Reversal of ABCG2/BCRP-Mediated Multidrug Resistance by 5,3',5'-Trihydroxy-3,6,7,4'-Tetramethoxyflavone Isolated from the Australian Desert Plant Eremophila galeata Chinnock

Malene J Petersen; Xamuel L Lund; Susan J Semple; Bevan Buirchell; Henrik Franzyk; Michael Gajhede; Kenneth T Kongstad; Jan Stenvang; Dan Staerk

doi:10.3390/biom11101534

Reversal of ABCG2/BCRP-Mediated Multidrug Resistance by 5,3',5'-Trihydroxy-3,6,7,4'-Tetramethoxyflavone Isolated from the Australian Desert Plant Eremophila galeata Chinnock

Biomolecules. 2021 Oct 18;11(10):1534. doi: 10.3390/biom11101534.

Authors

Malene J Petersen¹, Xamuel L Lund^{1

2}, Susan J Semple³, Bevan Buirchell⁴, Henrik Franzyk¹, Michael Gajhede¹, Kenneth T Kongstad¹, Jan Stenvang¹, Dan Staerk¹

Affiliations

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
² Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
³ Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
⁴ Wise Owl Consulting, Como, WA 6152, Australia.

Abstract

Multidrug resistance (MDR) is a major challenge in cancer treatment, and the breast cancer resistance protein (BCRP) is an important target in the search for new MDR-reversing drugs. With the aim of discovering new potential BCRP inhibitors, the crude extract of leaves of Eremophila galeata, a plant endemic to Australia, was investigated for inhibitory activity of parental (HT29_par) as well as BCRP-overexpressing HT29 colon cancer cells resistant to the chemotherapeutic SN-38 (i.e., HT29_SN38 cells). This identified a fraction, eluted with 40% acetonitrile on a solid-phase extraction column, which showed weak growth-inhibitory activity on HT29_SN38 cells when administered alone, but exhibited concentration-dependent growth inhibition when administered in combination with SN-38. The major constituent in this fraction was isolated and found to be 5,3',5'-trihydroxy-3,6,7,4'-tetramethoxyflavone (2), which at a concentration of 25 μg/mL potentiated the growth-inhibitory activity of SN-38 to a degree comparable to that of the known BCRP inhibitor Ko143 at 1 μM. A dye accumulation experiment suggested that 2 inhibits BCRP, and docking studies showed that 2 binds to the same BCRP site as SN-38. These results indicate that 2 acts synergistically with SN-38, with 2 being a BCRP efflux pump inhibitor while SN-38 inhibits topoisomerase-1.

Keywords: Eremophila galeata; breast cancer resistance protein; docking; multidrug resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / genetics
Drug Synergism
Eremophila Plant / chemistry*
Flavonoids / chemistry
Flavonoids / isolation & purification
Flavonoids / pharmacology*
Gene Expression Regulation, Neoplastic / drug effects
HT29 Cells
Humans
Irinotecan / adverse effects
Irinotecan / pharmacology
Neoplasm Proteins / genetics*

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
Flavonoids
Neoplasm Proteins
Irinotecan