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Published on: August 25, 2023
Xanthines down-regulate the drug transporter ABCG2 and reverse multidrug resistance
Rui Ding1, Jia Shi, Kirk Pabon
1Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
Molecular Pharmacology
|November 25, 2011
Summary
Certain xanthines like caffeine reduce ABCG2 protein, a key factor in multidrug resistance. This finding suggests xanthines could enhance chemotherapy effectiveness against cancer by improving drug retention and increasing cell death.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Biology
Background:
- ABCG2 (ATP-binding-cassette transporter) contributes to multidrug resistance (MDR) in cancer by exporting chemotherapeutics.
- Down-regulating ABCG2 is a strategy to overcome treatment failure in cancer therapy.
Purpose of the Study:
- To investigate the effect of xanthines on ABCG2 expression and function.
- To explore the potential of xanthines as adjuncts in cancer therapy.
Main Methods:
- Treatment of cell lines (BeWo, MCF-7/MX100) with xanthines (caffeine, theophylline, dyphylline).
- Analysis of ABCG2 protein levels, internalization, and degradation pathways (lysosomal inhibitors).
- Assessment of ABCG2 substrate retention and chemosensitization to mitoxantrone (MX).
Main Results:
- Xanthines significantly decreased ABCG2 protein in a time- and dose-dependent manner.
- Xanthines induced ABCG2 internalization and lysosome-mediated degradation.
- Caffeine increased mitoxantrone retention and sensitized multidrug-resistant cells, reducing IC(50) tenfold and enhancing apoptosis.
Conclusions:
- Xanthines represent a novel class of compounds that can down-regulate ABCG2.
- Xanthines show potential for combination therapy to improve efficacy of ABCG2 substrate anticancer drugs.
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