Abstract 1523: Caffeine antagonizes multidrug resistance by down-regulating ABCG2

Abstract ABCG2/BCRP (Breast Cancer Resistance Protein) is an ATP-binding-cassette (ABC) transporter that has been shown to confer multidrug resistance (MDR) in cancer cells, ultimately resulting in the failure of cancer chemotherapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Caffeine and its analogs are a category of natural/synthetic and cell-permeable compounds that are used therapeutically in the treatment of occurring migraines and asthma, radiosensitization and obesity. In this study, we found that caffeine, at pharmacologically relevant concentrations, can dramatically decrease ABCG2 protein in cells that have either moderate (BeWo, a placental choriocarcimoma cell line) or high (MCF7/MX100 cells, a breast cancer drug resistant cell subline) levels of ABCG2 expression. This downregulation is time-dependent, dose-dependent, and reversible. Immunofluorescence studies revealed that caffeine treatment decreases membrane-localized ABCG2 protein and significantly increases the retentions of an established ABCG2 substrate in MCF7/MX100, but not in the parental cells, demonstrating that the caffeine-mediated downregulation of ABCG2 directly decreases drug efflux. Importantly, we found that caffeine can sensitize cells to the chemotherapeutic agent mitoxantrone (MX), where combination treatment with MX and caffeine decreased the IC50 of MX ∼10-fold and induced a greater degree of apoptotic cell death compared to MX treatment alone. Additionally, several caffeine analogs were tested and exhibited a similar ability to down-regulate ABCG2; theophylline (a metabolite of caffeine, also naturally found in tea) appeared to be the most potent. Taken together, these findings suggest that caffeine or caffeine analogs could be developed as combination therapy to improve the efficacy of drugs that are ABCG2 substrates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1523.