Reversal effect of palbociclib on the resistance of breast cancer MCF-7 cells to doxorubicin / 肿瘤

ABSTRACT

Objective: To study the reversal effect of cyclin-dependent protein kinase 4/6 (CDK4/6) inhibitor palbociclib (PAL) on the resistance of breast cancer MCF-7/doxorubicin (DOX) cells to DOX, and to explore its mechanism from the view of drug efflux transporter ATP binding cassette protein B1 (ABCB1). Methods: The effect of PAL on the sensitivity of parental MCF-7 and resistant MCF-7/DOX cells to DOX was detected by CCK-8 method. The effect of PAL on intracellular accumulation of DOX in MCF-7 and MCF-7/DOX cells was determined by FCM analysis. The MDCK II cell model stably transfected with ABCB1 gene was constructed, then the effect of PAL on the ABCB1-mediated efflux function of DOX was detected by drug transmembrane bi-direction transport assay. The effect of PAL on the expressions of ABCB1 mRNA and protein in MCF-7 and MCF-7/DOX cells was detected by real-time fluorescent quantitative PCR and Western blotting, respectively. Results: After treatment with 0.2 and 0.4 μmol/L PAL, the half maximal inhibitory concentration (IC50) values of DOX in MCF-7/DOX cells were decreased by 39% and 51%, respectively (both P < 0.05), but the IC50 value of DOX in MCF-7 cells had no obvious change. In MCF-7/DOX cells treated with 0.4 μmol/L PAL, the intracellular accumulation of DOX was increased by 82% (P < 0.05), but the concentration of DOX in MCF-7 cells did not change. PAL significantly inhibited the ABCB1 -mediated efflux of DOX, but had no obvious regulatory effect on the expressions of ABCB1 mRNA and protein in MCF-7 cells and MCF-7/DOX cells. Conclusion: PAL can reverse DOX-resistance of breast cancer cells by inhibiting the function of drug transporter ABCB1, which suggests that coadministration of PAL and DOX maybe improve the effiocacy of DOX in breast cancer and optimize the clinical treatment.