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In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center




  • HM Sim
  • CP Wu
  • SV Ambudkar
  • ML Go


Introduction: Over-expression of ABCG2 is linked to multidrug resistance in cancer cells. Previously, we showed that functionalized aurones effectively reduced the efflux of pheophorbide A from ABCG2 over-expressing MDA-MB-231/R (“R”) cells. In the present study, we investigated the functional relevance of this observation and the mechanisms by which it occurs. Methods: Aurones and related analogs were investigated for re-sensitization of R cells to mitoxantrone (MX, a chemotherapeutic ABCG2 substrate) in cell-based assays, accumulation of intracellular MX by flow cytometry, interaction with ABCG2 by biochemical assays and in vivo efficacy in MX resistant nude mice xenografts. Results: Methoxylated aurones were found to interact directly with ABCG2 to inhibit the transport function. The present evidence suggests that they are not transported by ABCG2 although they stimulate ATPase activity, and compete for drug-substrate binding to the transporter. Alteration of ABCG2 protein expression was also discounted. One member was found to re-sensitize R cells to MX in both in vitro and in vivo settings. Conclusion: Our study identified methoxylated aurones as promising compounds associated with low toxicities and potent modulatory effects on ABCG2. Thus, they warrant further scrutiny as lead templates for development as reversal agents to increase efficiency of chemotherapy for cancer patients.

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