Decreased expression of breast cancer resistance protein in the duodenum in patients with obstructive cholestasis

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel

Drug Interaction Study Of Apixaban With Cyclosporine Or Tacrolimus: Results From A Phase 1, Randomized, Open-Label, Crossover Study In Healthy Volunteers

BACKGROUND Solid organ transplant recipients commonly require anticoagulation. Apixaban (APX) is principally metabolized by CYP3A4, undergoes direct intestinal excretion, and is a substrate to P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) transporters. We examined the potential drug interaction between cyclosporine (CsA) and tacrolimus (Tac) [combined inhibitors of CYP3A4, P-gp and, BCRP] with APX.https://jdc.jefferson.edu/petposters/1005/thumbnail.jp

Reporte de Inflación

Resumen del escenario actual y proyecciones de las variables macroeconómicas contenidas en el Reporte de Inflación de setiembre 2008.

DESIGN, SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF QUINAZOLINAMINE DERIVATIVES AS BCRP AND P-GP INHIBITORS WITH IMPROVED METABOLIC STABILITY

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on BCRP and P-gp was synthesized. The reversal study showed that when combined with the potent dual BCRP and P-gp inhibitors 7-8, 29-31, and 34, the IC50 value of mitoxantrone was decreased from 6.50 µM to the range of 0.24 - 0.35 µM for BCRP, and IC50 value of colchicine was decreased from 7.34 μM to the range of 0.12 - 0.29 µM for P-gp. Cyclopropyl quinazolinamine 29 (VKCY-1), which was a dual BCRP and P-gp inhibitor, and azide quinazolinamine 40 (VKCY-2), which was a BCRP inhibitor, were selected for mechanistic studies. The results revealed that target compound 29 (VKCY-1) changed the localization of BCRP in H460/MX20 cells and P-gp in KB-C2 cells rather than altering the expression level of BCRP or P-gp proteins, thus inhibiting the efflux of the anticancer drugs, which is different from the mechanisms of other reported ABC transporter inhibitors. Azide quinazolinamine 40 (VKCY-2), on the other hand, did not change the expression level or the localization of BCRP protein. In addition, compounds 29 (VKCY-1) and 40 (VKCY-2) significantly stimulated the ATP hydrolysis of BCRP transporter indicating that they can be competitive substrates of BCRP transporter, and thereby significantly increasing the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide quinazolinamine 40 (VKCY-2) with photoaffinity label can be a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. After activation by the UV light, azide quinazolinamine 40 (VKCY-2) showed greater inhibitory effect on BCRP. Overall, this study indicated that quinazolinamine analogues can significantly reverse both BCRP- and P-gp-mediated MDR by blocking the efflux of anticancer drugs. Target compounds have the potential to be useful as BCRP and P-gp modulators to overcome MDR. The target quinazolinamine derivatives 7-8, 29-32, and 34 exhibited potency similar to that of the known BCRP inhibitor, Ko143. In addition, the P-gp inhibitory activities of quinazolinamine derivatives 7-8, 29-31, and 34 were greater than that of verapamil. Notably, the selected dual BCRP and P-gp inhibitors 7-8, 29-31, 34, and 40 showed improved metabolic stability than the standard pharmacologic tool Ko143

Breast cancer resistance protein (BCRP) gene expression in a cohort of adult Egyptian patients with acute myeloid leukemia

Background: Acute myeloid leukemia (AML), an aggressive clonal disease, is genetically heterozygous. The prognostic role of expression of Breast Cancer Resistance Protein (BCRP) gene, which behaves as a multidrug transporter, in adult AML is ambiguous. Objective: The objective is to assess the level of mRNA expression of BCRP gene in newly diagnosed cytogenetically normal adult Egyptian AML patients; and to clarify its potential influence and association between therapeutic responsiveness and disease free survival.Methods: The BCRP gene expression was evaluated by quantifying its mRNA using real time RT-PCR in fifty newly diagnosed cytogenetically normal adult AML patients and 20 healthy normal controls. The expression was evaluated in relation to clinical and prognostic factors, response to treatment and the survival rate. Results: BCRP mRNA was over expressed in adult AML patients compared to controls. This study showed a positive statistical correlation between BCRP gene expression and the percent of CD34 expression. Statistical analysis did not reveal  any association between BCRP expression level and chemotherapeutic responsiveness or disease free survival rate. Conclusion: The significance of BCRP gene expression and its function in AML is very complicated, therefore more standardized clinical studies are needed.Keywords: BCRP, adult AML, gene expression, prognosis, Egypt

A model of secreting murine mammary epithelial HC11 cells comprising endogenous Bcrp/Abcg2 expression and function

Breast cancer resistance protein (Bcrp/Abcg2) and multidrug transporter 1 (Mdr1/Abcb1) are efflux proteins located in the apical membrane of mammary epithelial cells (MEC). Bcrp is induced in MEC during gestation and lactation, while Mdr1 is down-regulated during lactation. Numerous drugs and toxic compounds are known to be actively secreted into milk by Bcrp, but most chemicals have not been investigated in this respect, emphasizing the need for functional Bcrp studies in an established cell line with secreting mammary epithelial cells. The present study was undertaken to examine expressions of Bcrp and Mdr1 in mammary epithelial HC11 cells, derived from a mid-gestational murine mammary gland. In addition, Bcrp function was assessed by transport experiments with mitoxantrone (MX) in undifferentiated HC11 cells, in HC11 cells subjected to Bcrp RNA interference (RNAi) as well as in HC11 cells stimulated to differentiate by treatment with lactogenic hormones. Differentiated HC11 cells organized into alveolar-resembling structures and gene expression of the major milk protein B-casein was induced, whereas undifferentiated cells formed monolayers with lower B-casein expression. Bcrp and Mdr1 gene and protein were expressed in both undifferentiated and differentiated HC11 cells. Differentiation of HC11 cells resulted in increased Bcrp protein expression, while Mdr1 gene and protein expressions were reduced. The Bcrp inhibitor elacridar (GF120918) reduced secretion and increased accumulation of MX in both undifferentiated and differentiated HC11 cells. Silencing of the Bcrp gene caused an increased accumulation of MX. The results indicate that the HC11 cell model provides a promising tool to investigate transport of potential Bcrp substrates in mammary epithelial cells

Kurkumin Meningkatkan Sensitivitas Sel Kanker Payudara Terhadap Tamoksifen Melalui Penghambatan Ekspresi P-glikoprotein Dan Breast Cancer Resistance Protein: Curcumin Increased Breast Cancer Cells Sensitivity to Tamoxifen Through Inhibition of P-glycoprotein and Breast Cancer Resistance Protein Expressions

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 curcumi

Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier:an in-vitro study

Clinical translation of BCRP inhibitors have failed due to neurotoxicity and novel approaches are required to identify suitable modulators of BCRP to enhance CNS drug delivery. In this study we examine 18 compounds, primarily phytochemicals, as potential novel modulators of AhR-mediated regulation of BCRP expression and function in immortalised and primary porcine brain microvascular endothelial cells as a mechanism to enhance CNS drug delivery. The majority of modulators possessed a cellular viability IC50 > 100 µM in both cell systems. BCRP activity, when exposed to modulators for 1 hour, was diminished for most modulators through significant increases in H33342 accumulation at < 10 µM with 2,6,4-trimethoflavone increasing H33342 intracellular accumulation by 3.7–6.6 fold over 1–100 µM. Western blotting and qPCR identified two inducers of BCRP (quercetin and naringin) and two down-regulators (17-β-estradiol and curcumin) with associated changes in BCRP efflux transport function further confirmed in both cell lines. siRNA downregulation of AhR resulted in a 1.75 ± 0.08 fold change in BCRP expression, confirming the role of AhR in the regulation of BCRP. These findings establish the regulatory role AhR of in controlling BCRP expression at the BBB and confirm quercetin, naringin, 17-β-estradiol, and curcumin as novel inducers and down-regulators of BCRP gene, protein expression and functional transporter activity and hence potential novel target sites and candidates for enhancing CNS drug delivery

On-Line Portfolio Selection with Moving Average Reversion

On-line portfolio selection has attracted increasing interests in machine learning and AI communities recently. Empirical evidences show that stock's high and low prices are temporary and stock price relatives are likely to follow the mean reversion phenomenon. While the existing mean reversion strategies are shown to achieve good empirical performance on many real datasets, they often make the single-period mean reversion assumption, which is not always satisfied in some real datasets, leading to poor performance when the assumption does not hold. To overcome the limitation, this article proposes a multiple-period mean reversion, or so-called Moving Average Reversion (MAR), and a new on-line portfolio selection strategy named "On-Line Moving Average Reversion" (OLMAR), which exploits MAR by applying powerful online learning techniques. From our empirical results, we found that OLMAR can overcome the drawback of existing mean reversion algorithms and achieve significantly better results, especially on the datasets where the existing mean reversion algorithms failed. In addition to superior trading performance, OLMAR also runs extremely fast, further supporting its practical applicability to a wide range of applications.Comment: ICML201