Hu Bi-Yuan, Gu Yun-Hao, Cao Chen-Jie, Wang Jun, Han Dong-Dong, Tang Ying-Chao, Chen Hua-Sheng, Xu Aihua
Department of Pharmacology, Medical College of Yangzhou University, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225001, P.R. China.
Exp Ther Med. 2016 Oct;12(4):2053-2062. doi: 10.3892/etm.2016.3589. Epub 2016 Aug 11.
The aim of the present study was to investigate the reversal effect and its related mechanism of exocarp extracts (GBEEs) in obtained multidrug resistance (MDR) of mice S180 tumor cells and . In order to simulate the clinical PFC [cis-dichlorodiamineplatinum, cisplatin (DDP) + fluorouracil (FU), FU+cyclophosphamide and cyclophosphamide] scheme, a gradually increasing dose was administered in a phased induction in order to induce S180 cells and to make them obtain multidrug resistance. The results demonstrated that GBEE could significantly increase the IC of DDP on S180 MDR cells, increase the accumulation of Adriamycin (ADR) and rhodamine 123 (Rho 123), and reduce the efflux of Rho 123 of S180 MDR cells. The results from the treatment with a combination of GBEE and DDP to S180 MDR ascites tumor in mice demonstrated that each dose of GBEE could effectively reverse the drug-resistance of S180 MDR cells to DDP in order to extend the survival time of mice with ascite tumors and inhibit tumor growth in solid tumor mice. In addition, GBEE effectively inhibited the expression of MDR-1 mRNA and multidrug resistance-associated protein-1 mRNA in S180 MDR cells of ascites tumor in mice and improved the expression levels of cytokines, including interleukin (IL)-3, IL-18 and interferon-γ in the blood serum of S180 MDR tumor-bearing mice. The present study showed that the mechanism of GBEE reversal of MDR may be associated with the inhibition of the functional activity of P-glycoprotein, the downregulation of drug resistance related gene expression of S180 MDR cells and the improvement of the production of related serum cytokines of S180 MDR tumor mice.
本研究旨在探讨外果皮提取物（GBEEs）对小鼠S180肿瘤细胞获得性多药耐药（MDR）的逆转作用及其相关机制。为模拟临床PFC[顺二氯二氨铂、顺铂（DDP）+氟尿嘧啶（FU）、FU+环磷酰胺和环磷酰胺]方案，采用逐步递增剂量分阶段诱导，以使S180细胞获得多药耐药。结果表明，GBEE可显著增加DDP对S180 MDR细胞的半数抑制浓度（IC），增加阿霉素（ADR）和罗丹明123（Rho 123）的蓄积，并减少S180 MDR细胞Rho 123的外排。GBEE与DDP联合处理小鼠S180 MDR腹水瘤的结果表明，各剂量的GBEE均可有效逆转S180 MDR细胞对DDP的耐药性，从而延长腹水瘤小鼠的生存时间，并抑制实体瘤小鼠肿瘤生长。此外，GBEE有效抑制小鼠腹水瘤S180 MDR细胞中MDR-1 mRNA和多药耐药相关蛋白-1 mRNA的表达，并提高S180 MDR荷瘤小鼠血清中细胞因子的表达水平，包括白细胞介素（IL）-3、IL-18和干扰素-γ。本研究表明，GBEE逆转MDR的机制可能与抑制P-糖蛋白的功能活性、下调S180 MDR细胞耐药相关基因表达以及改善S180 MDR肿瘤小鼠相关血清细胞因子的产生有关。
