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Effects of α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport
Kohji Takara1, Kazuhiro Yamamoto, Mika Matsubara
1Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan. takara@gm.himeji-du.ac.jp
Abstract:
Acquired resistance of cancer cells to various chemotherapeutic agents is known as multidrug resistance, and remains a critical factor in the success of cancer treatment. It is necessary to develop the inhibitors for multidrug resistance. The aim of this study was to examine the effects of eight α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport. Previously established HeLa/SN100 cells, which overexpress ABCG2/BCRP but not ABCB1/MDR1, were used. The effects of the antagonists on sensitivity to mitoxantrone and the transport activity of Hoehst33342, both substrates for ABCG2/BCRP, were evaluated using the WST-1 assay and cellular kinetics, respectively. ABCG2/BCRP mRNA expression and the cell cycle were also examined by real-time RT-PCR and flow cytometry, respectively. Sensitivity to mitoxantrone was reversed by the α-adrenoceptor antagonists in a concentration-dependent manner, although such effects were also found in the parental HeLa cells. Levels of ABCG2/BCRP mRNA expression were not influenced by the antagonists. The transport activity of Hoechst33342 was decreased by doxazosin and prazosin, but unaffected by the other antagonists. In addition, doxazosin and prazosin increased the proportion of S phase cells in the cultures treated with mitoxantrone, whereas the other α-adrenoceptor antagonists increased the percentage of cells in G(2)/M phase. These findings suggested that doxazosin and prazosin reversed resistance mainly by inhibiting ABCG2/BCRP-mediated transport, but the others affected sensitivity to mitoxantrone via a different mechanism.
Insights
Eight alpha-adrenoceptor antagonists were tested against cancer multidrug resistance. Doxazosin and prazosin inhibited ABCG2/BCRP transport, reversing resistance, while others acted via different mechanisms.
Area of Science:
- Pharmacology
- Cancer Biology
- Molecular Biology
Background:
- Multidrug resistance (MDR) in cancer is a major treatment obstacle.
- Developing MDR inhibitors is crucial for effective cancer therapy.
- ABCG2/BCRP is a key transporter involved in MDR.
Purpose of the Study:
- To investigate the effects of eight alpha-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport.
- To evaluate the potential of these antagonists as MDR inhibitors.
Main Methods:
- Utilized HeLa/SN100 cells overexpressing ABCG2/BCRP.
- Assessed sensitivity to mitoxantrone using WST-1 assay.
- Measured Hoechst33342 transport and ABCG2/BCRP mRNA expression.
- Analyzed cell cycle progression via flow cytometry.
Main Results:
- Alpha-adrenoceptor antagonists reversed mitoxantrone resistance in a dose-dependent manner.
- Doxazosin and prazosin inhibited ABCG2/BCRP-mediated transport of Hoechst33342.
- Other antagonists affected mitoxantrone sensitivity through alternative mechanisms.
- Antagonists did not alter ABCG2/BCRP mRNA expression levels.
Conclusions:
- Doxazosin and prazosin show potential as ABCG2/BCRP inhibitors to overcome multidrug resistance.
- Different alpha-adrenoceptor antagonists may employ distinct mechanisms to affect cancer cell sensitivity.
- Further research is warranted to explore the therapeutic applications of these compounds.
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