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
Files
(Published version)
Date
2021
Authors
Petersen, M.J.
Lund, X.L.
Semple, S.J.
Buirchell, B.
Franzyk, H.
Gajhede, M.
Kongstad, K.T.
Stenvang, J.
Staerk, D.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Biomolecules, 2021; 11(10, article no. 1534):1-19
Statement of Responsibility
Conference Name
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 (HT29ₚₐᵣ) as well as BCRP-overexpressing HT29 colon cancer cells resistant to the chemotherapeutic SN-38 (i.e., HT29ₛₙ₃₈ cells).
This identified a fraction, eluted with 40% acetonitrile on a solid-phase extraction column, which showed weak growth-inhibitory activity on HT29ₛₙ₃₈ 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright 2021 The authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)