药学学报, 2021, 56(9): 2536-2543
引用本文:
曲晓宇, 翟婧卉, 高欢, 陶娌娜, 张月明, 巩佳威, 宋燕青*. OCT2/MRP2在黄芪甲苷联合顺铂的减毒增效作用中的机制研究[J]. 药学学报, 2021, 56(9): 2536-2543.
QU Xiao-yu, ZHAI Jing-hui, GAO Huan, TAO Li-na, ZHANG Yue-ming, GONG Jia-wei, SONG Yan-qing*. Suppression of OCT2/MRP2 decreases kidney injury and enhances the chemosensitivity of co-administration of cisplatin and astragaloside IV[J]. Acta Pharmaceutica Sinica, 2021, 56(9): 2536-2543.

OCT2/MRP2在黄芪甲苷联合顺铂的减毒增效作用中的机制研究
曲晓宇, 翟婧卉, 高欢, 陶娌娜, 张月明, 巩佳威, 宋燕青*
吉林大学第一医院药学部, 吉林 长春 130021
摘要:
肾损伤和肿瘤细胞化疗敏感性下降已成为顺铂(CDDP)临床应用中两个亟需解决的问题。抑制肾脏中的有机阳离子转运体2(OCT2)和肿瘤中的多药耐药相关蛋白2(MRP2)分别能够达到减轻CDDP肾损伤和增强CDDP化疗敏感性的作用。本研究考察黄芪中的代表性物质黄芪甲苷(AS IV)是否能够同时抑制肾脏中的OCT2和肿瘤中的MRP2,从而达到减轻CDDP诱导的肾损伤并增加其抗肿瘤效果的作用。本研究动物实验由吉林大学第一医院动物伦理委员会审核并批准。通过构建小鼠Lewis肺癌细胞(LLC)肿瘤荷瘤小鼠考察联合给予AS IV和CDDP对肿瘤的生长情况进行观察,并通过对肿瘤组织H&E和TUNEL染色评价肿瘤的凋亡情况。通过血清生化指标和肾脏组织H&E染色评价肾损伤情况。采用Western blotting和免疫组化染色的方法考察肾脏中OCT2和肿瘤中MRP2的蛋白表达,最后通过HPLC-MS/MS测定肾脏和肿瘤组织中CDDP的含量。结果表明,联用AS IV能够减慢肿瘤组织的增殖速度,并增强CDDP诱导的肿瘤凋亡作用。血清生化指标显示,联用AS IV后能够降低肌酐和尿素氮水平,结合H&E染色结果证明AS IV能够减轻CDDP诱导的肾损伤。其减毒增效作用可能与分别抑制肿瘤组织中MRP2和肾脏中OCT2的蛋白表达有关,并最终引起CDDP在肿瘤组织中的含量上升以及在肾脏组织的含量下降。此研究为合理的联合使用化疗药物与中草药资源提供了新的尝试。
关键词:    多药耐药相关蛋白2      有机阳离子转运体2      黄芪甲苷      顺铂      肾损伤      化疗敏感性     
Suppression of OCT2/MRP2 decreases kidney injury and enhances the chemosensitivity of co-administration of cisplatin and astragaloside IV
QU Xiao-yu, ZHAI Jing-hui, GAO Huan, TAO Li-na, ZHANG Yue-ming, GONG Jia-wei, SONG Yan-qing*
Department of Pharmacy, the First Hospital of Jilin University, Changchun 130021, China
Abstract:
Kidney injury and decreased chemosensitivity of tumor cells are obstacles with cisplatin (CDDP) chemotherapy. Down-regulation of the organic cation transporter 2 (OCT2) and multidrug resistance-associated protein 2 (MRP2) is a key means to alleviate CDDP-induced kidney injury and increase chemosensitivity. Astragaloside IV (AS IV) is obtained from the well-known traditional Chinese herb Astragalus membranaceus. This study explored the role of AS IV in preventing kidney injury and enhancing the antitumor effect of CDDP by suppressing OCT2 expression in kidney and MRP2 in tumors. This project was reviewed and approved by the Animal Ethics Committee of the First Hospital of Jilin University. The effects of AS IV on CDDP inhibition of tumor growth and promotion of apoptosis were assessed in Lewis lung tumor (LLC)-bearing mice by H&E and TUNEL staining. Kidney injury was assessed by serum biochemical parameters and H&E staining. We used Western blotting and immunohistochemistry assays to detect OCT2 and MRP2 expression in kidney and tumor. The concentration of CDDP in kidney and tumor was measured by HPLC-MS/MS. AS IV enhanced CDDP chemosensitivity by increasing tumor cell apoptosis and slowing tumor growth, and decreased kidney injury as evidenced by lower blood creatinine (Cr) and blood urea nitrogen (BUN). Co-administration of AS IV suppressed MRP2 overexpression induced by CDDP in tumor tissues and may be an important mechanism for enhancing CDDP chemosensitivity. Moreover, AS IV reduced CDDP-induced kidney injury in mice along with suppression of OCT2 expression in kidney. The concentration of CDDP was increased in tumor but decreased in kidney. In total, AS IV not only enhanced the antitumor effect of CDDP by suppressing MRP2 expression in tumor cells, but also decreased kidney injury induced by CDDP. The results provide new insight into the combined use of a chemotherapy drug and natural ingredients to treat cancer.
Key words:    multidrug resistance-associated protein 2    organic cation transporter 2    astragaloside IV    cisplatin    kidney injury    chemosensitivity   
收稿日期: 2021-01-14
DOI: 10.16438/j.0513-4870.2021-0074
基金项目: 国家自然科学基金资助项目(81803608).
通讯作者: 宋燕青,Tel:86-431-88782482,E-mail:songyanq@jlu.edu.cn
Email: songyanq@jlu.edu.cn
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