scholarly journals Arginine482 to threonine mutation in the breast cancer resistance protein ABCG2 inhibits rhodamine 123 transport while increasing binding

2004 ◽  
Vol 382 (2) ◽  
pp. 711-716 ◽  
Author(s):  
Omar ALQAWI ◽  
Susan BATES ◽  
Elias GEORGES
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Significant Inhibition ◽  
Carcinoma Cells ◽  
Rhodamine 123 ◽  
Cancer Resistance ◽  
Wild Type ◽  
Direct Binding ◽  
Resistance Protein ◽  
Mcf 7

ABCG2 [also known as BCRP (breast cancer resistance protein) or MXR] is an ABC (ATP-binding cassette) protein shown to confer multidrug resistance. ABCG2 was initially identified in resistant breast carcinoma cells (MCF-7/AdrVp1000) selected with doxorubicin and verapamil. Later studies demonstrated the presence of a point mutation (Arg482 to Thr) in ABCG2 in MCF-7/AdrVp1000 cells. This mutation was shown to modulate the transport of Rh123 (rhodamine 123). In the present study, we have used a previously characterized photoreactive drug analogue of Rh123, IAARh123 (iodoaryl-azido-Rh123), to examine the effects of the Arg482→Thr mutation on Rh123 binding and transport by ABCG2. Our results show that both wild-type (ABCG2R482) and mutant (ABCG2T482) ABCG2 bound directly to IAARh123. Surprisingly, however, wild-type ABCG2R482, which does not transport Rh123, was more intensely photolabelled than mutant ABCG2T482. In addition, inhibition of IAARh123 photolabelling using various drug substrates of ABCG2 revealed some differences between wild-type and mutant ABCG2. For example, a molar excess of mitoxantrone was more effective at inhibiting IAARh123 labelling of wild-type than of mutant ABCG2, while excess cisplatin, taxol and methotrexate showed significant inhibition of IAARh123 binding to both wild-type and mutant ABCG2. Taken together, the results of this study provide the first demonstration of the direct binding of drugs to ABCG2.

Transcriptional suppression of breast cancer resistance protein (BCRP) by wild-type p53 through the NF-κB pathway in MCF-7 cells

FEBS Letters ◽  
2010 ◽  
Vol 584 (15) ◽  
pp. 3392-3397 ◽  
Author(s):  
Xuedong Wang ◽  
Xingang Wu ◽  
Chengkun Wang ◽  
Weijia Zhang ◽  
Yongmei Ouyang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Wild Type ◽  
Transcriptional Suppression ◽  
Resistance Protein ◽  
Wild Type P53 ◽  
Mcf 7

Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide

2020 ◽  
Vol 21 (13) ◽  
pp. 1060-1067
Author(s):  
Xiaocui Li ◽  
Yushan Xie ◽  
Wei Qu ◽  
Xiaojun Ou ◽  
Xiaowen Ou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Breast Cancer Resistance Protein ◽  
Gene Knockout ◽  
Multidrug Resistance Protein ◽  
Cancer Resistance ◽  
Wild Type ◽  
Multidrug Resistance Protein 2 ◽  
Intestinal Microsomes ◽  
Resistance Protein

Background: Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) vivo. Objective: To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G. Methods: The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined. Results: After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05). Conclusion: Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.

Transcriptional Upregulation of Breast Cancer Resistance Protein by 17β-Estradiol in ERα-Positive MCF-7 Breast Cancer Cells

Oncology ◽  
2006 ◽  
Vol 71 (5-6) ◽  
pp. 446-455 ◽  
Author(s):  
Yuhua Zhang ◽  
Gengyin Zhou ◽  
Huaiping Wang ◽  
Xiaofang Zhang ◽  
Fulan Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
17Β Estradiol ◽  
Resistance Protein ◽  
Mcf 7

scholarly journals Kurkumin Meningkatkan Sensitivitas Sel Kanker Payudara terhadap Tamoksifen Melalui Penghambatan Ekspresi P-glikoprotein dan Breast Cancer Resistance Protein

2018 ◽  
Vol 4 (1) ◽  
pp. 1-11
Author(s):  
Erlia Anggrainy Sianipar ◽  
Melva Louisa ◽  
Septelia Inawati Wanandi
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cell Viability ◽  
Mrna Expression ◽  
Breast Cancer Resistance Protein ◽  
Cancer Cell Line ◽  
Cancer Resistance ◽  
Long Term Treatment ◽  
Resistance Protein ◽  
Mcf 7

The decreasing of sensitivity or resistance to tamoxifen occured after long-term treatment in breast cancer. One of the major factor in tamoxifen resistance is over expression of efflux transporter P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Curcumin has known as inhibitor of P-gp and BCRP. The addition of curcumin to the tamoxifen resistant cells is expected to increase the sensitivity of breast cancer cells to tamoxifen. This study aim to know the effect of curcumin in increasing the cell sensitivity to tamoxifen through inhibition of P-gp and BCRP transporter efflux. MCF-7 breast cancer cell line was induced with tamoxifen 1 µM for 10 passage (MCF-7(T)), then cell viability and mRNA expression of P-gp and BCRP were analyzed. To the MCF-7(T) cells, curcumin was given at of 5/10/20 µM with or without tamoxifen for 5 days and cell viability and mRNA expression of P-gp and BCRP were analyzed on day 5th.  As positive control, verapamil 50 µM was used as P-gp inhibitor, ritonavir 15 µM and nelfinavir 15 µM were used as BCRP inhibitor.  The results showed that MCF-7(T) cells sensitivity to tamoxifen decreased with 11.8 times, the cell viability increased 10.82 fold and mRNA expression of P-gp and BCRP increased 4.04 fold. Then after administration of curcumin with or without tamoxifen for 5 days, the cell viability and the mRNA expression of P-gp and BCRP decreased. As conclusion, curcumin increased the sensitivity of MCF-7(T) to tamoxifen characterized by the decreasing of cell viability and mRNA expression of P-gp and BCRP. However, the administration of combination of curcumin with tamoxifen was more potent than just curcumin. The increased sensitivity was estimated at least partly through the inhibition of P-gp and BCRP mRNA expression by curcumin

scholarly journals A Novel PET Protocol for Visualization of Breast Cancer Resistance Protein Function at the Blood–Brain Barrier

2012 ◽  
Vol 32 (11) ◽  
pp. 2002-2011 ◽  
Author(s):  
Thomas Wanek ◽  
Claudia Kuntner ◽  
Jens P Bankstahl ◽  
Severin Mairinger ◽  
Marion Bankstahl ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Blood Brain Barrier ◽  
Breast Cancer Resistance Protein ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Brain Distribution ◽  
Cancer Resistance ◽  
Wild Type ◽  
Blood Brain ◽  
Resistance Protein

Breast cancer resistance protein (BCRP) is the most abundant multidrug efflux transporter at the human blood–brain barrier (BBB), restricting brain distribution of various drugs. In this study, we developed a positron emission tomography (PET) protocol to visualize Bcrp function at the murine BBB, based on the dual P-glycoprotein (P-gp)/Bcrp substrate radiotracer [11C]tariquidar in combination with the Bcrp inhibitor Ko143. To eliminate the contribution of P-gp efflux to [11C]tariquidar brain distribution, we studied mice in which P-gp was genetically knocked out ( Mdri1a/b(−/−) mice) or chemically knocked out by pretreatment with cold tariquidar. We found that [11C]tariquidar brain uptake increased dose dependency after administration of escalating doses of Ko143, both in Mdr1a/b(−/−) mice and in tariquidar pretreated wild-type mice. After 15 mg/kg Ko143, the maximum increase in [11C]tariquidar brain uptake relative to baseline scans was 6.3-fold in Mdr1a/bf(−/−) mice with a half-maximum effect dose of 4.98 mg/kg and 3.6-fold in tariquidar (8 mg/kg) pretreated wild-type mice, suggesting that the presented protocol is sensitive to visualize a range of different functional Bcrp activities at the murine BBB. We expect that this protocol can be translated to the clinic, because tariquidar can be safely administered to humans at doses that completely inhibit cerebral P-gp.

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