Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice

Vlaming, Maria L. H.; Lagas, Jurjen S.; Schinkel, Alfred H.

doi:10.1016/j.addr.2008.08.007

Cited by 208 publications

(157 citation statements)

References 64 publications

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“…Moreover, in all reports on shared Pgp and ABCG2 substrates, an effect of Abcg2 deficiency on brain accumulation only becomes evident when P-gp is absent too (i.e., in Abcb1a/1b;Abcg2 −/− mice; reviewed in ref. 36). To the best of our knowledge, the present study is the first to show that the brain accumulation of a shared P-gp and ABCG2 substrate is not noticeably affected by single P-gp deficiency, whereas Abcg2 plays a leading role in restricting the entry into the brain.…”

Section: Discussionmentioning

confidence: 49%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

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166

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Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2 −/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2 −/− mice. Moreover, when wildtype mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2 −/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26. ©2010 AACR.

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Section: Discussionmentioning

confidence: 49%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

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166

123

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“…These technical issues readily explain why the interactions between clinically useful PET radiotracers and human P-gp are poorly documented. BCRP was discovered more recently, and its impact at the human BBB remains to be assessed (13).…”

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confidence: 99%

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Tournier¹,

Valette²,

Peyronneau³

et al. 2011

J Nucl Med

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Radiolabeled compounds used for brain imaging with PET must readily cross the blood-brain barrier (BBB) to reach their target. Efflux transporters at the BBB-P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP)-could limit their uptake by the brain. The assays were performed using the nonradioactive form of each compound (ultraviolet high-performance liquid chromatography analysis) and, when available, the 18 F-labeled analogs (g-counting). Results: Befloxatone appeared to be transported solely by BCRP. Loperamide, verapamil, and diprenorphine were the only P-gp substrates. Other ligands were transported by neither P-gp nor BCRP. Conclusion: The present method can readily be used to screen new-compound transport by Pgp or BCRP, even before any radiolabeling. Compounds that were previously thought to be transported by P-gp in rodents, such as p-MPPF, WAY-100635, and flumazenil, cannot be considered substrates of human P-gp. The impact of BCRP and P-gp at the BBB on the transport of befloxatone and diprenorphine in vivo remains to be evaluated with PET.

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“…Second, Abcg2 loss may lead to increased intracellular accumulation of Abcg2 substrates, porphyrins [42][43][44][45] and glutathione [46], in turn, altering the stem cell redox state [47] and leading to activation of the stem cell niche [48,49]. The cellular redox status is crucial to the balance between stem/progenitor self-renewal and differentiation in various tissues [50].…”

Section: Discussionmentioning

confidence: 99%

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

Samant

Jackson

Felix

et al. 2015

Stem Cells and Development

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Multi-drug resistance (MDR)-ATP binding cassette (ABC) transporters, ABCB1, ABCC1, and ABCG2 participate in the efflux of steroid hormones, estrogens, and androgens, which regulate prostate development and differentiation. The role of MDR-ABC efflux transporters in prostate epithelial proliferation and differentiation remains unclear. We hypothesized that MDR-ABC transporters regulate prostate differentiation and epithelium regeneration. Prostate epithelial differentiation was studied using histology, sphere formation assay, and prostate regeneration induced by cycles of repeated androgen withdrawal and replacement. Embryonic deletion of Abcg2 resulted in a decreased number of luminal cells in the prostate and increased sphere formation efficiency, indicating an imbalance in the prostate epithelial differentiation pattern. Decreased luminal cell number in the Abcg2 null prostate implies reduced differentiation. Enhanced sphere formation efficiency in Abcg2 null prostate cells implies activation of the stem/progenitor cells. Prostate regeneration was associated with profound activation of the stem/progenitor cells, indicating the role of Abcg2 in maintaining stem/progenitor cell pool. Since embryonic deletion of Abcg2 may result in compensation by other ABC transporters, pharmacological inhibition of MDR-ABC efflux was performed. Pharmacological inhibition of MDR-ABC efflux enhanced prostate epithelial differentiation in sphere culture and during prostate regeneration. In conclusion, Abcg2 deletion leads to activation of the stem/progenitor cells and enhances differentiating divisions; and pharmacological inhibition of MDR-ABC efflux leads to epithelial differentiation. Our study demonstrates for the first time that MDR-ABC efflux transporter inhibition results in enhanced prostate epithelial cell differentiation.

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Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice

Cited by 208 publications

References 64 publications

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

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