![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York
Breast cancer resistance protein (BCRP) is a newly identified ATP-binding cassette transporter, shown to confer multidrug resistance (MDR) to a number of important anticancer agents and play an important function in governing drug disposition. Flavonoids are a class of polyphenolic compounds widely present in foods and herbal products. The interactions of flavonoids with P-glycoprotein and multidrug resistance-associated protein 1 have been reported; however, their interaction with BCRP is unknown. Our objective was to evaluate the effects of 20 naturally occurring flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone in both BCRP-overexpressing and BCRP-negative human cell lines. BCRP-overexpressing and BCRP-negative human breast cancer cells (MCF-7) and large cell lung carcinoma cells (NCI-H460) were used in these studies. Many of the tested flavonoids (50 µM) increased mitoxantrone accumulation in BCRP-overexpressing cells, completely reversing mitoxantrone resistance, with no effect on the corresponding BCRP-negative cells, indicating that these flavonoids are BCRP inhibitors. The effects of these flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone were flavonoid concentration dependent, and significant changes were produced at concentrations lower than 10 µM for most of the flavonoids. Chrysin and biochanin A were the most potent BCRP inhibitors, producing significant increases in mitoxantrone accumulation at concentrations of 0.5 or 1.0 µM and in mitoxantrone cytotoxicity at a concentration of 2.5 µM. Flavonoid glycosides had no effects on the BCRP-mediated transport of mitoxantrone. The results obtained in this study could be clinically relevant in terms of both MDR reversal in cancer treatment and drug-flavonoid pharmacokinetic interactions.
Received October 15, 2003; accepted January 30, 2004.
Address correspondence to: Dr. Marilyn E. Morris, Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst NY, 14260-1200. E-mail: memorris{at}buffalo.edu
This article has been cited by other articles:
|
|
 |
|
  K. K.W. To, R. W. Robey, T. Knutsen, Z. Zhan, T. Ried, and S. E. Bates Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2 Mol. Cancer Ther., October 1, 2009; 8(10): 2959 - 2968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Pan, M. E. Morris, and A.-M. Yu MicroRNA-328 Negatively Regulates the Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Cancer Cells Mol. Pharmacol., June 1, 2009; 75(6): 1374 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Brand, P. A. I. van der Wel, M. J. Rein, D. Barron, G. Williamson, P. J. van Bladeren, and I. M. C. M. Rietjens Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers Drug Metab. Dispos., September 1, 2008; 36(9): 1794 - 1802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Henrich, R. W. Robey, H. R. Bokesch, S. E. Bates, S. Shukla, S. V. Ambudkar, M. Dean, and J. B. McMahon New inhibitors of ABCG2 identified by high-throughput screening Mol. Cancer Ther., December 1, 2007; 6(12): 3271 - 3278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ung and S. Nagar Variable Sulfation of Dietary Polyphenols by Recombinant Human Sulfotransferase (SULT) 1A1 Genetic Variants and SULT1E1 Drug Metab. Dispos., May 1, 2007; 35(5): 740 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang and M. E. Morris Effects of the Flavonoid Chrysin on Nitrofurantoin Pharmacokinetics in Rats: Potential Involvement of ABCG2 Drug Metab. Dispos., February 1, 2007; 35(2): 268 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Saito, H. Hirano, H. Nakagawa, T. Fukami, K. Oosumi, K. Murakami, H. Kimura, T. Kouchi, M. Konomi, E. Tao, et al. A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1114 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Henrich, H. R. Bokesch, M. Dean, S. E. Bates, R. W. Robey, E. I. Goncharova, J. A. Wilson, and J. B. McMahon A High-Throughput Cell-Based Assay for Inhibitors of ABCG2 Activity J Biomol Screen, March 1, 2006; 11(2): 176 - 183. [Abstract] [PDF]
|
|
|
|
|
|
X. Wang, A. W. Wolkoff, and M. E. Morris FLAVONOIDS AS A NOVEL CLASS OF HUMAN ORGANIC ANION-TRANSPORTING POLYPEPTIDE OATP1B1 (OATP-C) MODULATORS Drug Metab. Dispos., November 1, 2005; 33(11): 1666 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-f. Zhou, X. Yang, Q. Wang, R. A. Coburn, and M. E. Morris EFFECTS OF DIHYDROPYRIDINES AND PYRIDINES ON MULTIDRUG RESISTANCE MEDIATED BY BREAST CANCER RESISTANCE PROTEIN: IN VITRO AND IN VIVO STUDIES Drug Metab. Dispos., August 1, 2005; 33(8): 1220 - 1228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ahmed-Belkacem, A. Pozza, F. Munoz-Martinez, S. E. Bates, S. Castanys, F. Gamarro, A. Di Pietro, and J. M. Perez-Victoria Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2 Cancer Res., June 1, 2005; 65(11): 4852 - 4860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. A. Sesink, I. C. W. Arts, V. C. J. de Boer, P. Breedveld, J. H. M. Schellens, P. C. H. Hollman, and F. G. M. Russel Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Net Intestinal Uptake of Quercetin in Rats by Facilitating Apical Efflux of Glucuronides Mol. Pharmacol., June 1, 2005; 67(6): 1999 - 2006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, X. Wang, K. Sagawa, and M. E. Morris FLAVONOIDS CHRYSIN AND BENZOFLAVONE, POTENT BREAST CANCER RESISTANCE PROTEIN INHIBITORS, HAVE NO SIGNIFICANT EFFECT ON TOPOTECAN PHARMACOKINETICS IN RATS OR MDR1A/1B (-/-) MICE Drug Metab. Dispos., March 1, 2005; 33(3): 341 - 348. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
