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

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 G2/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.

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

“…1). Our results indicate that prazosin is an inducer of BCRP, although some authors reported that prazosin is a BCRP inhibitor and substrate [24][25][26][27] . The reason for this contradiction may be differences in the materials used in the studies and in the employed doses of BCRP inhibitors and substrates.…”

“…The inhibition of BCRP by prazosin may cause the activation of P-gp in the brain capillaries of mice. A compensatory relationship has been reported to exist between P-gp and BCRP, and P-gp has also been reported to be more prominent and inducible than BCRP at the BBB [33,34] Prazosin has been indicated to be only an inducer of P-gp [23][24][25][26][27] . In addition, many BCRP and P-gp substrates and modulators overlap [13,27,35] .…”

“…In addition, zosuquidar can be considered to be an inducer of P-gp or a dual P-gp/BCRP inducer in brain capillaries. Zosuquidar is described as a specific P-gp inhibitor [13,19,35] , and a number of BCRP and P-gp substrates and modulators overlap [3,27,35] .…”

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

“…One of the main MDR mechanisms involves the cellular efflux of chemotherapeutic agents mediated by the overexpression of the ATP-Binding Cassette (ABC) transporters: ABCB1/P-glycoprotein (MDR1), the ABCC/multidrug resistance protein (MRP) family, and the ABCG2/breast cancer resistance protein (BCRP) (Takara et al 2012). One of the first questions here is whether the proteins/genes of the ABC transporter are linked to the HSP response.…”

Identification of side population cells in human lung adenocarcinoma A549 cell line and elucidation of the underlying roles in lung cancer

“…Therefore, elevated ABCG2 expression may induce the efflux of these drugs from lung cancer cells and increase chemoresistance: When the efflux capacity increased, chemotherapeutic resistance within the cells occurred. Several studies investigating antagonists of ABCG2-mediated resistance and transport have confirmed that ABCG2 is a target for cancer treatment ( 31 , 32 ). Therefore, detecting ABCG2 expression may assist in predicting the chemotherapeutic outcome of patients, and serve as a useful target for curing lung cancer.…”