Back to Search
Start Over
Calcitriol and Calcipotriol Modulate Transport Activity of ABC Transporters and Exhibit Selective Cytotoxicity in MRP1-overexpressing Cells
- Source :
- Drug Metabolism and Disposition
- Publication Year :
- 2018
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 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 tritium-labeled 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.
- Subjects :
- 0301 basic medicine
Calcitriol
Abcg2
Cell Survival
Cell Culture Techniques
Pharmaceutical Science
Antineoplastic Agents
Pharmacology
Madin Darby Canine Kidney Cells
03 medical and health sciences
chemistry.chemical_compound
Dogs
0302 clinical medicine
Multidrug Resistance Protein 1
polycyclic compounds
medicine
Animals
Humans
Cytotoxicity
Calcipotriol
biology
Cell Membrane
Biological Transport
Articles
Calcein
HEK293 Cells
030104 developmental biology
chemistry
Doxorubicin
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
ABCC1
biology.protein
ATP-Binding Cassette Transporters
Efflux
Multidrug Resistance-Associated Proteins
medicine.drug
Subjects
Details
- ISSN :
- 1521009X and 00909556
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Drug Metabolism and Disposition
- Accession number :
- edsair.doi.dedup.....a6708884f8b454eaef6e06340bf5c268