Abstract 1746: Modulation of ABCG2 mediated multidrug resistance by xanthine derivatives

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL ABCG2 is an ATP-binding-cassette (ABC) transporter that confers multidrug resistance (MDR) in tumor cells by extruding a broad variety of chemotherapeutic agents, ultimately leading to failure of cancer therapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Adenosine receptors (ARs), belong to the G-protein coupled receptor superfamily, and play important roles in stimulating neuronal cells, regulating cell proliferation and controlling immune responses. Adenosine receptor antagonists, a large collection of small molecules mainly composed of methylxanthines and other xanthine derivatives, have been used or implicated in many therapeutic applications, such as treatment of asthma, chronic bronchitis, emphysema and neural degenerative diseases. Previously, we have shown that the non-selective AR antagonist 1,3,7-methyxanthine (caffeine) can dramatically downregulate ABCG2 expression levels in cancer cell lines, increasing the intracellular retention of the ABCG2 specific substrate Mitoxantrone (MX) and markedly sensitizing cells to this chemotherapeutic agent. In order to find more potent and specific modulators of ABCG2 expression, we recently tested other ARs antagonists. Among the compounds we have examined, the non-selective antagonists theophylline, theobromine, paraxanthine, and the A2R selective antagonists 8-(3-chlorostyryl), caffeine (CSC) and 3,7-dimethyl-1-propargylxanthine (DMPX), were capable of downregulating ABCG2 protein levels to varying degrees. An A1R selective antagonist, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), currently in clinical trials, also decreased the expression of ABCG2 significantly at physiologically- relevant concentrations. In addition, the natural ligand of the ARs, adenosine, completely blocked the downregulation of ABCG2 by caffeine, suggesting that adenosine receptors and their downstream signaling pathways are involved in the regulation of ABCG2 gene expression. These findings suggest that xanthine adenosine receptor antagonists 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 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2011-1746