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Modulation of ABCG2-Mediated Multidrug Resistance by Xanthine Derivatives

by
Rui Ding
B.S., Nankai University- 2006


Thesis Advisor: Kathleen W. Scotto Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

Clinical Academic Building Room 3403
New Brunswick

Friday, November 16, 2012
10:00 a.m.


Abstract

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. ABCG2 is also expressed in multiple tissue protective barriers, where it restricts bioavailability of its substrate drugs. Accordingly, the downregulation 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 drug resistant cells, causing a significant increase in the intracellular retention of ABCG2 substrates and sensitization of the cells to chemotherapeutic agents. This suggests that caffeine or other xanthines could be developed as combination therapy to improve the efficacy of drugs that are ABCG2 substrates. Importantly, two xanthine-based compounds (DPCPX and SLV320) that are currently in clinical trials were able to downregulate ABCG2 at concentrations close to their therapeutic indexes, identifying them as possible candidates for further development.
We then investigated the mechanism by which xanthine derivatives downregulated ABCG2, and found that they reduced ABCG2 by selectively inducing its rapid internalization and lysosome-mediated degradation. The xanthine-mediated internalization of ABCG2 is likely due to induced endocytosis of this transporter, as caffeine treatment significantly increased ABCG2 accumulation in early endosomes, the receptacles for endocytosed vesicles. In addition, the PI3K/AKT/mTORC1 signaling was found to be involved in mediating the effect of xanthines on ABCG2, since xanthines strongly inhibited activation of AKT and mTORC1, and inhibition of both AKT and mTORC1 mimicked the effect of xanthines on ABCG2.
One known function of caffeine and other xanthines is the antagonism of adenosine receptors (ARs). We therefore, considered a role for ARs in xanthine-mediated degradation of ABCG2. Unexpectedly, caffeine did not induce ABCG2 degradation via AR-mediated signaling pathways, although adenosine, the natural agonist of ARs, completely reversed the effect of caffeine on ABCG2. Instead, we found that adenosine influx was required for its reversal effect, and intracellular accumulation of adenosine caused by adenosine kinase inhibition also blocked the downregulation of ABCG2 by caffeine. This suggests that caffeine and caffeine analogs may induce the degradation of ABCG2 through a novel mechanism can that is influenced by intracellular levels of adenosine.
A preliminary, but highly significant set of experiments has identified, a novel drug-efflux independent cytoprotective function of ABCG2 in cancer cells. Expression of ABCG2 promoted resistance of cancer cells to nutrient starvation through enhancing cellular autophagy, particularly the autophagy flux capacity. Since autophagy is shown to promote tumor growth in established cancers, methods to downregulate ABCG2 expression will be beneficial for cancer treatment, given its multidrug resistant and pro-autophagic activities.


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