Document Type
Article
Publication Date
12-2018
Abstract
Efflux transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) can affect the efficacy and toxicity of a wide variety of drugs and are implicated in multidrug resistance (MDR). Eight test compounds, recently identified from an intramolecular FRET-based high throughput screening, were characterized for their interaction with MRP1. We report that the active metabolite of vitamin D3, calcitriol, and its analog calcipotriol are selectively cytotoxic to MRP1-overexpressing cells, besides inhibiting transport function of P-gp, MRP1, and BCRP. Calcitriol and calcipotriol consistently displayed a potent inhibitory activity on MRP1-mediated doxorubicin and calcein efflux in MRP1-overexpressing H69AR and HEK293/MRP1 cells. Vesicular transport studies confirmed a strong inhibitory effect of calcitriol and calcipotriol on MRP1-mediated uptake of tritiumlabeled estradiol glucuronide and leukotriene C4. In cytotoxicity assays, MRP1-overexpressing cells exhibited hypersensitivity toward calcitriol and calcipotriol. Such collateral sensitivity, however, was not observed in HEK293/P-gp and HEK293/BCRP cells, although the vitamin D3 analogs inhibited calcein efflux in P-gp-overexpressing cells, and mitoxantrone efflux in BCRP-overexpressing cells. The selective cytotoxicity of calcitriol and calpotriol toward MRP1 over-expressing cells can be eliminated with MRP1 inhibitor MK571. Our data indicate a potential role of calcitriol and its analogs in targeting malignancies in which MRP1 expression is prominent and contributes to MDR.
Publication Title
Drug Metabolism and Disposition
Volume
46
Issue
12
First Page
1856
Last Page
1866
Format
application/pdf
Language
en
DOI of Published Version
10.1124/dmd.118.081612
Publisher
ASPET
Rights
Copyright © 2018 the Author(s)
Recommended Citation
Tan, Kee W.; Sampson, Angelina; Osa-Andrews, Bremansu; and Iram, Surtaj H., "Calcitriol and Calcipotriol Modulate Transport Activity of ABC Transporters and Exhibit Selective Cytotoxicity in MRP1-overexpressing Cells" (2018). Chemistry and Biochemistry Faculty Publications. 33.
https://openprairie.sdstate.edu/chem_pubs/33
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.