Journal of Bioenergetics and Biomembranes

, Volume 33, Issue 6, pp 503–511 | Cite as

The Role of Half-Transporters in Multidrug Resistance

  • Susan E. Bates
  • Robert Robey
  • Keisuke Miyake
  • Koneti Rao
  • Douglas D. Ross
  • Thomas Litman


ATP-binding cassette proteins comprise a superfamily of transporter proteins, a subset of which have been implicated in multidrug resistance. Although P-glycoprotein was described over 15 years ago, the recent expansion in the number of transporters identified has prompted renewed interest in the role of drug transporters in clinical drug resistance. These newly identified transporters include additional members of the MRP family, ABC2, and a new half-transporter, MXR/BCRP/ABCP1. This half-transporter confers high levels of resistance to mitoxantrone, anthracyclines, and the camptothecins SN-38 and topotecan. At 72 kDa, MXR localizes to the plasma membrane in cells which highly overexpress the protein either through gene amplification or though gene rearrangement. Future studies will be aimed at identifying an inhibitor, and attempting to translate recognition of this new transporter into a target for anticancer treatment.

ABCG2 mitoxantrone ABC transporter drug resistance gene 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abele, R., and Tampe, R. (1999). Biochim. Biophys. Acta 1461, 405–419.Google Scholar
  2. Allen, J. D., Brinkhuis, R. F., Wijnholds, J., and Schinkel, A. H. (1999). Cancer Res. 59, 4237–4241.Google Scholar
  3. Allikmets, R., Gerrard, B., Hutchinson, A., and Dean, M. (1996). Hum. Mol. Genet. 5, 1649–1655.Google Scholar
  4. Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V., and Dean, M. (1998). Cancer Res. 58, 5337–5339.Google Scholar
  5. Beck, W. T., Grogan, T. M., Willman, C. L., Cordon-Cardo, C., Parham, D. M., Kuttesch, J. F., Andreeff, M., Bates, S. E., Berard, C. W., Boyett, J. M., Brophy, N. A., Broxterman, H. J., Chan, H. S. L., Dalton, W. S., Dietel, M., Fojo, A. T., Gascoyne, R. D., Head, D., Houghton, P. J., Srivastava, D. K., Lehnert, M., Leith, C. P., Paietta, E., Pavelic, Z. P., Rimsza, L., Roninson, I. B., Sikic, B. I., Twentyman, P. R., Warnke, R., and Weinstein, R. (1996). Cancer Res. 56, 3010–3020.Google Scholar
  6. Borst, P., Evers, R., Kool, M., and Wijnholds, J. (1999). Biochim. Biophys. Acta 1461, 347–357.Google Scholar
  7. Brangi, M., Litman, T., Ciotti, M., Nishiyama, K., Kohlhagen, G., Takimoto, C., Robey, R., Pommier, Y., Fojo, T., and Bates, S. E. (1999). Cancer Res. 59, 5938–5946.Google Scholar
  8. Childs, S., Yeh, R. L., Hui, D., and Ling, V. (1998). Cancer Res. 58, 4160–4167.Google Scholar
  9. Cole, S. P. C., 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
  10. Dalton, W. S., Cress, A. E., Alberts, D. S., and Trent, J. M. (1988). Cancer Res. 48, 1882–1888.Google Scholar
  11. de Bruin, M., Miyake, K., Litman, T., Robey, R., and Bates, S. E. (1999). Cancer Lett. 146, 117–126.Google Scholar
  12. Dietel, M., Arps, H., Lage, H., and Niendorf, A. (1990). Cancer Res. 50, 6100–6106.Google Scholar
  13. Doyle, L. A., Yang, W., Abruzzo, L. E., Krogmann, T., Gao, Y., Rishi, A. K., and Ross, D. D. (1998a). Proc. Am. Assoc. Cancer Res. 39A.Google Scholar
  14. Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., and Ross, D. D. (1998b). Proc. Natl. Acad. Sci. U.S.A. 95, 15665–15670.Google Scholar
  15. Ewart, G. D., and Howells, A. J. (1998). In Methods in Enzymology (Ambudkar, S., and Gottesman, M. M., eds.), Academic Press, San Diego, pp. 213–224.Google Scholar
  16. Hazlehurst, L. A., Foley, N. E., Gleason-Guzman, M. C., Hacker, M. P., Cress, A. E., Greenberger, L. W., De Jong, M. C., and Dalton, W. S. (1999). Cancer Res. 59, 1021–1028.Google Scholar
  17. Higgins, C. F. (1992). Annu. Rev. Cell Biol. 8, 67–113.Google Scholar
  18. Hipfner, D. R., Deeley, R. G., and Cole, S. P. (1999). Biochem. Biophys. Acta 1461, 359–376.Google Scholar
  19. Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., and Keppler, D. (1996). Cancer Res. 56, 988–994.Google Scholar
  20. Klein, I., Sarkadi, B., and Varadi, A. (1999). Biochim. Biophys. Acta 1461, 237–262.Google Scholar
  21. Knutsen, T., Rao, V. K., Ried, T., Mickley, L., Schneider, E., Miyake, K., Ghadimi, B. M., Padilla-Nash, H., Pack, S., Greenberger, L., Cowan, K., Dean, M., Fojo, T., and Bates, S. (2000). Genes Chromosomes Cancer 27, 110–116.Google Scholar
  22. 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
  23. 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. (1999). Proc. Natl. Acad. Sci. U.S.A. 96, 6914–6919.Google Scholar
  24. 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
  25. Lee, J. S., Paull, K., Alvarez, M., Hose, C., Monks, A., Grever, M., Fojo, A. T., and Bates, S. E. (1994). Mol. Pharmacol. 46, 627–638.Google Scholar
  26. Lee, J. S., Scala, S., Matsumoto, Y., Dickstein, B., Robey, R., Zhan, Z., Altenberg, G., and Bates, S. E. (1997). J. Cell. Biochem. 65, 513–526.Google Scholar
  27. Ling, V. (1997). Cancer Chemother. Pharmacol. 40(Suppl)., S3–S8.Google Scholar
  28. Litman, T., Brangi, M., Hudson, E., Fetsch, P., Abati, A., Ross, D. D., Miyake, K., Resau, J. H., and Bates, S. E. (2000). J. Cell Sci. 113, 2011–2021.Google Scholar
  29. Liu, L. X., Janvier, K., Berteaux-Lecellier, V., Cartier, N., Benarous, R., and Aubourg, P. (1999). J. Biol. Chem. 274, 32738–32743.Google Scholar
  30. Ma, J., Maliepaard, M., Nooter, K., Loos, W. J., Kolker, H. J., Verweij, J., Stoter, G., and Schellens, J. H. (1998). Br. J. Cancer 77, 1645–1652.Google Scholar
  31. Malayeri, R., Filipits, M., Suchomel, R. W., Zochbauer, S., Lechner, K., and Pirker, R. (1996). Leuk. Lymphoma 23, 451–458.Google Scholar
  32. Maliepaard, M., van Gastelen, M. A., de Jong, L. A., Pluim, D., van Waardenburg, R. C., Ruevekamp-Helmers, M. C., Floot, B. G., and Schellens, J. H. (1999). Cancer Res. 59, 4559–4563.Google Scholar
  33. 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
  34. Nakagawa, M., Schneider, E., Dixon, K. H., Horton, J., Kelley, K., Morrow, C., and Cowan, K. H. (1992). Cancer Res. 52, 6175–6181.Google Scholar
  35. Rabindran, S. K., He, H., Singh, M., Brown, E., Collins, K. I., Annable, T., and Greenberger, L. M. (1998). Cancer Res. 58, 5850–5858.Google Scholar
  36. Rabindran, S. K., Ross, D. D., Doyle, L. A., Yang, W., and Greenberger, L. M. (2000). Cancer Res. 60, 47–50.Google Scholar
  37. Rocchi, E., Khodjakov, A., Volk, E. L., Yang, C. H., Litman, T., Bates, S. E., and Schneider, E. (2000). Biochem. Biophys. Res. Commun. 271, 42–46.Google Scholar
  38. Ross, D. D. (2000). Leukemia 14, 467–473.Google Scholar
  39. Ross, D. D., Yang, W., Abruzzo, L. V., Dalton, W. S., Schneider, E., Lage, H., Dietel, M., Greenberger, L., Cole, S. P., and Doyle, L. A. (1999). J. Natl., Cancer Inst. 91, 429–433.Google Scholar
  40. Sandor, V., Fojo, T., and Bates, S. E. (1998). Drug Resist Updates 1, 190–200.Google Scholar
  41. Scheffer, G. L., Maliepaard, M., Pijnenborg, A. C. L. M., van Gastelen, M. A., de Jong, M. C., Schroeijers, A. B., van der Kolk, D. M., Allen, J. D., Ross, D. D., van der Valk, P., Dalton W. S., Schellens, J. H. M., and Scheper, R. J. (2000). Cancer Res. 60, 2589–2593.Google Scholar
  42. Strautnieks, S. S., Bull, L. N., Knisely, A. S., Kocoshis, S. A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M. S., Kagalwalla, A. F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N. B., Gardiner, R. M., and Thompson, R. J. (1998). Nat. Genet. 20, 233–238.Google Scholar
  43. Taylor, C. W., Dalton, W. S., Parrish, P. R., Gleason, M. C., Bellamy, W. T., Thompson, F. H., Roe, D. J., and Trent, J. M. (1991). Br. J. Cancer 63, 923–929.Google Scholar
  44. Trock, B. J., Leonessa, F., and Clarke, R. (1997). J. Natl. Cancer Inst. 89, 917–931.Google Scholar
  45. van den Heuvel-Eibrink, M. M., Sonneveld, P., and Pieters, R. (2000). Int. J. Clin. Pharmacol. Ther. 38, 94–110.Google Scholar
  46. Wallace, R. E., Lindh, D., and Durr, F. E. (1987). Cancer Invest. 5, 417–428.Google Scholar
  47. Yang, C. J., Horton, J. K., Cowan, K. H., and Schneider, E. (1995). Cancer Res. 55, 4004–4009.Google Scholar
  48. Zeng, H., Bain, L. J., Belinsky, M. G., and Kruh, G. D. (1999). Cancer Res. 59, 5964–5967.Google Scholar
  49. Zhang, X. P., Ritke, M. K., Yalowich, J. C., Slovak, M. L., Pelkey, H. J., Collins K. L., Annable, T., Arceci, R. J., Durr, F. E., and Greenberger, L. M. (1994). Oncol. Res. 6, 291–301.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Susan E. Bates
  • Robert Robey
  • Keisuke Miyake
  • Koneti Rao
  • Douglas D. Ross
  • Thomas Litman

There are no affiliations available

Personalised recommendations