Abstract
Cisplatin, one of the most common antitumor agents, is widely applied to treat various cancerous diseases and is included in the World Health Organization Model List of Essential Medicines. Cisplatin therapy is used to treat 10–20% of all cancerous cases, and its cure rate is especially high in testicular cancer (over 90%). However, a major side effect of this anticancer drug is nephrotoxicity, limiting treatment effect and reducing the quality of life in cancer patients. Muscone, an odoriferous constituent of musk, was confirmed to inhibit cisplatin-induced LLC-PK1 kidney proximal tubule cell death in a dose-dependent manner. In term of renal protective mechanism, muscone inhibited cisplatin oxidative toxicity by decreasing reactive oxygen species (ROS) level and stimulating HO-1 expression. Muscone also exerted anti-inflammation effect through inhibition of p38 phosphorylation. Furthermore, muscone mitigated cisplatin-induced apoptosis in LLC-PK1 cells via both intrinsic and extrinsic pathways by inhibiting pro-apoptotic protein Bax expression, and cleaved caspase-3, 7, and 8; and increase of anti-apoptotic protein Bcl-2 level. In addition, the anti-apoptotic effect of muscone also was enhanced by preventing p53 expression and its phosphorylation. Our study showed that muscone may be a potential protective agent against cisplatin-induced nephrotoxicity.
Highlights
Cisplatin, known as cis-diamminedichloroplatinum, is one of the most common antineoplastic agents used to treat various cancerous diseases, including ovarian, breast, testicular, brain, lung, and bladder cancer, and is included in the World Health Organization Model List of Essential Medicines
The curing rate of cisplatin is high in testicular cancer [5] and 10–20% of all cancerous cases are prescribed cisplatin-based chemotherapy [6]
LLC-PK1 cells (ATCC, Manassas, VA, USA) were propagated in Medium 199 (Welgene, GyeoLnLgCsa-nPgKb1ukce, lKlsor(eAa)TcCoCn,taMinainngas1s0a%s, fVetAal, bUovSiAn)e swereuremp(Rroepgaegnaetreadtioinn BMioelodgiuy,mOt1ta9w9 a(,WCealngaednae), aGnydeo1n%gssatrnegpbtoumk,yKcoinr-epae)nciocniltlainin(iCngor1n0i%ngf,eMtalanboasvsianse, sVeAru, mUS(ARe).gTenheertaytpioincaBl igorloowgyth, Ocottnadwiati,oCnasnwaderae) saentdas1%37s◦trCe,p9t5o%myrecliant-ipveenhicuilmlinid(iCtyo, rannidng5,%MCanOa2s.sAas,1V00Am, UMSAst)o.cTkhseotlyuptiiocnalogfrmowutshcocnoend(TithioenNsawtuerree Nseettawso3r7k,°CVe, s9t5e%nbreerlgastgivreeuhtuhm, Gideirtmy,aannyd) a5n%dCNO-a2.cAety1l0c0ysmteMinest(oNckACso;lAutbiocanmo,f Cmaumscborindeg(eT, hUeKN) awtuerree pNreetpwaroerdk,inVedsitmenebtheyrgl ssgurlefouxtihd,eG(eDrMmaSnOy;)SaanndtaNC-rauczetByilocytesctheinnoelo(NgyA, TCX; A, UbScaAm).,ACa2mmbMridsgtoec,kUsKo)luwtieorne prepared in dimethyl sulfoxide (DMSO; Santa Cruz Biotechnology, TX, USA)
Summary
Known as cis-diamminedichloroplatinum, is one of the most common antineoplastic agents used to treat various cancerous diseases, including ovarian, breast, testicular, brain, lung, and bladder cancer, and is included in the World Health Organization Model List of Essential Medicines. Renal toxicity is considered one of the biggest challenges in cisplatin-based chemotherapy besides other common side effects such as gastrointestinal toxicity, ototoxicity, neurotoxicity, and hematological toxicity. One-third of patients undergoing cisplatin treatment show symptoms of acute kidney. AAlltthhoouugghh cciissppllaattiinn tthheerraappyy pprreesseennttss rriisskkss ffoorr kkiiddnneeyyss aanndd ootthheerr oorrggaannss,, tthhee cclliinniiccaall eeffffeeccttiivveenneessss ooff cciissppllaattiinn iiss uunnddeenniiaabbllee iinn ccaanncceerr ttrreeaattmmeenntt. IInn aaddddiittiioonn,, iinn rreecceenntt yyeeaarrss,, tthhee ccoommbbiinnaattiioonn ooff cciissppllaattiinn tthheerraappyywwitihthrenreanl aplroptercottievcetisvueppsluepmpelnemts eonritgsinoartiignignafrtoinmgnfartoumralnsoatuurrcaels hsaosubrceeesn whaidselbyereensewaricdheeldy irnesbeoatrhchinedviitnroboatnhdininvvitirvooamndodinelvsiv[1o1m–1o6d].els [11,12,13,14,15,16]. IInn aaddddiittiioonn,, mmuussccoonnee ((33--mmeetthhyyllccyyccllooppeennttaaddeeccaannoonnee,, FFiigguurree 11)),, tthhee kkeeyy ccoommppoouunndd rreegguullaattiinngg tthhee ooddoorr ooff mmuusskk,, aallssoo ppoosssseesssseess sseevveerraall vvaalluuaabbllee pphhaarrmmaacceeuuttiiccaall aaccttiivviittiieess ssuucchh asaasnti-aenatril-yeaprrleygnapnrecgy,naanntci-yc,ereabnratil-cisecrheebmraila, aisncthi-ecmanicae,r, naenutir-ocparnocteerc,tivne,eaunrodpcraortdeicotpivreo,tecatinvde ecffaredcitosp[r1o7t]e.
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