Chemical inhibition and stable knock-down of efflux transporters leads to reduced glucuronidation of wushanicaritin in UGT1A1-overexpressing HeLa cells: the role of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in the excretion of glucuronides

2018 ◽  
Vol 9 (3) ◽  
pp. 1410-1423 ◽  
Author(s):  
Zifei Qin ◽  
Shishi Li ◽  
Zhihong Yao ◽  
Xiaodan Hong ◽  
Baojian Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Hela Cells ◽  
Breast Cancer Resistance Protein ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Associated Proteins ◽  
Resistance Protein ◽  
Chemical Inhibition

We determine the contributions of BCRP and MRP transporters in HeLa cells.

scholarly journals Folium Sennae Increased the Bioavailability of Methotrexate through Modulation on MRP 2 and BCRP

2021 ◽  
Vol 14 (10) ◽  
pp. 1036
Author(s):  
Chung-Ping Yu ◽  
Yu-Hsuan Peng ◽  
Ching-Ya Huang ◽  
Yow-Wen Hsieh ◽  
Yu-Chi Hou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Breast Cancer Resistance Protein ◽  
Systemic Exposure ◽  
Cancer Resistance ◽  
Parallel Design ◽  
Dosage Regimens ◽  
Combined Use ◽  
Associated Proteins ◽  
Resistance Protein

Folium Sennae (FS), a popular laxative (Senna), contains polyphenolic anthranoids, whose conjugation metabolites are probable modulators of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). We suspected that the combined use of FS might alter the pharmacokinetics of various medicines transported by MRPs or BCRP. This study investigated the effect of FS on the pharmacokinetics of methotrexate (MTX), an anticancer drug and a probe substrate of MRPs/BCRP. Rats were orally administered MTX alone and with two dosage regimens of FS in a parallel design. The results show that 5.0 g/kg of FS significantly increased the AUC0–2880, AUC720–2880 and MRT of MTX by 45%, 102% and 42%, and the seventh dose of 2.5 g/kg of FS significantly enhanced the AUC720–2880 and MRT by 78% and 42%, respectively. Mechanism studies indicated that the metabolites of FS (FSM) inhibited MRP 2 and BCRP. In conclusion, the combined use of FS increased the systemic exposure and MRT of MTX through inhibition on MRP 2 and BCRP.

scholarly journals Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

ADMET & DMPK ◽  
2016 ◽  
Vol 4 (4) ◽  
pp. 302
Author(s):  
Rhiannon N. Hardwick ◽  
Marina Snellings ◽  
Brian C. Ferslew ◽  
Yang Lu ◽  
Kim L.R. Browuer
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Abc Transporters ◽  
Breast Cancer Resistance Protein ◽  
Kinase Inhibitors ◽  
Efflux Transporters ◽  
Atp Binding ◽  
Cancer Resistance ◽  
Sulfate Uptake ◽  
Resistance Protein

<p class="PaperKeywordTitle">Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer agents specifically designed to target such signaling pathways through TKI/AKI binding to the ATP-binding pocket of kinases thereby leading to diminished kinase activity. Some TKIs have been identified as inhibitors of ATP-binding cassette (ABC) transporters such as P-glycoprotein and breast cancer resistance protein (BCRP), which are commonly upregulated in malignant cells. TKI/AKIs have been investigated as ABC transporter inhibitors in order to facilitate the accumulation of concomitantly administered chemo-therapeutics within cancer cells. However, ABC transporters are prominently expressed in the liver and other eliminating organs, and their inhibition has been linked to intracellular accumulation of drugs, altered disposition, and toxicity. The potential for TKIs/AKIs to inhibit other important hepatic efflux transporters, particularly multidrug resistance-associated proteins (MRPs), remains unknown. The aim of the current study was to compare the inhibitory potency of 20 selected TKI/AKIs against MRP4 and BCRP through the use of inverted membrane vesicle assays. Relative IC<sub>50 </sub>values were estimated by determining TKI/AKI inhibition of MRP4-mediated [<sup>3</sup>H]-dehydroepiandrosterone sulfate uptake and BCRP-mediated [<sup>3</sup>H]-estrone sulfate uptake. To provide insight to the clinical relevance of TKI/AKI inhibition of ABC efflux transporters, the ratio of the steady-state maximum total plasma concentration (C<sub>ss</sub>) to the IC<sub>50</sub> for each compound was calculated with C<sub>ss</sub>/IC<sub>50</sub> ratio &gt;0.1 deemed potentially clinically relevant. Such analysis identified several potentially clinically relevant inhibitors of MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib. These findings indicate the significant potential for TKI/AKIs to inhibit multiple ABC efflux transporters. The resulting inhibition data could provide insight regarding the clinical interpretation of pharmacokinetic/pharmacodynamic outcomes when TKI/AKIs are administered concomitantly with additional chemotherapeutic agents.</p>

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