Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1-and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study
Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1-and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study
复制标题
薏苡仁提取物通过调节 ABCB1 和 ABCG2 介导的药物流出增强吉西他滨的抗胰腺癌功效：生物发光药代动力学和药效学研究
DOI：
10.3390/ijms20215250
复制
发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Gu, Mancang
中科院分区：
文献类型：
--
作者：
Qian, Yifan;Xiong, Yang;Gu, Mancang
深入了解ATP结合盒（ABC）转运蛋白的功能和动力学可能有助于开发能够最大限度地减少化学抗性的特定方面的药物。我们利用生物发光成像监测ABC转运蛋白介导的细胞内药物外排功能。我们还研究了薏苡仁提取物和吉西他滨在体外和体内对胰腺癌细胞的细胞内生物发光药代动力学特征与抗肿瘤功效之间的潜在关联。测定生物发光药代动力学参数和药效学指数（IC_（50）和TGI）。评估ABCB 1和ABCG 2的表达水平。结果表明，薏苡仁提取物能协同增强吉西他滨的抗肿瘤作用（p < 0.05）。薏苡仁提取物单用或与吉西他滨合用均能显著增加AUC（luc），降低K-luc（p < 0.01）。Western blot和免疫组化结果表明，薏苡仁提取物能显著抑制吉西他滨诱导的ABCB 1和ABCG 2蛋白表达上调。Pearson相关性分析表明，生物发光药动学参数与药效学指标在体内外均具有较强的相关性。结论：薏仁提取物可以增强吉西他滨治疗胰腺癌细胞的疗效，这可能至少部分是由于ABC转运蛋白介导的药物外排功能的改变。
A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We also investigated the potential association between the intracellular bioluminescent pharmacokinetic profiles and the anti-tumor efficacy of the coix seed extract and gemcitabine against pancreatic cancer cells in vitro and in vivo. The bioluminescent pharmacokinetic parameters and pharmacodynamic index (IC50 and TGI) were determined. The expression levels ABCB1 and ABCG2 were assessed. Results showed that coix seed extract could synergistically enhance the anti-cancer efficacy of gemcitabine (p < 0.05). Meanwhile coix seed extract alone or in combination with gemcitabine could significantly increase the AUC(luc) while decreasing the K-luc (p < 0.01). Western blot and immunohistochemistry assay demonstrated that coix seed extract could significantly mitigate gemcitabine-induced upregulation of ABCB1 and ABCG2 protein. The Pearson correlation analysis demonstrated that the bioluminescent pharmacokinetic parameters and pharmacodynamic index have strong association in vitro and in vivo. In conclusion coix seed extract could augment the efficacy of gemcitabine therapy in pancreatic cancer cells may at least partly due to the alteration of ABC transporter-mediated drug efflux function.