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Journal of Bioenergetics and Biomembranes

, Volume 33, Issue 6, pp 493–501 | Cite as

MRP Subfamily Transporters and Resistance to Anticancer Agents

  • Gary D. Kruh
  • Hao Zeng
  • Philip A. Rea
  • Guosheng Liu
  • Zhe-Sheng Chen
  • Kun Lee
  • Martin G. Belinsky
Article

Abstract

The MRP subfamily of ABC transporters from mammals consists of at least seven members, six of which have been implicated in the transport of amphipathic anions. MRP1, MRP2, and MRP3 bear a close structural resemblance, confer resistance to a variety of natural products as well as methotrexate, and have the facility for transporting glutathione and glucuronate conjugates. MRP1 is a ubiquitously expressed efflux pump for the products of phase II of xenobiotic detoxification, while MRP2, whose hereditary deficiency results in Dubin–Johnson syndrome, functions to extrude organic anions into the bile. MRP3 is distinguished by its capacity to transport the monoanionic bile constituent glycocholate, and may function as a basolateral back-up system for the detoxification of hepatocytes when the usual canalicular route is impaired by cholestatic conditions. MRP4 and MRP5 resemble each other more closely than they resemble MRPs 1–3 and confer resistance to purine and nucleotide analogs which are either inherently anionic, as in the case of the anti-AIDS drug PMEA, or are phosphorylated and converted to anionic amphiphiles in the cell, as in the case of 6-MP. Given their capacity for transporting cyclic nucleotides, MRP4 and MRP5 have also been implicated in a broad range of cellular signaling processes. The drug resistance activity and physiological substrates of MRP6 are unknown. However, its hereditary deficiency results in pseudoxanthoma elasticum, a multisystem disorder affecting skin, eyes, and blood vessels. It is hoped that elucidation of the resistance profiles and physiological functions of the different members of the MRP subfamily will provide new insights into the molecular basis of clinical drug resistance and spawn new strategies for combating this phenomenon.

MRP drug resistance ABC transporter 

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REFERENCES

  1. Allikmets, R., Gerrard, B., Hutchinson, A., and Dean, M. (1996). Hum. Mol. Genet. 5, 1649–1655.Google Scholar
  2. Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V., and Dean, M. (1998). Cancer Res. 58, 5337–5339.Google Scholar
  3. Bakos, E., Evers, R., Szakacs, G., Tusnady, G. E., Welker, E., Szabo, K., de Haas, M., van Deemter, L., Borst, P., Varadi, A., and Sarkadi, B. (1998). J. Biol. Chem. 273, 32167–32175.Google Scholar
  4. Bartosz, G., Konig, J., Keppler, D., and Hagmann, W. (1998). Biol. Chem. 379, 1121–1126.Google Scholar
  5. Belinsky, M. G., Bain, L. J., Balsara, B. B., Testa, J. R., and Kruh, G. D. (1998). J. Natl. Cancer Inst. 90, 1735–1741.Google Scholar
  6. Belinsky, M. G., and Kruh, G. D. (1999). Br. J. Cancer. 80, 1342–1349.Google Scholar
  7. Bergen, A. A., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., and de Jong, P. T. (2000). Nat. Genet. 25, 228–231.Google Scholar
  8. Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A., and Kruh, G. D. (1995). Cancer Res. 55, 5342–5347.Google Scholar
  9. Buchler, M., Konig, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., and Keppler, D. (1996). J. Biol. Chem. 271, 15091–15098.Google Scholar
  10. Chen, Z. S., Lee, K., and Kruh, G. D. (2001). J. Biol. Chem. 276, 33747–33754.Google Scholar
  11. Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M., and Deeley, R. G. (1992). Science 258, 1650–1654.Google Scholar
  12. Cole, S. P., Sparks, K. E., Fraser, K., Loe, D. W., Grant, C. E., Wilson, G. M., and Deeley, R. G. (1994). Cancer Res. 54, 5902–5910.Google Scholar
  13. Cui, Y., Konig, J., Buchholz, J. K., Spring, H., Leier, I., and Keppler, D. (1999). Mol. Pharmacol. 55, 929–937.Google Scholar
  14. Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., and Ross, D. D. (1998). Proc. Natl. Acad. Sci. U.S.A. 95, 15665–15670.Google Scholar
  15. Elferink, R. P., Ottenhoff, R., Liefting, W., de Haan, J., and Jansen, P. L. (1989). J. Clin. Invest. 84, 476–483.Google Scholar
  16. Evers, R., de Haas, M., Sparidans, R., Beijnen, J., Wielinga, P. R., Lankelma, J., and Borst, P. (2000). Br. J. Cancer. 83, 375–383.Google Scholar
  17. Evers, R., Kool, M., van Deemter, L., Janssen, H., Calafat, J., Oomen, L. C., Paulusma, C. C., Oude Elferink, R. P., Baas, F., Schinkel, A. H., and Borst, P. (1998). J. Clin. Invest. 101, 1310–1319.Google Scholar
  18. Evers, R., Zaman, G. J., van Deemter, L., Jansen, H., Calafat, J., Oomen, L. C., Oude Elferink, R. P., Borst, P., and Schinkel, A. H. (1996). J. Clin. Invest. 97, 1211–1218.Google Scholar
  19. Gottesman, M. M., and Pastan, I. (1993). Annu. Rev. Biochem. 62, 385–427.Google Scholar
  20. Grant, C. E., Valdimarsson, G., Hipfner, D. R., Almquist, K. C., Cole, S. P., and Deeley, R. G. (1994). Cancer Res. 54, 357–361.Google Scholar
  21. Hirohashi, T., Suzuki, H., Chu, X. Y., Tamai, I., Tsuji, A., and Sugiyama, Y. (2000). J. Pharmacol. Exp. Ther. 292, 265–270.Google Scholar
  22. Hirohashi, T., Suzuki, H., Ito, K., Ogawa, K., Kume, K., Shimizu, T., and Sugiyama, Y. (1998). Mol. Pharmacol. 53, 1068–1075.Google Scholar
  23. Hooijberg, J. H., Broxterman, H. J., Kool, M., Assaraf, Y. G., Peters, G. J., Noordhuis, P., Scheper, R. J., Borst, P., Pinedo, H. M., and Jansen, G. (1999). Cancer Res. 59, 2532–2535.Google Scholar
  24. Ishikawa, T., and Ali-Osman, F. (1993). J. Biol. Chem. 268, 20116–20125.Google Scholar
  25. Ishikawa, T., Bao, J. J., Yamane, Y., Akimaru, K., Frindrich, K., Wright, C. D., and Kuo, M. T. (1996). J. Biol. Chem. 271, 14981–14988.Google Scholar
  26. Ishikawa, T., Muller, M., Klunemann, C., Schaub, T., and Keppler, D. (1990). J. Biol. Chem. 265, 19279–19286.Google Scholar
  27. Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y. (1998). J. Biol. Chem. 273, 1684–1688.Google Scholar
  28. Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y. (1997). Am. J. Physiol. 272, G16–G22.Google Scholar
  29. Jedlitschky, G., Burchell, B., and Keppler, D. (2000). J. Biol. Chem. 275, 30069–30074.Google Scholar
  30. Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., and Keppler, D. (1996). Cancer Res. 56, 988–994.Google Scholar
  31. Jedlitschky, G., Leier, I., Buchholz, U., Center, M., and Keppler, D. (1994). Cancer Res. 54, 4833–4836.Google Scholar
  32. Kartenbeck, J., Leuschner, U., Mayer, R., and Keppler, D. (1996). Hepatology 23, 1061–1066.Google Scholar
  33. Kawabe, T., Chen, Z. S., Wada, M., Uchiumi, T., Ono, M., Akiyama, S., and Kuwano, M. (1999). FEBS Lett. 456, 327–331.Google Scholar
  34. Kitamura, T., Jansen, P., Hardenbrook, C., Kamimoto, Y., Gatmaitan, Z., and Arias, I. M. (1990). Proc. Natl. Acad. Sci. U.S.A. 87, 3557–3561.Google Scholar
  35. Koike, K., Kawabe, T., Tanaka, T., Toh, S., Uchiumi, T., Wada, M., Akiyama, S., Ono, M., and Kuwano, M. (1997). Cancer Res. 57, 5475–5479.Google Scholar
  36. Konig, J., Rost, D., Cui, Y., and Keppler, D. (1999). Hepatology 29, 1156–1163.Google Scholar
  37. Kool, M., de Haas, M., Scheffer, G. L., Scheper, R. J., van Eijk, M. J., Juijn, J. A., Baas, F., and Borst, P. (1997). Cancer Res. 57, 3537–3547.Google Scholar
  38. Kool, M., van der Linden, M., de Haas, M., Baas, F., and Borst, P. (1999a). Cancer Res. 59, 175–182.Google Scholar
  39. Kool, M., van der Linden, M., de Haas, M., Scheffer, G. L., de Vree, J. M., Smith, A. J., Jansen, G., Peters, G. J., Ponne, N., Scheper, R. J., Elferink, R. P., Baas, F., and Borst, P. (1999b). Proc. Natl. Acad. Sci. U.S.A. 96, 6914–6919.Google Scholar
  40. Krishnamachary, N., and Center, M. S. (1993). Cancer Res. 53, 3658–3661.Google Scholar
  41. Kruh, G. D., Chan, A., Myers, K., Gaughan, K., Miki, T., and Aaronson, S. A. (1994). Cancer Res. 54, 1649–1652.Google Scholar
  42. Kruh, G. D., Gaughan, K. T., Godwin, A., and Chan, A. (1995). J. Natl. Cancer. Inst. 87, 1256–1258.Google Scholar
  43. Kuo, M. T., Bao, J. J., Curley, S. A., Ikeguchi, M., Johnston, D. A., and Ishikawa, T. (1996). Cancer Res. 56, 3642–3644.Google Scholar
  44. Lacave, R., Coulet, F., Ricci, S., Touboul, E., Flahault, A., Rateau, J. G., Cesari, D., Lefranc, J. P., and Bernaudin, J. F. (1998). Br. J. Cancer. 77, 694–702.Google Scholar
  45. Laing, N. M., Belinsky, M. G., Kruh, G. D., Bell, D. W., Boyd, J. T., Barone, L., Testa, J. R., and Tew, K. D. (1998). Cancer Res. 58, 1332–1337.Google Scholar
  46. Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., and Boyd, C. D. (2000). Nat. Genet. 25, 223–227.Google Scholar
  47. Lee, K., Belinsky, M. G., Bell, D. W., Testa, J. R., and Kruh, G. D. (1998). Cancer Res. 58, 2741–2747.Google Scholar
  48. Lee, K., Klein-Szanto, A., and Kruh, G. D. (2000). J. Natl. Cancer. Inst. 92, 1934–1940.Google Scholar
  49. Leier, I., Jedlitschky, G., Buchholz, U., Cole, S. P., Deeley, R. G., and Keppler, D. (1994). J. Biol. Chem. 269, 27807–27810.Google Scholar
  50. Ling, V. (1997). Cancer Chemother. Pharmacol. 40, S3–S8.Google Scholar
  51. Loe, D. W., Almquist, K. C., Cole, S. P., and Deeley, R. G. (1996a). J. Biol. Chem. 271, 9683–9689.Google Scholar
  52. Loe, D. W., Almquist, K. C., Deeley, R. G., and Cole, S. P. (1996b). J. Biol. Chem. 271, 9675–9682.Google Scholar
  53. Longhurst, T. J., O'Neill, G. M., Harvie, R. M., and Davey, R. A. (1996). Br. J. Cancer 74, 1331–1335.Google Scholar
  54. Lorico, A., Rappa, G., Finch, R. A., Yang, D., Flavell, R. A., and Sartorelli, A. C. (1997). Cancer Res. 57, 5238–5242.Google Scholar
  55. Lorico, A., Rappa, G., Flavell, R. A., and Sartorelli, A. C. (1996). Cancer Res. 56, 5351–5355.Google Scholar
  56. Lutzky, J., Astor, M. B., Taub, R. N., Baker, M. A., Bhalla, K., Gervasoni, J. E., Jr., Rosado, M., Stewart, V., Krishna, S., and Hindenburg, A. A. (1989). Cancer Res. 49, 4120–4125.Google Scholar
  57. Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., and Meier, P. J. (1997). FEBS Lett. 406, 75–78.Google Scholar
  58. Madon, J., Hagenbuch, B., Landmann, L., Meier, P. J., and Stieger, B. (2000). Mol. Pharmacol. 57, 634–641.Google Scholar
  59. Marquardt, D., McCrone, S., and Center, M. S. (1990). Cancer Res. 50, 1426–1430.Google Scholar
  60. Marsh, W., and Center, M. S. (1987). Cancer Res. 47, 5080–5161.Google Scholar
  61. Marsh, W., Sicheri, D., and Center, M. S. (1986). Cancer Res. 46, 4053–4057.Google Scholar
  62. Masuda, M., I'izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni'inuma, K., Suzuki, H., and Sugiyama, Y. (1997). Cancer Res. 57, 3506–3510.Google Scholar
  63. Mayer, R., Kartenbeck, J., Buchler, M., Jedlitschky, G., Leier, I., and Keppler, D. (1995). J. Cell. Biol. 131, 137–150.Google Scholar
  64. McAleer, M. A., Breen, M. A., White, N. L., and Matthews, N. (1999). J. Biol. Chem. 274, 23541–23548.Google Scholar
  65. McGrath, T., and Center, M. S. (1987). Biochem. Biophys. Res. Commun. 145, 1171–1176.Google Scholar
  66. McGrath, T., Latoud, C., Arnold, S. T., Safa, A. R., Felsted, R. L., and Center, M. S. (1989). Biochem. Pharmacol. 38, 3611–3619.Google Scholar
  67. Miyake, K., Mickley, L., Litman, T., Zhan, Z., Robey, R., Cristensen, B., Brangi, M., Greenberger, L., Dean, M., Fojo, T., and Bates, S. E. (1999). Cancer Res. 59, 8–13.Google Scholar
  68. Morrow, C. S., Smitherman, P. K., Diah, S. K., Schneider, E., and Townsend, A. J. (1998). J. Biol. Chem. 273, 20114–20120.Google Scholar
  69. O'Brien, M., Kruh, G. D., and Tew, K. D. (2000). J. Pharmacol. Exp. Ther. 294, 480–487.Google Scholar
  70. Ortiz, D. F., Li, S., Iyer, R., Zhang, X., Novikoff, P., and Arias, I. M. (1999). Am. J. Physiol. 276, G1493–G1500.Google Scholar
  71. Paulusma, C. C., Bosma, P. J., Zaman, G. J., Bakker, C. T., Otter, M., Scheffer, G. L., Scheper, R. J., Borst, P., and Oude Elferink, R. P. (1996). Science 271, 1126–1128.Google Scholar
  72. Paulusma, C. C., Kool, M., Bosma, P. J., Scheffer, G. L., ter Borg, F., Scheper, R. J., Tytgat, G. N., Borst, P., Baas, F., and Oude Elferink, R. P. (1997). Hepatology 25, 1539–1542.Google Scholar
  73. Paulusma, C. C., van Geer, M. A., Evers, R., Heijn, M., Ottenhoff, R., Borst, P., and Oude Elferink, R. P. (1999). Biochem. J. 338, 393–401.Google Scholar
  74. Ringpfeil, F., Lebwohl, M. G., Christiano, A. M., and Uitto, J. (2000). Proc. Natl. Acad. Sci. U.S.A. 97, 6001–6006.Google Scholar
  75. Saxena, M., and Henderson, G. B. (1995). J. Biol. Chem. 270, 5312–5319.Google Scholar
  76. Schneider, E., Yamazaki, H., Sinha, B. K., and Cowan, K. H. (1995). Br. J. Cancer. 71, 738–743.Google Scholar
  77. Schuetz, J. D., Connelly, M. C., Sun, D., Paibir, S. G., Flynn, P. M., Srinivas, R. V., Kumar, A., and Fridland, A. (1999). Nat. Med. 5, 1048–1051.Google Scholar
  78. Suzuki, T., Nishio, K., Sasaki, H., Kurokawa, H., Saito-Ohara, F., Ikeuchi, T., Tanabe, S., Terada, M., and Saijo, N. (1997). Biochem. Biophys. Res. Commun. 238, 790–794.Google Scholar
  79. Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., Mikami, T., and Tagaya, O. (1991). Hepatology 14, 352–360.Google Scholar
  80. Taniguchi, K., Wada, M., Kohno, K., Nakamura, T., Kawabe, T., Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., and Kuwano, M. (1996). Cancer Res. 56, 4124–4129.Google Scholar
  81. Tusnady, G. E., Bakos, E., Varadi, A., and Sarkadi, B. (1997). FEBS Lett. 402, 1–3.Google Scholar
  82. Uchiumi, T., Hinoshita, E., Haga, S., Nakamura, T., Tanaka, T., Toh, S., Furukawa, M., Kawabe, T., Wada, M., Kagotani, K., Okumura, K., Kohno, K., Akiyama, S., and Kuwano, M. (1998). Biochem. Biophys. Res. Commun. 252, 103–110.Google Scholar
  83. van Aubel, R. A., Koenderink, J. B., Peters, J. G., Van Os, C. H., and Russel, F. G. (1999). Mol. Pharmacol. 56, 714–719.Google Scholar
  84. van Aubel, R. A., van Kuijck, M. A., Koenderink, J. B., Deen, P. M., van Os, C. H., and Russel, F. G. (1998). Mol. Pharmacol. 53, 1062–1067.Google Scholar
  85. Versantvoort, C. H., Broxterman, H. J., Bagrij, T., Scheper, R. J., and Twentyman, P. R. (1995). Br. J. Cancer. 72, 82–89.Google Scholar
  86. Wijnholds, J., Evers, R., van Leusden, M. R., Mol, C. A., Zaman, G. J., Mayer, U., Beijnen, J. H., van der Valk, M., Krimpenfort, P., and Borst, P. (1997). Nat. Med. 3, 1275–1279.Google Scholar
  87. Wijnholds, J., Mol, C. A., van Deemter, L., de Haas, M., Scheffer, G. L., Baas, F., Beijnen, J. H., Scheper, R. J., Hatse, S., De Clercq, E., Balzarini, J., and Borst, P. (2000). Proc. Natl. Acad. Sci. U.S.A. 97, 7476–7481.Google Scholar
  88. Wijnholds, J., Scheffer, G. L., van der Valk, M., van der Valk, P., Beijnen, J. H., Scheper, R. J., and Borst, P. (1998). J. Exp. Med. 188, 797–808.Google Scholar
  89. Zaman, G. J., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., and Borst, P. (1994). Proc. Natl. Acad. Sci.U.S.A. 91, 8822–8826.Google Scholar
  90. Zaman, G. J., Lankelma, J., van Tellingen, O., Beijnen, J., Dekker, H., Paulusma, C., Oude Elferink, R. P., Baas, F., and Borst, P. (1995). Proc. Natl. Acad. Sci. U.S.A. 92, 7690–7694.Google Scholar
  91. Zeng, H., Bain, L. J., Belinsky, M. G., and Kruh, G. D. (1999). Cancer Res. 59, 5964–5967.Google Scholar
  92. Zeng, H., Liu, G., Rea, P. A., and Kruh, G. D. (2000). Cancer Res. 60, 4779–4784.Google Scholar
  93. Zeng, H., Chen, Z. S., Belinsky, M. G., Rea, P. A., and Kruh, G. D. (2001). Cancer Res. 61, 7225–7232.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Gary D. Kruh
  • Hao Zeng
  • Philip A. Rea
  • Guosheng Liu
  • Zhe-Sheng Chen
  • Kun Lee
  • Martin G. Belinsky

There are no affiliations available

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