New uses for old drugs: Pharmacophore-based screening for the discovery of P-glycoprotein inhibitors

Chemical Biology and Drug Design

Volumn 78, Issue 1, 2011, Pages 57-72

  Palmeira, Andreia ^a   Rodrigues, Freddy ^b   Sousa, Emília ^a   Pinto, Madalena ^a   Vasconcelos, M Helena ^a   Fernandes, Miguel X ^b  

^a UNIVERSITY OF PORTO   (Portugal)

^b UNIVERSITY OF MADEIRA   (Portugal)

Author keywords

Cancer; Multidrug resistance transporters; Oxazepine; P glycoprotein inhibitors; Pharmacophore; Virtual screening

Indexed keywords

AMOXAPINE; AZELASTINE; BICALUTAMIDE; BLEBBISTATIN; COELENTERAMIDE; CYCLIC PIFITHRYN ALPHA; DANTRON; DAUNORUBICIN; DILTIAZEM; DOXORUBICIN; ECONAZOLE; GLYCOPROTEIN P INHIBITOR; HYCANTHONE; INDAPAMIDE; INDIRUBIN; ITRACONAZOLE; KETOCONAZOLE; LEFLUNOMIDE; LOXAPINE; MIBEFRADIL; PRANLUKAST; PRAZOSIN; PROPAFENONE; QUINIDINE; RHODAMINE 123; SULFINPYRAZONE; TIOCONAZOLE; UNCLASSIFIED DRUG; VERAPAMIL; WARFARIN; ZOMEPIRAC;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL GROWTH; CRYSTAL STRUCTURE; CYTOTOXICITY; DRUG POTENTIATION; DRUG SCREENING; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SUBSTRATE; FLOW CYTOMETRY; HUMAN; HUMAN CELL; LEUKEMIA CELL; PHARMACOPHORE; PRINCIPAL COMPONENT ANALYSIS; PRIORITY JOURNAL; PROTEIN EXPRESSION;

ADENOSINE TRIPHOSPHATASES; ANTINEOPLASTIC AGENTS; BLOTTING, WESTERN; DATABASE MANAGEMENT SYSTEMS; DOXORUBICIN; DRUG DISCOVERY; FLOW CYTOMETRY; HUMANS; K562 CELLS; P-GLYCOPROTEIN; PRINCIPAL COMPONENT ANALYSIS;

EID: 79958812376     PISSN: 17470277     EISSN: 17470285     Source Type: Journal    
DOI: 10.1111/j.1747-0285.2011.01089.x     Document Type: Article

References (83)

1. Higgins C.F. (2007) Multiple molecular mechanisms for multidrug resistance transporters. Nature;446:749-757.
2. Kaszubiak A., Kupstat A., Muller U., Hausmann R., Holm P.S., Lage H. (2007) Regulation of MDR1 gene expression in multidrug-resistant cancer cells is independent from YB-1. Biochem Biophys Res Commun;357:295-301.
3. Vecchio S.D., Ciarmiello A., Potena M.I., Carriero M.V., Mainolfi C., Botti G., Thomas R., Cerra M., D'aiuto G., Tsuruo T., Salvatore M. (1997) In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients. Eur J Nucl Med;24:150-159.
4. Kaur P. (2002) Multidrug resistance: can different keys open the same lock? Drug Resist Updat;5:61-64.
5. Higgins C.F. (1993) The multidrug resistance P-glycoprotein. Curr Opin Cell Biol;5:684-687.
6. Clarke R., Leonessa F., Trock B. (2005) Multidrug resistance/P-glycoprotein and breast cancer: review and meta-analysis. Semin Oncol;32:S9-S15.
7. Teodori E., Dei S., Scapecchi S., Gualtieri F. (2002) The medicinal chemistry of multidrug resistance (MDR) reversing drugs. Farmaco;57:385-415.
8. Higgins C.F., Callaghan R., Linton K.J., Rosenberg M.F., Ford R.C. (1997) Structure of the multidrug resistance P-glycoprotein. Semin Cancer Biol;8:135-142.
9. Johnstone R.W., Ruefli A.A., Smyth M.J. (2000) Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem Sci;25:1-6.
10. Badhan R., Penny J., Galetin A., Houston J.B. (2009) Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption. J Pharm Sci;98:2180-2197.
11. Hassan H.E., Myers A.L., Coop A., Eddington N.D. (2009) Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: in vitro and in vivo evaluation. J Pharm Sci;98:4928-4940.
12. Zhou S.F., Xue C.C., Yu X.Q., Li C., Wang G. (2007) Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit;29:687-710.
13. Benet L.Z. (2009) The drug transporter-metabolism alliance: uncovering and defining the interplay. Mol Pharm;6:1631-1643.
14. Zhou S.F. (2008) Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab;9:310-322.
15. Szakacs G., Varadi A., Ozvegy-Laczka C., Sarkadi B. (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today;13:379-393.
16. Thiel-Demby V.E., Tippin T.K., Humphreys J.E., Serabjit-Singh C.J., Polli J.W. (2004) In vitro absorption and secretory quotients: practical criteria derived from a study of 331 compounds to assess for the impact of P-glycoprotein-mediated efflux on drug candidates. J Pharm Sci;93:2567-2572.
17. Campillos M., Kuhn M., Gavin A.C., Jensen L.J., Bork P. (2008) Drug target identification using side-effect similarity. Science;321:263-266.
18. Pal D., Mitra A.K. (2006) MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol;1:323-339.
19. Huang S.M., Woodcock J. (2010) Transporters in drug development: advancing on the Critical Path. Nat Rev Drug Discov;9:175-176.
20. Polli J.W., Baughman T.M., Humphreys J.E., Jordan K.H., Mote A.L., Salisbury J.A., Tippin T.K., Serabjit-Singh C.J. (2003) P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine. J Pharm Sci;92:2082-2089.
21. Loo T.W., Clarke D.M. (1999) Determining the structure and mechanism of the human multidrug resistance P-glycoprotein using cysteine-scanning mutagenesis and thiol-modification techniques. Biochim Biophys Acta;1461:315-325.
22. Rosenberg M.F., Callaghan R., Modok S., Higgins C.F., Ford R.C. (2005) Three-dimensional structure of P-glycoprotein: the transmembrane regions adopt an asymmetric configuration in the nucleotide-bound state. J Biol Chem;280:2857-2862.
23. Cianchetta G., Singleton R.W., Zhang M., Wildgoose M., Giesing D., Fravolini A., Cruciani G., Vaz R.J. (2005) A pharmacophore hypothesis for P-glycoprotein substrate recognition using GRIND-based 3D-QSAR. J Med Chem;48:2927-2935.
24. Li W.X., Li L., Eksterowicz J., Ling X.B., Cardozo M. (2007) Significance analysis and multiple pharmacophore models for differentiating P-glycoprotein substrates. J Chem Inf Model;47:2429-2438.
25. Pajeva I.K., Wiese M. (2002) Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis). J Med Chem;45:5671-5686.
26. Penzotti J.E., Lamb M.L., Evensen E., Grootenhuis P.D. (2002) A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein. J Med Chem;45:1737-1740.
27. Boccard J., Bajot F., Di Pietro A., Rudaz S., Boumendjel A., Nicolle E., Carrupt P.A. (2009) A 3D linear solvation energy model to quantify the affinity of flavonoid derivatives toward P-glycoprotein. Eur J Pharm Sci;36:254-264.
28. Boumendjel A., Di Pietro A., Dumontet C., Barron D. (2002) Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance. Med Res Rev;22:512-529.
29. Froimowitz M. (1993) HyperChem: a software package for computational chemistry and molecular modeling. BioTechniques;14:1010-1013.
30. Grippo L., Lucidi S. (1997) A globally convergent version of the Polak-Ribière conjugate gradient method. Math Program;78:375-391.
31. Schneidman-Duhovny D., Dror O., Inbar Y., Nussinov R., Wolfson H.J. (2008) PharmaGist: a webserver for ligand-based pharmacophore detection. Nucleic Acids Res;36:W223-W228.
32. Wishart D.S., Knox C., Guo A.C., Cheng D., Shrivastava S., Tzur D., Gautam B., Hassanali M. (2008) DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res;36:D901-D906.
33. Lima R.T., Martins L.M., Guimaraes J.E., Sambade C., Vasconcelos M.H. (2004) Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther;11:309-316.
34. Houghton P., Fang R., Techatanawat I., Steventon G., Hylands P.J., Lee C.C. (2007) The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity. Methods;42:377-387.
35. Chong C.R., Sullivan D.J. Jr. (2007) New uses for old drugs. Nature;448:645-646.
36. Wermuth C.G. (2004) Selective optimization of side activities: another way for drug discovery. J Med Chem;47:1303-1314.
37. Wermuth C.G. (2006) Selective optimization of side activities: the SOSA approach. Drug Discov Today;11:160-164.
38. Lipinski C.A. (2003) Chris Lipinski discusses life and chemistry after the Rule of Five. Drug Discov Today;8:12-16.
39. Yan Ping H., Robert J. (1995) Azelastine and flezelastine as reversing agents of multidrug resistance: pharmacological and molecular studies. Biochem Pharmacol;50:169-175.
40. Colabufo N.A., Pagliarulo V., Berardi F., Contino M., Inglese C., Niso M., Ancona P., Albo G., Perrone R. (2008) Bicalutamide failure in prostate cancer treatment: involvement of Multi Drug Resistance proteins. Eur J Pharmacol;601:38-42.
41. Sterz K., Mollmann L., Jacobs A., Baumert D., Wiese M. (2009) Activators of P-glycoprotein: structure-activity relationships and investigation of their mode of action. ChemMedChem;4:1897-1911.
42. Molden E., Christensen H., Sund R.B. (2000) Extensive metabolism of diltiazem and P-glycoprotein-mediated efflux of desacetyl-diltiazem (M1) by rat jejunum in vitro. Drug Metab Dispos;28:107-109.
43. Wang E.J., Lew K., Casciano C.N., Clement R.P., Johnson W.W. (2002) Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother;46:160-165.
44. Efferth T., Volm M. (1993) Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms. Cancer Lett;70:197-202.
45. Kis E., Nagy T., Jani M., Molnar E., Janossy J., Ujhellyi O., Német K., Herédi-Szabó K., Krajcsi P. (2009) Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis;68:1201-1207.
46. Ramu A., Ramu N. (1992) Reversal of multidrug resistance by phenothiazines and structurally related compounds. Cancer Chemother Pharmacol;30:165-173.
47. Zsila F. (2007) Overlapping ligand specificity of P-glycoprotein and serum alpha(1)-acid glycoprotein: evidences and potential implications. Curr Drug Metab;8:563-593.
48. Shapiro A.B., Fox K., Lam P., Ling V. (1999) Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. Eur J Biochem;259:841-850.
49. Schmid D., Ecker G., Kopp S., Hitzler M., Chiba P. (1999) Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol;58:1447-1456.
50. Hollo Z., Homolya L., Hegedus T., Sarkadi B. (1996) Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Lett;383:99-104.
51. Duffy C.P., Elliott C.J., O'Connor R.A., Heenan M.M., Coyle S., Cleary I.M., Kavanagh K., Verhaegen S., O'Loughlin C.M., NicAmhlaoibh R., Clunes M. (1998) Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs). Eur J Cancer;34:1250-1259.
52. Sussman N. (2002) The predictive nature of high throughput toxicity screening using a human hepatocyte cell line. Cell Notes;3:7-10.
53. Kim R.B. (2002) Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev;34:47-54.
54. Wandel C., Kim R.B., Guengerich F.P., Wood A.J. (2000) Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos;28:895-898.
55. Tatu C.A., Paunescu V., Stanescu D.I., Schneider F. (1997) P-glycoprotein mediated multidrug resistance assessment by flow-cytometry in malignant hemopathies. Anticancer Res;17:2583-2586.
56. Wang E.J., Casciano C.N., Clement R.P., Johnson W.W. (2000) In vitro flow cytometry method to quantitatively assess inhibitors of P-glycoprotein. Drug Metab Dispos;28:522-528.
57. Akazawa Y., Kawaguchi H., Funahashi M., Watanabe Y., Yamaoka K., Hashida M., Takakura Y. (2002) Effect of interferons on P-glycoprotein-mediated rhodamine-123 efflux in cultured rat hepatocytes. J Pharm Sci;91:2110-2115.
58. Ludescher C., Thaler J., Drach D., Drach J., Spitaler M., Gattringer C., Huber H., Hofmann J. (1992) Detection of activity of P-glycoprotein in human tumour samples using rhodamine 123. Br J Haematol;82:161-168.
59. Petriz J., Garcia-Lopez J. (1997) Flow cytometric analysis of P-glycoprotein function using rhodamine 123. Leukemia;11:1124-1130.
60. Efferth T., Dunn T.A., Berlion M., Langenbahn H., Pommerenke E.W., Volm M. (1993) Reversal of inherent multidrug-resistance in primary human renal cell carcinoma cell cultures by S 9788. Anticancer Res;13:905-908.
61. Denis-Gay M., Petit J.M., Ratinaud M.H. (1995) Rhodamine 123: is it an appropriate dye to study P-glycoprotein activity in adriamycin-resistant K562 cells? Anticancer Res;15:121-126.
62. Slapak C.A., Mizunuma N., Kufe D.W. (1994) Expression of the multidrug resistance associated protein and P-glycoprotein in doxorubicin-selected human myeloid leukemia cells. Blood;84:3113-3121.
63. Garrigos M., Mir L.M., Orlowski S. (1997) Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase--further experimental evidence for a multisite model. Eur J Biochem;244:664-673.
64. Litman T., Zeuthen T., Skovsgaard T., Stein W.D. (1997) Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim Biophys Acta;1361:169-176.
65. Belli S., Elsener P.M., Wunderli-Allenspach H., Kramer S.D. (2009) Cholesterol-mediated activation of P-glycoprotein: distinct effects on basal and drug-induced ATPase activities. J Pharm Sci;98:1905-1918.
66. Urbatsch I.L., al-Shawi M.K., Senior A.E. (1994) Characterization of the ATPase activity of purified Chinese hamster P-glycoprotein. Biochemistry;33:7069-7076.
67. Tchamo D.N., Dijoux-Franca M.G., Mariotte A.M., Tsamo E., Daskiewicz J.B., Bayet C., Barron D., Conseil G., Pietro A. (2000) Prenylated xanthones as potential P-glycoprotein modulators. Bioorg Med Chem Lett;10:1343-1345.
68. Dayan G., Jault J.M., Baubichon-Cortay H., Baggetto L.G., Renoir J.M., Baulieu E.E., Gros P., Di Pietro A. (1997) Binding of steroid modulators to recombinant cytosolic domain from mouse P-glycoprotein in close proximity to the ATP site. Biochemistry;36:15208-15215.
69. Maki N., Hafkemeyer P., Dey S. (2003) Allosteric modulation of human P-glycoprotein. Inhibition of transport by preventing substrate translocation and dissociation. J Biol Chem;278:18132-18139.
70. Martin C., Berridge G., Higgins C.F., Callaghan R. (1997) The multi-drug resistance reversal agent SR33557 and modulation of vinca alkaloid binding to P-glycoprotein by an allosteric interaction. Br J Pharmacol;122:765-771.
71. 2+ transport pathways in thymic lymphocytes by econazole, miconazole, and SKF 96365. Am J Physiol;264:C654-C662.
72. Loo T.W., Clarke D.M. (1999) Identification of residues in the drug-binding domain of human P-glycoprotein. Analysis of transmembrane segment 11 by cysteine-scanning mutagenesis and inhibition by dibromobimane. J Biol Chem;274:35388-35392.
73. Loo T.W., Clarke D.M. (2000) Identification of residues within the drug-binding domain of the human multidrug resistance P-glycoprotein by cysteine-scanning mutagenesis and reaction with dibromobimane. J Biol Chem;275:39272-39278.
74. Eytan G.D., Regev R., Assaraf Y.G. (1996) Functional reconstitution of P-glycoprotein reveals an apparent near stoichiometric drug transport to ATP hydrolysis. J Biol Chem;271:3172-3178.
75. Dongping M. (2007) Identify P-glycoprotein Substrates and Inhibitors with the Rapid, HTS Pgp-Glo™ Assay System. Promega Notes;96:11-14.
76. Shoji Y., Fisher M.H., Periasamy A., Herman B., Juliano R.L. (1991) Verapamil and cyclosporin A modulate doxorubicin toxicity by distinct mechanisms. Cancer Lett;57:209-218.
77. Vezmar M., Georges E. (2000) Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs. Biochem Pharmacol;59:1245-1252.
78. Chiba P., Ecker G., Schmid D., Drach J., Tell B., Goldenberg S., Gekeler V. (1996) Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance. Mol Pharmacol;49:1122-1130.
79. Zamora J.M., Pearce H.L., Beck W.T. (1988) Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol Pharmacol;33:454-462.
80. Ecker G., Huber M., Schmid D., Chiba P. (1999) The importance of a nitrogen atom in modulators of multidrug resistance. Mol Pharmacol;56:791-796.
81. Muller H., Pajeva I.K., Globisch C., Wiese M. (2008) Functional assay and structure-activity relationships of new third-generation P-glycoprotein inhibitors. Bioorg Med Chem;16:2448-2462.
82. Reyes C.P., Munoz-Martinez F., Torrecillas I.R., Mendoza C.R., Gamarro F., Bazzocchi I.L., Núñez M.J., Pardo L., Castanys S., Campillo M., Jiménez I.A. (2007) Biological evaluation, structure-activity relationships, and three-dimensional quantitative structure-activity relationship studies of dihydro-beta-agarofuran sesquiterpenes as modulators of P-glycoprotein-dependent multidrug resistance. J Med Chem;50:4808-4817.
83. Gombar V.K., Polli J.W., Humphreys J.E., Wring S.A., Serabjit-Singh C.S. (2004) Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model. J Pharm Sci;93:957-968.