Department of Pathology, School of Basic Medical Sciences, Beihua University, Jilin, P.R. China.
Eur Rev Med Pharmacol Sci. 2017 Oct;21(19):4437-4445.
Multidrug resistance (MDR) is a major cause of chemotherapy failure in the treatment of cancer patients. This study aimed to determine whether saikosaponin D (SSd) can enhance the efficacy of the anticancer drug doxorubicin (Dox) both in vitro and in vivo and whether SSd can alter Dox pharmacokinetics in the serum of mice.
MCF-7/adr cells were used to investigate the effect of SSd on reversing MDR. Cell viability was assessed by MTT assay. Pharmacokinetic tests were used to evaluate the effects of SSd on serum Dox disposition. An MCF-7/adr cell xenograft model was established to investigate the effect of SSd on reversing MDR in vivo. Tumor growth and weights were measured. Immunohistochemistry staining was used to detect the expression of P-gp (P-glycoprotein), an ATP-dependent efflux pump that mediates MDR in xenograft tumor tissues.
SSd could effectively reverse MDR in MCF-7/adr cells in vitro and had no cytotoxic effects on human amniotic epithelial cells (hAEC). There was no significant difference between the Dox pharmacokinetic parameters obtained in the mice that received Dox only and Dox combined with SSd, indicating that SSd did not alter the pharmacokinetic profiles of Dox. Furthermore, the combination of Dox and SSd had a stronger anticancer effect than Dox alone or SSd alone by inhibiting tumor growth and P-gp expression.
Our results suggest that SSd could effectively reverse MDR in vitro and in vivo and could be a potential MDR reversal agent for P-gp-mediated MDR in breast cancer therapy.
多药耐药（MDR）是癌症患者化疗失败的主要原因。本研究旨在确定柴胡皂苷 D（SSd）是否能增强抗癌药物阿霉素（Dox）在体外和体内的疗效，以及 SSd 是否能改变小鼠血清中 Dox 的药代动力学。
MCF-7/adr 细胞用于研究 SSd 对逆转 MDR 的影响。通过 MTT 法评估细胞活力。药代动力学试验用于评估 SSd 对血清 Dox 分布的影响。建立 MCF-7/adr 细胞异种移植模型，研究 SSd 对体内逆转 MDR 的影响。测量肿瘤生长和重量。免疫组织化学染色用于检测 P-糖蛋白（P-gp）的表达，P-gp 是一种 ATP 依赖性外排泵，介导异种移植肿瘤组织中的 MDR。
SSd 能有效逆转 MCF-7/adr 细胞的 MDR，对人羊膜上皮细胞（hAEC）无细胞毒性作用。仅接受 Dox 和 Dox 联合 SSd 的小鼠的 Dox 药代动力学参数无显著差异，表明 SSd 未改变 Dox 的药代动力学特征。此外，与 Dox 单药或 SSd 单药相比，Dox 联合 SSd 抑制肿瘤生长和 P-gp 表达的抗癌效果更强。
我们的研究结果表明，SSd 能有效逆转体内外 MDR，可能是乳腺癌治疗中 P-gp 介导的 MDR 的潜在 MDR 逆转剂。
