Enhanced reversal of ABCG2‐mediated drug resistance by replacing a phenyl ring in baicalein with a meta‐carborane

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5‐year survival rate of human patients. Co‐tr...

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Bibliographic Details
Published in:	Molecular oncology Vol. 18; no. 2; pp. 280 - 290
Main Authors:	Kuhnert, Lydia, Kuhnert, Robert, Sárosi, Menyhárt B., Lakoma, Cathleen, Scholz, Birte K., Lönnecke, Peter, Hey‐Hawkins, Evamarie, Honscha, Walther
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-02-2024 John Wiley and Sons Inc Wiley
Subjects:	ABC transporters ABCG2 Affinity Antineoplastic Agents - pharmacology Antineoplastic drugs ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism baicalein Boron Breast Cancer breast cancer resistance protein/BCRP Cancer Cancer Therapies carborane Chemoresistance Chemotherapy Cytotoxicity Drug resistance Drug resistance in microorganisms Drug Resistance, Neoplasm Drug therapy Ethylenediaminetetraacetic acid Flavanones Humans Kinases Ligands Mitoxantrone Mitoxantrone - pharmacology Multidrug resistance Neoplasm Proteins - metabolism Physiological aspects Proteins Scientific equipment and supplies industry Short Report United States Germany Lithuania United States > US Berlin Germany Switzerland baicalein breast cancer resistance protein/BCRP drug resistance carborane ABCG2
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Summary:	Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5‐year survival rate of human patients. Co‐treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron‐based clusters as meta‐carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta‐carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2‐mediated efflux and caused a fivefold increase in mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7‐trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 μm without reversing mitoxantrone resistance, its carborane analogue 5,6,7‐trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 μm) and caused a stronger increase in mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta‐carborane and three methoxy substituents leads to an enhanced reversal of ABCG2‐mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors. Multidrug resistance mediated by the breast cancer resistance protein (BCRP, ABCG2) is challenging in cancer therapy. Therefore, combined use of ABCG2 inhibitors with anticancer agents seems to be useful to overcome drug resistance. Based on baicalein, used in traditional Chinese medicine, we replaced a phenyl group by boran‐based cluster (meta‐carborane) to enhance ABCG2 inhibition and successfully reversed mitoxantrone resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.13527