YHO-13177 is a selective and potent inhibitor of BCRP, it potentiates the cytotoxicity of SN-38 in cancer cells and has no effect on P-glycoprotein–mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells.
Breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette (ABC) transporter superfamily that regulates drug resistance. YHO-13177 is a novel acrylonitrile derivative that has been shown to reverse BCRP-mediated drug resistance both in vitro and in vivo. In BCRP-transduced HCT116 cells, treatment with YHO-13177 at 0.01-1 μM reversed the drug resistance to BCRP substrates (SN-38, topotecan, and mitoxantrone) in a dose-dependent manner, while it showed no effect on the drug sensitivity of parental HCT116 cells expressing no BCRP. YHO-13177 at the concentrations of 0.01-1 μM also reversed the drug resistance in A549 cells with BCRP-mediated acquired resistance to SN-38. The cytotoxicity of SN-38 in cells that intrinsically express BCRP (RPMI-8226, NCI-H23, NCI-H460, and AsPC-1 cell lines) was significantly potentiated by YHO-13177 at 0.01-1 μM. Treatment with YHO-13177 (0.1 to 10 μM) significantly induced the intracellular accumulation of Hoechst 33342 in both A549/SN4 and HCT116/BCRP cells. YHO-13177 from 0.01-1 μM partially suppressed the expression of BCRP protein in both A549/SN4 and HCT116/BCRP cells without affecting the mRNA expression of BCRP. In mice inoculated with BCRP-transduced murine leukemia P388 cells, the combined treatment of irinotecan (i.v., 45 mg/kg) and YHO-13351 (p.o., 50, 100, or 200 mg/kg), a prodrug of YHO-13177, significantly enhanced the survival time of mice in a dose-dependent manner[2].
作用机制
YHO-13177 is a novel acrylonitrile derivative that reverses the drug resistance and enhances the cytotoxicity of anticancer drugs in BCRP-expressing cancer cells and xenografts by inhibiting the drug transport function and the posttranscriptional expression of BCRP.
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