导致肿瘤化疗治疗失败的其中一个主要原因即为肿瘤多药耐药的产生，而其同样也很大程度上影响着患者疗效与预后。研究发现P-糖蛋白的过表达在肿瘤多药耐药中扮演着重要的角色。因此，许多P-糖蛋白抑制剂已被相继研制出来并试图逆转肿瘤多药耐药作用和提高细胞内药物浓度，然而，目前尚无一种药物被投入临床应用，其原因多为缺少高选择靶器官性及不可耐受的毒性。在近一段时间内，研究者已经利用一些其他的创新手段试图逆转肿瘤多药耐药作用，如基因沉默、药物运输系统、改变细胞膜完整性及中药相关应用等。作者将从P-糖蛋白结构与功能、P-糖蛋白在肿瘤多药耐药中的作用及通过抑制P-糖蛋白介导的多药耐药相关机制及策略等方面进行综述。

[1] FORD J M,HALT W N.Pharmacology of drugs that alter multidrug resistance in cancer[J].Pharmacol Rev,1990,42(3):155-199.
[2] CHIN K V,PASTAN I,GOTTESMAN M M.Function and regulation of the human multidrug resistance gene[J].Adv Cancer Res,1993,60:157-180.
[3] 王敏捷,胡卫列.氯硝柳胺抗肿瘤分子机制的研究进展[J].现代医学,2017,45(1):138-143.
[4] GOTTESMAN M M.Mechanisms of cancer drug resistance[J].Annu Rev Med,2002,53:615-627.
[5] JARDETZKY O.Simple allosteric model for membrane pumps[J].Nature,1966,211(5052):969-970.
[6] DEAN M,HAMON Y,CHIMINI G.The human ATP-binding cassette(ABC) transporter superfamily[J].J Lipid Res,2001,42(7):1007-1017.
[7] JULIANO R L,LING V.A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants[J].Biochim Biophys Acta,1976,455(1):152-162.
[8] GOTTESMAN M M,PASTAN I.Biochemistry of multidrug resistance mediated by the multidrug transporter[J].Annu Rev Biochem,1993,62:385-427.
[9] SCHINKELl A H.The physiological function of drug-transporting p-glycoproteins[J].Semin Cancer Biol,1997,8(3):161-170.
[10] SHUSTIK C,DALTON W,GROS P.P-glycoprotein-mediated multidrug resistance in tumor cells:biochemistry,clinical relevance and modulation[J].Mol Aspects Med,1995,16(1):1-78.
[11] JOHNSTONE R W,RUEFLI A A,SMYTH M J.Multiple physiological function for multidrug transporter p-glycoprotein[J].Trends Biochem Sci,2000,25(1):1-6.
[12] OSTERBERG T,NORINDER U.Theoretical calculation and prediction of p-glycoprotein-interacting drugs using Molsurf parametrization and PLS statistics[J].Eur J Pharm Sci,2000,10(4):295-303.
[13] HO R H,KIM R B.Transporters and drug therapy:implications for drug disposition and disease[J].Clin Pharmacol Ther,2005,78(3):260-277.
[14] AMBUDKAR S V,DEY S,HRYCYNA C A,et al.Biochemical,cellular,and pharmacological aspects of the multidrug transporter[J].Annu Rev Pharmacol Toxicol,1999,39:361-398.
[15] GOLDSTEIN L J,GALSKI H,FOJO A,et al.Expression of a multidrug resistance gene in human cancers[J].J Natl Cancer Inst,1989,81(2):116-124.
[16] GODA K Z,BASCO Z,SZABO G.Multidrug resistance through the spectacle of p-glycoprotein[J].Curr Cancer Drug Targets,2009,9(3):281-297.
[17] FORD J M,HAIT W N.Pharmacologic circumvention of multidrug resistance[J].Cytotechnology,1993,12(1-3):171-212.
[18] KRISHNA R,MAYER L D.Multidrug resistance(MDR) in cancer:mechanisms,reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs[J].Eur J Pharm Sci,2000,11(4):265-283.
[19] LAMPIDIS T J,KRISHAN A,PLANAS L,et al.Reversal of intrinsic resistance to adriamycin in normal cells by verapamil[J].Cancer Drug Deliv,1986,3(4):251-259.
[20] KRISHAN R,de JONG G,MAYER L D.Pulsed exposure of SDZ PSC833 to multidrug resistant P388/adr and MCF7/ADR cells in the absense of anticancer drugs can fully restore sensitivity to doxorubicin[J].Anticancer Res,1997,17(5a):3329-3334.
[21] PECK R A,HEWETT J,HARDING M W,et al.Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin[J].J Clin Oncol,2001,19(12):3130-3141.
[22] ALTENBERG G A,VANOVE C G,HORTON J K,et al.Unidirectional fluxes of rhodamine 123 in multidrug-resistant cells:evidence against direct drug extrusion from the plasma membrane[J].Proc Natl Acad Sci U S A,1994,91(11):4654-4657.
[23] HIGGINS C F,GOTTESMAN M M.Is the multidrug transporter a flippase?[J].Trends Biochem Sci,1992,17(1):18-21.
[24] ALLER S G,YU J,WARD A,et al.Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding[J].Science,2009,323(5922):1718-1722.
[25] ZIYAD B,AFSANEH L.P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer:current status and future perspectives[J].Curr Cancer Drug Targets,2013,13(3):326-346.
[26] MATOS A M,REIS M,DUARTE N,et al.Epoxylathyol derivatives:modulation of ABCB1-mediated multidrug resistance in human colon adenocarcinoma and mouse T-lymphoma cells[J].J Nat Prod,2015,78(9):2215-2228.
[27] KIM M K,PARK K S,CHOO H,et al.Quercetin-POM(pivaloxymethyl) conjugates:Modulatory activity for P-glycoprotein-based multidrug resistance[J].Phytomedicine,2015,22(7-8):778-785.
[28] MACKEIGAN J P,MURPHY L O,BLENIS J.Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance[J].Nat Cell Biol,2005,7(6):591-600.
[29] WANG F,CHEN Y,HUANG L,et al.Cetuximab enhanced the efficacy of chemotherapeutic agent in ABCB1/P-glycoprotein-overexpressing cancer cells[J].Oncotarget,2015,6(38):40850-40865.
[30] HU Z,ZHOU Z,HU Y,et al.HZ08 reverse P-glycoprotein mediated multidrug resistance in vitro and in vivo[EB/OL].[2015-02-17].https://doi.org/10.1371/journal.pone.0116886.
[31] MOTOMURA S,MOTOJI T,TAKANASHI M,et al.Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene(mdr1) antisense oligonucleotides[J].Blood,1998,91(9):3163-3171.
[32] Alahari S K,DEAN N M,FISHER M H,et al.Inhibition of expression of the multidrug resistance-associated P-glycoprotein of by phosphorothioate and 5' cholesterol-conjugated phosphorothioate antisense oligonucleotides[J].Mol Pharmacol,1996,50(4):808-819.
[33] RAO D D,VORHIES J S,SENZER N,et al.siRNA vs.shRNA:similarities and differences[J].Adv Drug Deliv Rev,2009,61(9):746-759.
[34] WU Y,ZHANG Y,ZHANG W,et al.Reversing of multidrug resistance breast cancer by co-delivery of P-gp siRNA and doxorubicin via folic acid-modified core-shell nanomicelles[J].Colloids Surf B Biointerfaces,2016,138:60-69.
[35] ZHANG C G,ZHU W J,LIU Y,et al.Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy[EB/OL].[2016-03-31].https://doi.org/10.1038/srep23859.
[36] ZAUNG A J,CECH T R.The intervening sequence RNA of Tetrahymena is an enzyme[J].Science,1986,231(4737):470-475.
[37] GAO P,ZHOU G Y,GUO L L,et al.Reversal of drug resistance in breast carcinoma cells by anti-mdr1 ribozyme regulated by the tumor-specific MUC-1 promoter[J].Cancer Lett,2007,256(1):81-89.
[38] SCOTTO K W,JOHNSON R A.Transcription of the multidrug resistance gene MDR1:a therapeutic target[J].Mol Interv,2001,1(2):117-125.
[39] CHEN T,WANG C,LIU Q,et al.Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway[J].Cancer Biol Ther,2015,16(1):106-114.
[40] JANSSON P J,YAMAGISHI T,ARVIND A,et al.Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone(Dp44mT) overcomes multidrug resistance by a novel mechanism involving the hijacking of lysosomal P-glycoprotein(Pgp)[J].J Biol Chem,2015,290(15):9588-9603.
[41] URBATSCH I L,SENIOR A E.Effects of lipids on ATPase activity of purified Chinese hamster P-glycoprotein[J].Arch Biochem Biophys,1995,316(1):135-140.
[42] LESLIE E M,DEELEY R G,COLE S P.Multidrug resistance proteins:role of P-glycoprotein,MRP1,MRP2,and BCRP(ABCG2) in tissue defense[J].Toxicol Appl Pharmacol,2005,204(3):216-237.