Xanthines down-regulate the drug transporter ABCG2 and reverse multidrug resistance.

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Ding R, Shi J, Pabon K, Scotto KW

Xanthines down-regulate the drug transporter ABCG2 and reverse multidrug resistance.

Mol Pharmacol. 2012 Mar;81(3):328-37. doi: 10.1124/mol.111.075556. Epub 2011 Nov 23.

PubMed ID

22113078 [ View in PubMed

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Abstract

ABCG2 is an ATP-binding-cassette (ABC) transporter that confers multidrug resistance (MDR) to tumor cells by extruding a broad variety of chemotherapeutic agents, ultimately leading to failure of cancer therapy. Thus, the down-regulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. In this study, we found that a group of xanthines including caffeine, theophylline, and dyphylline can dramatically decrease ABCG2 protein in cells that have either moderate (BeWo, a placental choriocarcinoma cell line) or high (MCF-7/MX100, a breast cancer drug-resistant cell subline) levels of ABCG2 expression. This down-regulation is time-dependent, dose-dependent, and reversible. Using lysosomal inhibitors, we found that xanthines decreased ABCG2 by inducing its rapid internalization and lysosome-mediated degradation. As a consequence, caffeine treatment significantly increased the retention of an established ABCG2 substrate in MCF-7/MX100 cells but not in parental MCF-7 cells and sensitized the MDR cells to the chemotherapeutic agent mitoxantrone (MX); combination treatment with MX and caffeine decreased the IC(50) of MX ~10-fold and induced a greater degree of apoptotic cell death than MX treatment alone. Taken together, our results describe a novel function for this large class of therapeutically relevant compounds and suggest that a subset of xanthines could be developed as combination therapy to improve the efficacy of anticancer drugs that are ABCG2 substrates.

DrugBank Data that Cites this Article

Drugs

Caffeine

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Caffeine	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details