New Anti-Leukemic Effect of Carvacrol and Thymol Combination through Synergistic Induction of Different Cell Death Pathways.

Fatima Bouhtit,Makram Merimi,Douâa Moussa Agha,Philippe Lewalle,Khalid Sadki,Abdellah Hamal,Mehdi Najar,Nathalie Meuleman,Noureddine Boukhatem,Mustapha Najimi,Laurence Lagneaux,Dominique Bron,Rahma Melki

doi:10.3390/molecules26020410

Abstract

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells, and treatment for AML is lengthy and can be very expensive. Medicinal plants and their bioactive molecules are potential candidates for improving human health. In this work, we studied the effect of Ptychotis verticillata (PV) essential oil and its derivatives, carvacrol and thymol, in AML cell lines. We demonstrated that a combination of carvacrol and thymol induced tumor cell death with low toxicity on normal cells. Mechanistically, we highlighted that different molecular pathways, including apoptosis, oxidative, reticular stress, autophagy, and necrosis, are implicated in this potential synergistic effect. Using quantitative RT-PCR, Western blotting, and apoptosis inhibitors, we showed that cell death induced by the carvacrol and thymol combination is caspase-dependent in the HL60 cell line and caspase-independent in the other cell lines tested. Further investigations should focus on improving the manufacturing of these compounds and understanding their anti-tumoral mechanisms of action. These efforts will lead to an increase in the efficiency of the oncotherapy strategy regarding AML.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic stem cell disease that may be cured in some patients with intensive chemotherapy and/or allogeneic stem cell transplantation [1]
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Natural compounds from certain plants exhibit antiproliferative properties and cell death induction in various cancers through different pathways, including apoptosis, autophagy, and necroptosis [1]

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic stem cell disease that may be cured in some patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT) [1]. Despite the approval of new targeted treatments, including FMS-like tyrosine kinase 3 (FLT3) or antiapoptotic B-cell lymphoma 2 (BCL-2) protein inhibitors, up to 50% of AML patients will eventually relapse or die. The major reasons that may explain why patients are not cured are the inability of the treatment to eliminate. Molecules 2021, 26, 410 protein inhibitors, up to 50% of AML patients will eventually relapse or die. The major reasons that may explain why patients are not cured are the inability of the treatment to eallilmciannacteeraolulscacnelclesraonuds cderlulsga-rnedladterdugto-rxeilcaitteydtotodxiicffietyretnot doirfgfearnesn[t2o].rgCanelsl [d2e].atChelelvdaesaiothn emveacshioannimsmecshaarneisamhsalalmreaarkhoaflltmumarokrorfestuismtaonrceretsoiscthaenmceotthoecrhapemy o[1t]h.eTrahpeym[a1j]o.rTchhealmleanjgoer cohfanlleewngaentoifcannecweratnhteircaapnecuerticthseorlauptieountsicissotolurteioanctsivisatteocreelal cdteivaathtepcreolgl rdaemasthinpcroangcraemr cselilns cwahnicleerhcaevllins gwlhowiletohxaivciintygtloonwortmoxailcicteyllsto. Annorimncarleacseilnlsg. nAunmibnecrreoafssintugdnieusmhabveer sohfoswtundtihese hbaevneefishcioawl enfftehcetsboefndefiifcfeiarleneftfmecetsdiocfindaiflfperlaenntt emxetrdaicctisn.aAl pcclaunmt uelxattriancgtse.vAidcceunmceuslhaotiwngs ethvai-t dmeendceicsinhaolwpslatnhtatcommedpiocuinnadlspelxanerttcdoammpaoguinndgseeffxeecrttsdoanmcaagnicnegr ceefflelsc.tsBoionacctainvceemr coellelcs.uBleisoaarcetcivaepamboleleocfukleisllianrge ccaapnacebrleouosf ckeillllisntghcroanucgehrovuasricoeullssmthorloeucughlavr amrieocuhsamniosmlecsu, ilnarclmudeicnhgainntisrimnssi,cinorcleuxdtirningsiicntcrainspsiacseo-rdeepxetrnidnseinct caapsoppatsoes-dise, paeuntodpenhtagayp,oapntdosnise,craouptotopshisag[1y],. aPntdynchecortiospvtoerstiisci[l1la]t.aP(tPyVch)oitsisavneretnicdilelamtaic(PMVa)gihs raenbieanndpemlanict Musaegdhirnebtiraandiptiloanntalumseeddiincintreadfoi-r ttihoenatrlematemdeincitnoef ffoervethr,emturesactlme sepnatsomfsf,euvreirn,amryuisncfleectsipoanssm, dsi,aubreitneasr, yanindfhecytpioontesn, sdiioanbe[3te,4s],. aTnhde heysspeontteinasl iooinl ([E3,O4]). oTfhPeVescsoennttaiainl soisle(vEeOra)locfoPmVpocounntdasin, smsoesvtelyrapl hceonmopliocucnodms,pmonoesntltys p(4h8e.n0%ol)icwciothmcpaorvnaecnrtosl((4484..06%%)) wanitdhtchayrmvaoclr(o3l.4(%44).6a%s t)haenmdatihnycmomolp(o3.u4n%d)sa[s5]t.hTehme acihnemcoimca-l pstoruuncdtusr[e5o].fTchaervcahcermolicaanldstrhuycmtuorleios fshcaorwvancrinolFaingdurteh1ymusoilnigs Mshiocwronsoifnt Fpiagiunrteso1ftuwsianrge M(Micircorososoftftp, aCionrtps.o, fRtwedamreo(nMdi,cWroAso, fUt,SCAo)r.pF.e,wRewdomrokns dh,aWveAb,eUenSAde).vFoetewd wtootrhkiss hpalavnet,baenend dtheevyotheadvteootnhliys fpolcaunst,edanodntihtseyanhtaimveicoronblyiafloacnudseadntoindiiatbseatnictiemffieccrtosb. iTalhuans,dnaonsttiuddiaybehtaics ebfefecntsp.uTbhluissh,endotsotusdhoywhatshbeeaenntipcaunbcliesrheefdfetcot sohfoPwtytcheotaisnvtiecratinccilelarteaff(ePcVt)oefsPsteyncthiaotlios ivle(rEtiOc-) iollratiats(cPyVto)toesxsicenetfifaelctooiln(nEoOr)moarl cietsllsc.yRtoetcoexnitclye,fwfeecthaovnendoermmoanl sctrealltse.dRtehcaetnEtlOy,owf PeVhanvde ditesmconstirtautednttsh, actarEvOacorfoPl Vanadntdhiytms cooln, shtaitvueesnhtso,wcanrvbaecnreofilcainaldetfhfeycmtsool,nhdavifefesrheonwt bniobleong--

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