Department of Medical Biology, Faculty of Medicine, Sakarya University, Sakarya, Turkey.
Department of Medical Biology, Faculty of Medicine, Uludag University, Bursa, Turkey.
J Cell Physiol. 2020 Sep;235(9):6230-6245. doi: 10.1002/jcp.29552. Epub 2020 Feb 3.
Herein, we investigated efflux pumps-mediated talazoparib-resistance in the treatment of triple-negative breast cancer (TNBC). Furthermore, we produced a novel talazoparib-solid lipid nanoparticles (SLNs) and then explored in vitro therapeutic efficacy of talazoparib-SLNs to overcome talazoparib-resistance in TNBC cells. Talazoparib-SLNs formulation was produced and then characterized. Calcein and Rho-123 were used to analyze the functional activity of drug efflux pumps in these cells. Additionally, RT-PCR, western blot and immunofluorescence analysis were used to detect the messenger RNA, and protein expression level, and cellular localization of the multidrug resistance (MDR1), breast cancer resistance protein (BCRP), and MRP1. We found that talazoparib efflux was mediated by BCRP and MRP1 pumps in TNBC cells. Talazoparib-SLNs could significantly enhance therapeutic efficacy of talazoparib. Furthermore, talazoparib-SLNs were more effective in the suppression of MDR1, BCRP, and MRP1 gene and protein expression levels than talazoparib. Consequently, this study suggests that talazoparib-SLNs formulation represents a promising therapeutic carrier to reverse MDR-mediated resistance in TNBC.
在这里，我们研究了外排泵介导的他拉唑帕尼耐药性在三阴性乳腺癌（TNBC）治疗中的作用。此外，我们制备了一种新型他拉唑帕尼固体脂质纳米粒（SLNs），然后探讨了他拉唑帕尼-SLNs 在体外治疗 TNBC 细胞中克服他拉唑帕尼耐药性的疗效。制备了他拉唑帕尼-SLNs 制剂，并对其进行了表征。使用钙黄绿素和 Rho-123 分析这些细胞中药物外排泵的功能活性。此外，通过 RT-PCR、western blot 和免疫荧光分析检测多药耐药基因 1（MDR1）、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白 1（MRP1）的信使 RNA 和蛋白表达水平及细胞定位。结果发现，他拉唑帕尼在 TNBC 细胞中通过 BCRP 和 MRP1 泵外排。他拉唑帕尼-SLNs 可显著增强他拉唑帕尼的治疗效果。此外，他拉唑帕尼-SLNs 在抑制 MDR1、BCRP 和 MRP1 基因和蛋白表达水平方面比他拉唑帕尼更有效。因此，本研究表明他拉唑帕尼-SLNs 制剂是一种有前途的治疗载体，可逆转 TNBC 中 MDR 介导的耐药性。
