| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
The recent identification of mutations at arginine 482 (R482) in human BreastCancer Resistance Protein (BCRP) in two drug-selected cell lines largely explains some discrepancies observed in the cross-resistance profiles of human cell lines overexpressing this multidrug transporter. We find that each of three mouse cell lines independently selected for resistance to the anthracycline doxorubicin also acquired mutations in the cognate mouse transporter Bcrp1 exclusively at R482. Although the mouse Bcrp1 amino acid substitutions (M or S) are distinct from those seen in the human cell lines (G or T), they all have similar consequences: (a) greater resistance to anthracyclines (and bisantrene); (b) relatively lower resistance to topotecan; (c) greatly enhanced efflux of the dye rhodamine 123. The ready selection of R482X mutations seen in vitro might also occur in tumors treated with anthracyclines. Thus, it is noteworthy that the efficacy of Bcrp1 inhibitors applicable in vivo was not markedly affected by the presence of the mutations. We found that the Bcrp1 mutations all occurred after previous amplification and overexpression of the wild-type gene under doxorubicin selection; wild-type Bcrp1 is evidently able to mediate substantial resistance to anthracyclines, and this was confirmed in Bcrp1-transduced cell lines. These observations emphasize the general importance of the arginine at amino acid 482 for substrate specificity of the transporter, while reminding us that unmutated Bcrp1 remains a potential source of resistance to anthracyclines and a potential factor in anthracycline pharmacokinetics. The same is most likely true of human BCRP, given its profound similarities to mouse Bcrp1.
This article has been cited by other articles:
|
|
 |
|
  U. D. Lichtenauer, I. Shapiro, K. Geiger, M. Quinkler, M. Fassnacht, R. Nitschke, K.-D. Ruckauer, and F. Beuschlein Side Population Does Not Define Stem Cell-Like Cancer Cells in the Adrenocortical Carcinoma Cell Line NCI h295R Endocrinology, March 1, 2008; 149(3): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Kruger, C. D. Kaplan, Y. Luo, H. Zhou, D. Markowitz, R. Xiang, and R. A. Reisfeld Characterization of stem cell-like cancer cells in immune-competent mice Blood, December 1, 2006; 108(12): 3906 - 3912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chearwae, S. Shukla, P. Limtrakul, and S. V. Ambudkar Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol. Cancer Ther., August 1, 2006; 5(8): 1995 - 2006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F.K. Ejendal, N. K. Diop, L. C. Schweiger, and C. A. Hrycyna The nature of amino acid 482 of human ABCG2 affects substrate transport and ATP hydrolysis but not substrate binding. Protein Sci., July 1, 2006; 15(7): 1597 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shafran, I. Ifergan, E. Bram, G. Jansen, I. Kathmann, G. J. Peters, R. W. Robey, S. E. Bates, and Y. G. Assaraf ABCG2 Harboring the Gly482 Mutation Confers High-Level Resistance to Various Hydrophilic Antifolates Cancer Res., September 15, 2005; 65(18): 8414 - 8422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Q. Xia, N. Liu, D. Yang, G. Miwa, and L.-S. Gan EXPRESSION, LOCALIZATION, AND FUNCTIONAL CHARACTERISTICS OF BREAST CANCER RESISTANCE PROTEIN IN CACO-2 CELLS Drug Metab. Dispos., May 1, 2005; 33(5): 637 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. K. Ejendal and C. A. Hrycyna Differential Sensitivities of the Human ATP-Binding Cassette Transporters ABCG2 and P-Glycoprotein to Cyclosporin A Mol. Pharmacol., March 1, 2005; 67(3): 902 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kobayashi, I. Ieiri, T. Hirota, H. Takane, S. Maegawa, J. Kigawa, H. Suzuki, E. Nanba, M. Oshimura, N. Terakawa, et al. FUNCTIONAL ASSESSMENT OF ABCG2 (BCRP) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA Drug Metab. Dispos., January 1, 2005; 33(1): 94 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pavek, G. Merino, E. Wagenaar, E. Bolscher, M. Novotna, J. W. Jonker, and A. H. Schinkel Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 144 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Burger, H. van Tol, A. W. M. Boersma, M. Brok, E. A. C. Wiemer, G. Stoter, and K. Nooter Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump Blood, November 1, 2004; 104(9): 2940 - 2942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Bates, W. Y. Medina-Perez, G. Kohlhagen, S. Antony, T. Nadjem, R. W. Robey, and Y. Pommier ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. van Zon, M. H. Mossink, M. Schoester, R. J. Scheper, P. Sonneveld, and E. A. C. Wiemer Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression Cancer Res., July 15, 2004; 64(14): 4887 - 4892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gupta, Y. Zhang, J. D. Unadkat, and Q. Mao HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cisternino, C. Mercier, F. Bourasset, F. Roux, and J.-M. Scherrmann Expression, Up-Regulation, and Transport Activity of the Multidrug-Resistance Protein Abcg2 at the Mouse Blood-Brain Barrier Cancer Res., May 1, 2004; 64(9): 3296 - 3301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Robey, K. Steadman, O. Polgar, K. Morisaki, M. Blayney, P. Mistry, and S. E. Bates Pheophorbide a Is a Specific Probe for ABCG2 Function and Inhibition Cancer Res., February 15, 2004; 64(4): 1242 - 1246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Volk and E. Schneider Wild-Type Breast Cancer Resistance Protein (BCRP/ABCG2) is a Methotrexate Polyglutamate Transporter Cancer Res., September 1, 2003; 63(17): 5538 - 5543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wierdl, A. Wall, C. L. Morton, J. Sampath, M. K. Danks, J. D. Schuetz, and P. M. Potter Carboxylesterase-Mediated Sensitization of Human Tumor Cells to CPT-11 Cannot Override ABCG2-Mediated Drug Resistance Mol. Pharmacol., August 1, 2003; 64(2): 279 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nakanishi, J. E. Karp, M. Tan, L. A. Doyle, T. Peters, W. Yang, D. Wei, and D. D. Ross Quantitative Analysis of Breast Cancer Resistance Protein and Cellular Resistance to Flavopiridol in Acute Leukemia Patients Clin. Cancer Res., August 1, 2003; 9(9): 3320 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Chen, R. W. Robey, M. G. Belinsky, I. Shchaveleva, X.-Q. Ren, Y. Sugimoto, D. D. Ross, S. E. Bates, and G. D. Kruh Transport of Methotrexate, Methotrexate Polyglutamates, and 17{beta}-Estradiol 17-({beta}-D-glucuronide) by ABCG2: Effects of Acquired Mutations at R482 on Methotrexate Transport Cancer Res., July 15, 2003; 63(14): 4048 - 4054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Lockhart, R. G. Tirona, and R. B. Kim Pharmacogenetics of ATP-binding Cassette Transporters in Cancer and Chemotherapy Mol. Cancer Ther., July 1, 2003; 2(7): 685 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Rajendra, M. K. Gounder, A. Saleem, J. H. M. Schellens, D. D. Ross, S. E. Bates, P. Sinko, and E. H. Rubin Differential Effects of the Breast Cancer Resistance Protein on the Cellular Accumulation and Cytotoxicity of 9-Aminocamptothecin and 9-Nitrocamptothecin Cancer Res., June 15, 2003; 63(12): 3228 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Allen, S. C. van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel Mouse Breast Cancer Resistance Protein (Bcrp1/Abcg2) Mediates Etoposide Resistance and Transport, but Etoposide Oral Availability Is Limited Primarily by P-glycoprotein Cancer Res., March 15, 2003; 63(6): 1339 - 1344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ozvegy, A. Varadi, and B. Sarkadi Characterization of Drug Transport, ATP Hydrolysis, and Nucleotide Trapping by the Human ABCG2 Multidrug Transporter. MODULATION OF SUBSTRATE SPECIFICITY BY A POINT MUTATION J. Biol. Chem., December 6, 2002; 277(50): 47980 - 47990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Jonker, M. Buitelaar, E. Wagenaar, M. A. van der Valk, G. L. Scheffer, R. J. Scheper, T. Plosch, F. Kuipers, R. P. J. O. Elferink, H. Rosing, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria PNAS, November 26, 2002; 99(24): 15649 - 15654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Volk, K. M. Farley, Y. Wu, F. Li, R. W. Robey, and E. Schneider Overexpression of Wild-Type Breast Cancer Resistance Protein Mediates Methotrexate Resistance Cancer Res., September 1, 2002; 62(17): 5035 - 5040. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
