay, Meotheioma Appied Reearch Foudatio (MARF), Sata Barbara, CA, USA, the Regioe Piemote Ricerca Saitaria Fiaizzata, Torio, Itay, ad the Aociazioe Itaiaa per a Ricerca u Cacro (AIRC), Mia, Itay (fudig to G. Gaudio). STATEMENT OF INTEREST Noe decared. ACKNOWLEDGEMENTS We thak Gruppo Itaiao Meoteioma (GIMe), Caae M., Itay, for ogitic upport. We ao thak F. Boccafochi (Dept of Ciica ad Experimeta Medicie, Uiverity of Piemote orietae, Novara, Itay), A. Locatei ad S. Soigo (Dept DISCAFF, Uiverity of Piemote orietae), for preimiary or compemetary experimet, ad M. Riadi (Dept DISCAFF), for advice o the tatitica aayi. REFERENCES 1 Pa HI, Vogezag N, Hah S, et a. Maigat peura meotheioma. Curr Prob Cacer 24; 28: Carboe M, Emri S, Doga AU, et a. A meotheioma epidemic i Cappadocia: cietific deveopmet ad uexpected ocia outcome. Nat Rev Cacer 27; 7: Kroczyka B, Cutroe R, Bocchetta M, et a. Crocidoite abeto ad SV4 are cocarcioge i huma meotheia ce ad i cauig meotheioma i hamter. Proc Nat Acad Sci USA 26; 13: VOLUME 34 NUMBER 6 EUROPEAN RESPIRATORY JOURNAL

9 N. ACETO ET AL. THORACIC ONCOLOGY 4 Cacciotti P, Barboe D, Porta C, et a. SV4-depedet AKT activity drive meotheia ce traformatio after abeto expoure. Cacer Re 25; 65: Bertio P, Marcoi A, Paumbo L, et a. Erioite ad abeto differety caue traformatio of huma meotheia ce. It J Cacer 27; 121: Treuter KH, Bertram P, Lerch MM, et a. Prevetio of potoperative adheio by ige itraperitoea medicatio. J Surg Re 1995; 59: Brauma C, Heke W, Jacobi CA, et a. The tumor-uppreive reaget tauroidie i a ihibitor of protei bioythei. It J Cacer 24; 112: Jacobi CA, Meeako C, Brauma C. Tauroidie a ew drug with ati-tumor ad ati-agiogeic effect. Aticacer Drug 25; 16: Stede R, Stoteburg-Didiger G, A Keikh CL, et a. The effect of tauroidie o brai tumor ce. Aticacer Re 22; 22: McCourt M, Wag JH, Sookhai S, et a. Tauroidie ihibit tumor ce growth i vitro ad i vivo. A Surg Oco 2; 7: Brauma C, Stuhdreier B, Bobrich E, et a. High doe of tauroidie ihibit advaced itraperitoea tumor growth i rat. J Surg Re 25; 129: Atomare DA, You H, Xiao GH, et a. Huma ad moue meotheioma exhibit eevated AKT/PKB activity, which ca be targeted pharmacoogicay to ihibit tumor ce growth. Ocogee 25; 24: Bertio P, Porta C, Barboe D, et a. Preimiary data uggetive of a ove traatioa approach to meotheioma treatmet: imatiib meyate with gemcitabie or pemetrexed. Thorax 27; 62: Bertio P, Piccardi F, Porta C, et a. Imatiib meyate ehace therapeutic effect of gemcitabie i huma maigat meotheioma xeograft. Ci Cacer Re 28; 14: Gao N, Rahmai M, Det P, et a. 2-Methoxyetradio-iduced apoptoi i huma eukemia ce proceed through a reactive oxyge pecie ad -depedet proce. Ocogee 25; 24: Rodak R, Kubota H, Ihihara H, et a. Iductio of reactive oxyge itermediate-depedet programmed ce death i huma maigat ex vivo gioma ce ad ihibitio of the vacuar edotheia growth factor productio by tauroidie. J Neurourg 25; 12: Moma T. Rapid coorimetric aay for ceuar growth ad urviva: appicatio to proiferatio ad cytotoxicity aay. J Immuo Method 1983; 65: Toyokui S, Sagripati JL. Aociatio betwee 8-hydroxy-29- deoxyguaoie formatio ad DNA trad break mediated by copper ad iro. Free Radic Bio Med 1996; 2: Stewart JHt, Nguye DM, Che GA, et a. Iductio of apoptoi i maigat peura meotheioma ce by activatio of the Fa (Apo-1/CD95) death-iga pathway. J Thorac Cardiovac Surg 22; 123: Atomare DA, Vaet CA, Skee KL, et a. A moue mode recapituatig moecuar feature of huma meotheioma. Cacer Re 25; 65: Catey LC, Nee BG. New iight ito tumor uppreio: PTEN uppree tumor formatio by retraiig the phophoioitide 3-kiae/AKT pathway. Proc Nat Acad Sci USA 1999; 96: Ramawamy S, Nakamura N, Vazquez F, et a. Reguatio of G1 progreio by the PTEN tumor uppreor protei i iked to ihibitio of the phophatidyioito 3-kiae/ pathway. Proc Nat Acad Sci USA 1999; 96: Wu LL, Chiou CC, Chag PY, et a. Uriary 8-OHdG: a marker of oxidative tre to DNA ad a rik factor for cacer, atheroceroi ad diabetic. Ci Chim Acta 24; 339: Satageo F. Itraceuar thio cocetratio moduatig ifammatory repoe: ifuece o the reguatio of ce fuctio through cyteie prodrug approach. Curr Med Chem 23; 1: Ribizzi I, Darowki JW, Gouette FA, et a. Tauroidie: preciica evauatio of a ove, highy eective, aget for boe marrow purgig. Boe Marrow Trapat 22; 29: Nici L, Mofi B, Caabrei P. The effect of tauroidie, a ove atieopatic aget, o huma maigat meotheioma. Ci Cacer Re 24; 1: Opitz I, Sigrit B, Hiiger S, et a. Tauroidie ad povidoeiodie iduce differet type of ce death i maigat peura meotheioma. Lug Cacer 27; 56: Torre M, Forma HJ. Redox igaig ad the MAP kiae pathway. Biofactor 23; 17: Stapeberg M, Geert N, Swetteham E, et a. Apha-tocophery ucciate ihibit maigat meotheioma by diruptig the fibrobat growth factor autocrie oop: mechaim ad the roe of oxidative tre. J Bio Chem 25; 28: Arroyo JD, Hah WC. Ivovemet of PP2A i vira ad ceuar traformatio. Ocogee 25; 24: Jae V, Gori J, Va Hoof C. PP2A: the expected tumor uppreor. Curr Opi Geet Dev 25; 15: Ruvoo PP. Ceramide reguate ceuar homeotai via divere tre igaig pathway. Leukemia 21; 15: e-remey AB, Bartoi M, Patt DH, et a. Oxidative tre iactivate VEGF urviva igaig i retia edotheia ce via PI 3-kiae tyroie itratio. J Ce Sci 25; 118: Epoito F, Chirico G, Moteao Geuadi N, et a. Protei kiae B activatio by reactive oxyge pecie i idepedet of tyroie kiae receptor phophoryatio ad require SRC activity. J Bio Chem 23; 278: Sato S, Fujita N, Turuo T. Moduatio of kiae activity by bidig to Hp9. Proc Nat Acad Sci USA 2; 97: EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 6 147

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