The epigallocatechin gallate derivative Y_6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo
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摘要
Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.
Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.
Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.
引文
1.Gottesman MM,Fojo T,Bates SE.Multidrug resistance in cancer.Role of ATP-dependent transporters.Nat Rev Cancer 2002;92:48-58.
2.Sodani K,Patel A,Kathawala RJ,Chen ZS.Multidrug resistance associated proteins in multidrug resistance.Chin J Cancer 2012;31:58-72.
3.Gottesman MM.Mechanisms of cancer drug resistance.Ann Rev Med2002;53:615-27.
4.Fan YF,Zhang W,Zeng L,Lei ZN,Cai CY,Gupta P,et al.Dacomitinib antagonizes multidrug resistance(MDR)in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters.Cancer Lett 2018;421:186-98.
5.An X,Sarmiento C,Tan T,Zhu H.Regulation of multidrug resistance by micro RNAs in anti-cancer therapy.Acta Pharm Sin B 2017;7:38-51.
6.Borths EL,Locher KP,Lee AT,Rees DC.The structure of Escherichia coli BtuF and binding to its cognate ATP binding cassette transporter.Proc Nati Acad Sci U S A 2002;99:16642-7.
7.Locher KP.Structure and mechanism of ABC transporters.Curr Opin Struct Biol 2004;14:426-31.
8.Locher KP,Borths E.ABC transporter architecture and mechanism:implications from the crystal structures of BtuCD and BtuF.FEBS Lett2004;564:264-8.
9.Dean M,Allikmets R.Complete characterization of the human ABCgene family.J Bioenerg Biomembr 2001;33:475-9.
10.Dean M,Annilo T.Evolution of the ATP-binding cassette(ABC)transporter superfamily in vertebrates.Annu Rev Genom Hum Genet2005;6:123-42.
11.Schinkel AH,Jonker JW.Mammalian drug efflux transporters of the ATP binding cassette(ABC)family:an overview.Adv Drug Deliv Rev2003;55:3-29.
12.Juliano RL,Ling V.A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.Biochim Biophys Acta1976;455:152-62.
13.Ueda K,Cornwell MM,Gottesman MM,Pastan I,Roninson IB,Ling V,et al.The mdr1 gene,responsible for multidrug-resistance,codes for P-glycoprotein.Biochem Biophys Res Commun 1986;141:956-62.
14.Tiwari AK,Sodani K,Dai CL,Ashby Jr CR,Chen ZS.Revisiting the ABCs of multidrug resistance in cancer chemotherapy.Curr Pharm Biotechnol 2011;12:570-94.
15.Wu CP,Hsieh CH,Wu YS.The emergence of drug transportermediated multidrug resistance to cancer chemotherapy.Mol Pharm2011;8:1996-2011.
16.Roninson IB,Chin JE,Choi KG,Gros P,Housman DE,Fojo A,et al.Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells.Proc Natl Acad Sci U S A 1986;83:4538-42.
17.Van der Bliek AM,Baas F,Ten Houte de Lange T,Kooiman PM,van der Velde-Koerts T,Borst P.The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver.EMBO J 1987;6:3325-31.
18.de Bruijn MH,Van der Bliek AM,Biedler JL,Borst P.Differential amplification and disproportionate expression of five genes in three multidrug-resistant Chinese hamster lung cell lines.Mol Cell Biol1986;6:4717-22.
19.Gros P,Raymond M,Bell J,Housman D.Cloning and characterization of a second member of the mouse mdr gene family.Mol Cell Biol1988;8:2770-8.
20.Aller SG,Yu J,Ward A,Weng Y,Chittaboina S,Zhuo R,et al.Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.Science 2009;323:1718-22.
21.Wu CP,Calcagno AM,Ambudkar SV.Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells:evaluation of current strategies.Curr Mol Pharmacol 2008;1:93-105.
22.Wen Y,Zhao RQ,Zhang YK,Gupta P,Fu LX,Tang AZ,et al.Effect of Y6,an epigallocatechingallate derivative,on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells.Oncotarget2017;8:29760-70.
23.Liang G,Tang A,Lin X,Li L,Zhang S,Huang Z,et al.Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer.Int J Oncol 2010;37:111-23.
24.Kitagawa S,Nabekura T,Kamiyama S.Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells.J Pharm Pharmacol2004;56:1001-5.
25.Zhang H,Zhang YK,Wang YJ,Kathawala RJ,Patel A,Zhu H,et al.WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.Cancer Sci 2014;105:1071-8.
26.Li J,Jaimes KF,Aller SG.Refined structures of mouse P-glycoprotein.Protein Sci 2014;23:34-46.
27.Zhang YK,Zhang GN,Wang YJ,Patel BA,Talele TT,Yang DH,et al.Bafetinib(INNO-406)reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters.Sci Rep2016;6:25694.
28.Zhang YK,Zhang H,Zhang GN,Wang YJ,Kathawala RJ,Si R,et al.Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.Oncotarget 2015;6:24277-90.
29.Jain AN.Surflex:fully automatic flexible molecular docking using a molecular similarity-based search engine.J Med Chem 2003;46:499-511.
30.Wang YJ,Kathawala RJ,Zhang YK,Patel A,Kumar P,Shukla S,et al.Motesanib(AMG706),a potent multikinase inhibitor,antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1.Biochem Pharmacol 2014;90:367-78.
31.Sauna ZE,Ambudkar SV.Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein.Proc Natl Acad Sci U S A2000;97:2515-20.
32.Sauna ZE,Ambudkar SV.Characterization of the catalytic cycle of ATP hydrolysis by human P-glycoprotein the two ATP hydrolysis events in a single catalytic cycle are kinetically similar but affect different functional outcomes.J Biol Chem 2001;276:11653-61.
33.Ambudkar SV,Dey S,Hrycyna CA,Ramachandra M,Pastan I,Gottesman MM.Biochemical,cellular,and pharmacological aspects of the multidrug transporter 1.Annu Rev Pharmacol Toxicol1999;39:361-98.
34.Pajeva IK,Globisch C,Wiese M.Combined pharmacophore modeling,docking,and 3D QSAR studies of ABCB1 and ABCC1transporter inhibitors.Chem Med Chem 2009;4:1883-96.
2.Sodani K,Patel A,Kathawala RJ,Chen ZS.Multidrug resistance associated proteins in multidrug resistance.Chin J Cancer 2012;31:58-72.
3.Gottesman MM.Mechanisms of cancer drug resistance.Ann Rev Med2002;53:615-27.
4.Fan YF,Zhang W,Zeng L,Lei ZN,Cai CY,Gupta P,et al.Dacomitinib antagonizes multidrug resistance(MDR)in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters.Cancer Lett 2018;421:186-98.
5.An X,Sarmiento C,Tan T,Zhu H.Regulation of multidrug resistance by micro RNAs in anti-cancer therapy.Acta Pharm Sin B 2017;7:38-51.
6.Borths EL,Locher KP,Lee AT,Rees DC.The structure of Escherichia coli BtuF and binding to its cognate ATP binding cassette transporter.Proc Nati Acad Sci U S A 2002;99:16642-7.
7.Locher KP.Structure and mechanism of ABC transporters.Curr Opin Struct Biol 2004;14:426-31.
8.Locher KP,Borths E.ABC transporter architecture and mechanism:implications from the crystal structures of BtuCD and BtuF.FEBS Lett2004;564:264-8.
9.Dean M,Allikmets R.Complete characterization of the human ABCgene family.J Bioenerg Biomembr 2001;33:475-9.
10.Dean M,Annilo T.Evolution of the ATP-binding cassette(ABC)transporter superfamily in vertebrates.Annu Rev Genom Hum Genet2005;6:123-42.
11.Schinkel AH,Jonker JW.Mammalian drug efflux transporters of the ATP binding cassette(ABC)family:an overview.Adv Drug Deliv Rev2003;55:3-29.
12.Juliano RL,Ling V.A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.Biochim Biophys Acta1976;455:152-62.
13.Ueda K,Cornwell MM,Gottesman MM,Pastan I,Roninson IB,Ling V,et al.The mdr1 gene,responsible for multidrug-resistance,codes for P-glycoprotein.Biochem Biophys Res Commun 1986;141:956-62.
14.Tiwari AK,Sodani K,Dai CL,Ashby Jr CR,Chen ZS.Revisiting the ABCs of multidrug resistance in cancer chemotherapy.Curr Pharm Biotechnol 2011;12:570-94.
15.Wu CP,Hsieh CH,Wu YS.The emergence of drug transportermediated multidrug resistance to cancer chemotherapy.Mol Pharm2011;8:1996-2011.
16.Roninson IB,Chin JE,Choi KG,Gros P,Housman DE,Fojo A,et al.Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells.Proc Natl Acad Sci U S A 1986;83:4538-42.
17.Van der Bliek AM,Baas F,Ten Houte de Lange T,Kooiman PM,van der Velde-Koerts T,Borst P.The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver.EMBO J 1987;6:3325-31.
18.de Bruijn MH,Van der Bliek AM,Biedler JL,Borst P.Differential amplification and disproportionate expression of five genes in three multidrug-resistant Chinese hamster lung cell lines.Mol Cell Biol1986;6:4717-22.
19.Gros P,Raymond M,Bell J,Housman D.Cloning and characterization of a second member of the mouse mdr gene family.Mol Cell Biol1988;8:2770-8.
20.Aller SG,Yu J,Ward A,Weng Y,Chittaboina S,Zhuo R,et al.Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.Science 2009;323:1718-22.
21.Wu CP,Calcagno AM,Ambudkar SV.Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells:evaluation of current strategies.Curr Mol Pharmacol 2008;1:93-105.
22.Wen Y,Zhao RQ,Zhang YK,Gupta P,Fu LX,Tang AZ,et al.Effect of Y6,an epigallocatechingallate derivative,on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells.Oncotarget2017;8:29760-70.
23.Liang G,Tang A,Lin X,Li L,Zhang S,Huang Z,et al.Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer.Int J Oncol 2010;37:111-23.
24.Kitagawa S,Nabekura T,Kamiyama S.Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells.J Pharm Pharmacol2004;56:1001-5.
25.Zhang H,Zhang YK,Wang YJ,Kathawala RJ,Patel A,Zhu H,et al.WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.Cancer Sci 2014;105:1071-8.
26.Li J,Jaimes KF,Aller SG.Refined structures of mouse P-glycoprotein.Protein Sci 2014;23:34-46.
27.Zhang YK,Zhang GN,Wang YJ,Patel BA,Talele TT,Yang DH,et al.Bafetinib(INNO-406)reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters.Sci Rep2016;6:25694.
28.Zhang YK,Zhang H,Zhang GN,Wang YJ,Kathawala RJ,Si R,et al.Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.Oncotarget 2015;6:24277-90.
29.Jain AN.Surflex:fully automatic flexible molecular docking using a molecular similarity-based search engine.J Med Chem 2003;46:499-511.
30.Wang YJ,Kathawala RJ,Zhang YK,Patel A,Kumar P,Shukla S,et al.Motesanib(AMG706),a potent multikinase inhibitor,antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1.Biochem Pharmacol 2014;90:367-78.
31.Sauna ZE,Ambudkar SV.Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein.Proc Natl Acad Sci U S A2000;97:2515-20.
32.Sauna ZE,Ambudkar SV.Characterization of the catalytic cycle of ATP hydrolysis by human P-glycoprotein the two ATP hydrolysis events in a single catalytic cycle are kinetically similar but affect different functional outcomes.J Biol Chem 2001;276:11653-61.
33.Ambudkar SV,Dey S,Hrycyna CA,Ramachandra M,Pastan I,Gottesman MM.Biochemical,cellular,and pharmacological aspects of the multidrug transporter 1.Annu Rev Pharmacol Toxicol1999;39:361-98.
34.Pajeva IK,Globisch C,Wiese M.Combined pharmacophore modeling,docking,and 3D QSAR studies of ABCB1 and ABCC1transporter inhibitors.Chem Med Chem 2009;4:1883-96.