ABC Transporters and Cancer, PDF
Preview ABC Transporters and Cancer,
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ISBN:978-0-12-801251-2 ISSN:0065-230X ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com DEDICATION WededicatethisbooktoMs.NaokoIshikawawhopassedawayonDecem- ber10,2014.Shewasdiagnosedwithstage4ovariancancerandtreatedwith carboplatin,paclitaxel,andavastin.However,becauseofthesevereadverse effectsofavastin(anti-VEGFagent),Naokosufferedgastrointestinalperfo- ration and peritonitis secondary to the perforation. Therefore, she was not allowedtoeatordrinkanything.Duringcancertherapyover4months,she wasmaintainedbyCV-TPNandtreatmentwithvariouskindsofantibiotics. ShechallengedTCchemotherapy(paclitaxelandcarboplatin)fourtimesin total. However, she could not succeed in fighting against multidrug resis- tanceinbothovariancancerandperitonitismicrobesinherownbody.This indicates the difficulty of ABC transporter-mediated multidrug resistance. Our further research (both basic and clinic) is needed to solve this tough problem and to save patients’ lives. v CONTRIBUTORS SureshV.Ambudkar CenterforCancerResearch,LaboratoryofCellBiology,NationalCancerInstitute,National InstitutesofHealth,Bethesda,Maryland,USA EduardoE.Chufan CenterforCancerResearch,LaboratoryofCellBiology,NationalCancerInstitute,National InstitutesofHealth,Bethesda,Maryland,USA SelviDurmus DivisionofMolecularOncology,TheNetherlandsCancerInstitute,Amsterdam, TheNetherlands YuFukuda DepartmentofPharmaceuticalSciences,St.JudeChildren’sResearchHospital,Memphis, Tennessee,USA MichelleHaber LowyCancerResearchCentre,Children’sCancerInstitute,UniversityofNewSouth Wales,Sydney,NewSouthWales,Australia CsillaHegedu€s InstituteofEnzymology,ResearchCentreforNaturalSciences,HungarianAcademyof Sciences,Budapest,Hungary Tama´sHegedu˝s MTA-SEMolecularBiophysicsResearchGroupoftheHungarianAcademyofSciences, DepartmentofBiophysicsandRadiationBiology,SemmelweisUniversity,Budapest, Hungary JeroenJ.M.A.Hendrikx DepartmentofPharmacyandPharmacology,TheNetherlandsCancerInstitute,Amsterdam, TheNetherlands TonyHuynh LowyCancerResearchCentre,Children’sCancerInstitute,UniversityofNewSouth Wales,Sydney,NewSouthWales,Australia YojiIkegami DepartmentofDrugMetabolismandDisposition,MeijiPharmaceuticalUniversity,Tokyo, Japan YutakaInoue DepartmentofDrugMetabolismandDisposition,MeijiPharmaceuticalUniversity,Tokyo, Japan ToshihisaIshikawa NGOPersonalizedMedicine&Healthcare,Yokohama,andDepartmentofNeurosurgery, OsakaMedicalCollege,Takatsuki,Osaka,Japan xi xii Contributors YoshinagaKajimoto DepartmentofNeurosurgery,OsakaMedicalCollege,Takatsuki,Osaka,Japan ToshihikoKuroiwa DepartmentofNeurosurgery,OsakaMedicalCollege,Takatsuki,Osaka,Japan ShangliLian DepartmentofPharmaceuticalSciences,St.JudeChildren’sResearchHospital,Memphis, Tennessee,USA TarekMagdy* Dr.MargareteFischer-BoschInstituteofClinicalPharmacology,Stuttgart,Germany DavidS.Miller LaboratoryofToxicologyandPharmacology,NationalInstituteofEnvironmentalHealth Sciences,NationalInstitutesofHealth,NorthCarolina,USA AnneT.Nies Dr.MargareteFischer-BoschInstituteofClinicalPharmacology,Stuttgart,Germany MurrayD.Norris LowyCancerResearchCentre,Children’sCancerInstitute,UniversityofNewSouth Wales,Sydney,NewSouthWales,Australia € CsillaOzvegy-Laczka MTA-SEMolecularBiophysicsResearchGroupoftheHungarianAcademyofSciences, DepartmentofBiophysicsandRadiationBiology,SemmelweisUniversity,Budapest, Hungary Bala´zsSarkadi InstituteofEnzymology,ResearchCentreforNaturalSciences,HungarianAcademyof Sciences,andMTA-SEMolecularBiophysicsResearchGroupoftheHungarianAcademyof Sciences,DepartmentofBiophysicsandRadiationBiology,SemmelweisUniversity, Budapest,Hungary AlfredH.Schinkel DivisionofMolecularOncology,TheNetherlandsCancerInstitute,Amsterdam, TheNetherlands JohnD.Schuetz DepartmentofPharmaceuticalSciences,St.JudeChildren’sResearchHospital,Memphis, Tennessee,USA MatthiasSchwab Dr.MargareteFischer-BoschInstituteofClinicalPharmacology,Stuttgart,andDepartment ofClinicalPharmacology,InstituteofExperimentalandClinicalPharmacologyand Toxicology,UniversityHospital,Tu€bingen,Germany *Presentaddress:DepartmentofPharmacologyandToxicology,FacultyofPharmacy,PharosUniver- sity,Alexandria,Egypt Contributors xiii Hong-MaySim CenterforCancerResearch,LaboratoryofCellBiology,NationalCancerInstitute,National InstitutesofHealth,Bethesda,Maryland,USA A´gnesTelbisz InstituteofEnzymology,ResearchCentreforNaturalSciences,HungarianAcademyof Sciences,Budapest,Hungary AlanM.Truong LowyCancerResearchCentre,Children’sCancerInstitute,UniversityofNewSouth Wales,Sydney,NewSouthWales,Australia DeniseM.T.Yu LowyCancerResearchCentre,Children’sCancerInstitute,UniversityofNewSouth Wales,Sydney,NewSouthWales,Australia UlrichM.Zanger Dr.MargareteFischer-BoschInstituteofClinicalPharmacology,Stuttgart,Germany PREFACE ATP-binding cassette (ABC) transporters typically consist of two integral membrane domains containing six alpha helices and two cytosolic nucleotide-binding domains that, for plasma membrane proteins, couple ATP hydrolysis to the movement of substances to the extracellular space. WhileABCtransportersformalargesuperfamilyofactivetransportsystems, inmultiplephyla,thefocusofthisspecialissueofAdvancesinCancerResearch is on their role in the biology and therapy of cancer. The first mammalian drug resistance ABC transporter, P-glycoprotein (aka P-gp, MDR1, ABCB1), functionally identified almost 40 years ago, heraldedtheideathatmostformsofimpairedtumorresponsetochemother- apy(drugresistance)wouldbeaccountedforbythisoneprotein.However, despiteitspolyspecificity,certainclassesofdrugs(e.g.,nucleosides,antifolates, and camptothecins) were not exported by P-glycoprotein. As we moved forward,amorecomplexcontemporaryviewofABCtransportersincancer chemotherapy has evolved. The role of ABC transporters in cancer can now be viewed from multiple complementary perspectives, all of which arelikelytoimpacttherapeuticresponse.First,somecancersexpressinghigh levels of ABC transporters poorly respond to therapy due to drug export. Second, expression of ABC transporters in normal tissues limits absorption, distribution, and excretion (ADME) of chemotherapeutic drugs. Third, the polyspecificity of many ABC transporters impacts drug classes. Fourth, exportersofendogenousmolecules,someABCtransportershavethepoten- tial toimpacttumorgrowth andsurvival. Within thisABCtransporters and InputAdvancesinCancerResearchvolume,authorsvariouslydiscusstherapeu- tically relevant transporters impact on ADME, in particular limiting brain penetration, and also describe how transporters in the blood–brain barrier (BBB) are regulated, either up or down; in essence, the BBB provided by ABC transporters is dynamic and potentially modulateable. Other authors review the current state of our biochemical and structural knowledge of P-gp. In particular, two reviews highlight insights garnered not just from recent structural studies but also from knowledge of how a transporter’s membrane milieu affects activity. The membrane environment, especially membrane cholesterol content, has a marked impact on activity. ABC transporters are expressed in many cells that form barriers (e.g., intestinal epithelial cells and the BBB). Two reviews not only highlight xv xvi Preface ABCtransporters’role,withrespecttoanticancerdrugoralabsorption,but also describe ABC transporters’ impact and regulation at the BBB, an increasingly important area in the treatment of brain tumors or metastasis. Highlights include conceptual insights into how genetic deletion of two prominent BBB ABC transporters disproportionately increases the brain accumulation of their drug substrates. Based on this knowledge, one could envisionconcurrentinhibitionoftheseBBBtransportersasaviablestrategy to increase the brain penetration of many anticancer drugs (e.g., TKIs and PARP inhibitors) that are substrates of these ABC transporters. The other concept of the BBB is that ABC transporter expression in this endothelial barrierisnotstatic,butdynamic.Thisreviewsummarizesthecomplexsig- naling and transcription networks that respond to xenobiotic ligands or other exogenousor endogenous internal signals (e.g., reactive oxygen spe- cies) that might be activated during the course of disease. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters (poten- tially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established. Twochaptershighlightrecentinvestigationsintothestructureandbio- chemical properties of ABC transporters, providing insights into issues regarding polyspecificity and the role of membrane environment. For instance, the large, apparently flexible, internal cavity of murine ABCB1 providesastructuralbasisforearlierkineticstudiescharacterizingtheprop- erties of its multiple binding sites. Further, studies reveal how membrane lipidinteractions(e.g.,cholesterol),insomecasesviaspecificdomains,affect the catalytic activity of ABCB1 and ABCG2. Moreover, these studies underscorehowsubstratesofthesetransportersgainaccesstothetransporter through the membrane lipid phase rather than through the cytosol. InsightsintotheimpactofABCtransportersontherapeuticresponseand biologyareprovidedbythreechapters,focusingonneuroblastoma,myeloid leukemia,orbraintumors.Withrespecttoneuroblastoma,survivalratesare lessthan50%,forthosepatientsharboringMYCNoverexpressionorampli- fication, survival rates are much less. This might be related to ABC trans- porters, some are upregulated by MYCN, with consequent drug resistance. Another possibility is that upregulated ABC transporters affect thegrowthandsurvivaloftheneuroblastomacells.Someendogenoussub- stancesaffecthematopoieticgrowth,survival,andself-renewal,andtheabil- ityofABCtransporterstoexporttheseendogenoussubstancesmayfacilitate Preface xvii leukemogenesis by providing these same advantages to leukemic progeni- tors. If so, ABC transporter inhibitors might provide a direct benefit to AML chemotherapy by both increasing intracellular drug accumulation and removing potential survival advantages to leukemic progenitors. The surgical treatment and diagnosis of brain tumors, such as glioblastomas, can potentially be enhanced by disrupting porphyrin homeostasis in these cancercells.Exogenousadministrationofaporphyrinprecursor,alongwith an inhibitor of ABCG2 (a regulator of cellular porphyrin accumulation), is likely to impact diagnosis and treatment of these highly resistant tumors. The final review provides an overview of a widely used pyrimidine- basedanticancerdrug,5-fluorouracil(5-FU),fromatransporterperspective. Following uptake, 5-FU is anabolized to nucleosides then nucleotides. While there are well-known mechanisms of enzymatic resistance to 5-FU, the role of transporters in 5-FU resistance is just beginning to be appreciated. This review summarizes the current knowledge on the role of drug transporters with particular focus on ABC transporters in fluoropyrimidine-based chemotherapy response. We wouldlike to thank all those who have made this volumepossible, especially Ms. Camille Miller Doty, Sarah Lay, and members of the “Schuetz labs” (Satish Cheepala, John Lynch, Jessie Morgan, Yu Fukuda, AaronPitre). JOHN D. SCHUETZ AND TOSHIHISA ISHIKAWA CHAPTER ONE Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition Selvi Durmus*, Jeroen J.M.A. Hendrikx†, Alfred H. Schinkel*,1 *DivisionofMolecularOncology,TheNetherlandsCancerInstitute,Amsterdam,TheNetherlands †DepartmentofPharmacyandPharmacology,TheNetherlandsCancerInstitute,Amsterdam,TheNetherlands 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. IntroductiontoApicalABCTransporters 2 2. ImpactofApicalABCTransportersonIntestinalAbsorptionofOral ChemotherapeuticDrugs 5 2.1 ApicalABCtransportersaffectingtheoralbioavailabilityoftaxanes 8 2.2 ApicalABCtransportersintheoralbioavailabilityofrationallydesigned anticancerdrugs 13 3. ImpactofApicalABCTransportersonBrainDispositionofOralChemotherapeutic Drugs 20 3.1 DoestheBBBmatterindrugdeliverytobraintumors? 20 3.2 ApicaleffluxtransportersintheBBBaffectingbrainaccumulationofanticancer drugs 21 4. ConcludingRemarks 31 References 31 Abstract ATP-binding cassette (ABC) transporters are transmembrane efflux transporters that mediate cellular extrusion of a broad range of substrates ranging from amino acids, lipids, and ions to xenobiotics including many anticancer drugs. ABCB1 (P-GP) and ABCG2(BCRP)arethemostextensivelystudiedapicalABCdrugeffluxtransporters.They arehighlyexpressedinapicalmembranesofmanypharmacokineticallyrelevanttissues suchasepithelialcellsofthesmallintestineandendothelialcellsofthebloodcapillaries inbrainandtestis,andintheplacentalmaternal–fetalbarrier.Inthesetissues,theyhave aprotectivefunctionastheyeffluxtheirsubstratesbacktotheintestinallumenorblood andthusrestricttheintestinaluptakeandtissuedispositionofmanycompounds.This presentsamajorchallengefortheuseofmany(anticancer)drugs,asmostcurrently usedanticancerdrugsaresubstratesofthesetransporters.Herein,wereviewthelatest findingsontheroleofapicalABCtransportersinthedispositionofanticancerdrugs.We discuss that many new, rationally designed anticancer drugs are substrates of these transportersandthattheiroralavailabilityand/orbraindispositionareaffectedbythis AdvancesinCancerResearch,Volume125 #2015ElsevierInc. 1 ISSN0065-230X Allrightsreserved. http://dx.doi.org/10.1016/bs.acr.2014.10.001 2 SelviDurmusetal. interaction.Wealsosummarizestudiesthatinvestigatetheimprovementoforalavail- abilityandbraindispositionofmanycytotoxic(e.g.,taxanes)andrationally designed (e.g.,tyrosinekinaseinhibitor)anticancerdrugs,usingchemicalinhibitorsofthesetrans- porters.ThesefindingsprovideabetterunderstandingoftheimportanceofapicalABC transportersinchemotherapyandmaythereforeadvancetranslationofpromisingpre- clinicalinsightsandapproachestoclinicalstudies. ABBREVIATIONS ABC ATP-bindingcassette AUC areaunderthecurve BBB blood–brainbarrier CNS centralnervoussystem EGFR epidermalgrowthfactorreceptor FGFR fibroblastgrowthfactorreceptor JAK Januskinase MDR multidrugresistance mTOR mammaliantargetofrapamycin PDGFR platelet-derivedgrowthfactorreceptor RET rearrangedduringtransfection TKI tyrosinekinaseinhibitor VEGFR vascularendothelialgrowthfactorreceptor WT wildtype 1. INTRODUCTION TO APICAL ABC TRANSPORTERS ATP-binding cassette (ABC) transporters are active multispanning transmembrane protein pumps that, in higher organisms, are widely expressedinabroadrangeofmembranesoftissues.Formingoneofthelarg- estproteinfamilies,theseproteinsarepreservedacrosslivingorganismswith differentcomplexities,frombacteriatohigherplantsandanimals,including humans,illustratingtheiressentialfunctions(Glavinas,Krajcsi,Cserepes,& Sarkadi, 2004). ABC transporters utilize the energy generated by ATP hydrolysis to translocate a broad range of endogenous and exogenous sub- strates across membranes, often against a strong concentration gradient. In mammals, especially the well-studied rodents and man, typical substrates includeaminoacids,vitamins,lipids,sterols,bilesalts,peptides,nucleotides, ions, toxins, and (anticancer) drugs (Borst & Elferink, 2002; Borst & Schinkel, 2013; Franke, Gardner, & Sparreboom, 2010; Hayashi & Sugiyama, 2013; Klaassen & Aleksunes, 2010; Lagas, Vlaming, &
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