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1. PLoS One. 2012;7(2):e30697. Epub 2012 Feb 15.

Effects of α-Adrenoceptor Antagonists on ABCG2/BCRP-Mediated Resistance and
Transport.

Takara K, Yamamoto K, Matsubara M, Minegaki T, Takahashi M, Yokoyama T, Okumura
K.

Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji
Dokkyo University, Himeji, Japan.

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.

PMID: 22355323 [PubMed - in process]