Chen Liying, Chen Zhi, Zheng Shuang, Fan Luhui, Zhu Lixin, Yu Jiandong, Tang Chaoyuan, Liu Qi, Xiong Yang
Department of Pharmaceutical Science, College of Pharmaceutical Science, Zhejiang Chinese Medical University Hangzhou 311400 Zhejiang China.
The First People's Hospital of Jiande Jiande 311600 Zhejiang China.
RSC Adv. 2020 Sep 21;10(57):34928-34937. doi: 10.1039/d0ra00184h. eCollection 2020 Sep 16.
While elemene (ELE) can reverse tumor multidrug resistance (MDR), the mechanisms for ELE reversing MDR remain unclear. Numerous studies have suggested that the efflux functionality of ATP-binding cassette (ABC) transporters, not their quantity, is more relevant to tumor MDR. However, no appropriate methods exist for real-time detection of the intracellular drug efflux caused by ABC transporters , especially , which hinders the examination of MDR reversal mechanisms. This study directly investigates the correlation between efflux functionality of ABC transporters and MDR reversal ELE, using d-luciferin potassium salt (d-luc) as the chemotherapeutic substitute to study the intracellular drug efflux. Here, a luciferase reporter assay system combined with bioluminescence imaging confirmed that the efflux of d-luc from MCF-7/DOX cells and was significantly reduced by ELE and when combined with Doxorubicin (DOX), ELE showed a synergistically anti-tumor effect and . Additionally, the luminescence pharmacokinetics of d-luc in MCF-7/DOX cells and pharmacodynamics of the combined ELE and DOX showed a great correlation, implying that d-luc might be used as a probe to study ABC transporters-mediated efflux in order to explore mechanisms of traditional Chinese medicines reversing MDR.
虽然榄香烯（ELE）可逆转肿瘤多药耐药性（MDR），但其逆转MDR的机制尚不清楚。众多研究表明，ATP结合盒（ABC）转运蛋白的外排功能而非其数量与肿瘤MDR更为相关。然而，目前尚无适用于实时检测ABC转运蛋白引起的细胞内药物外排的方法，这尤其阻碍了对MDR逆转机制的研究。本研究使用d - 荧光素钾盐（d - luc）作为化疗替代物来研究细胞内药物外排，直接探究ABC转运蛋白的外排功能与ELE逆转MDR之间的相关性。在此，一种结合生物发光成像的荧光素酶报告基因检测系统证实，ELE可显著减少MCF - 7/DOX细胞中d - luc的外排，并且当与阿霉素（DOX）联合使用时，ELE显示出协同抗肿瘤作用。此外，d - luc在MCF - 7/DOX细胞中的发光药代动力学以及ELE与DOX联合使用的药效学显示出高度相关性，这意味着d - luc可能用作研究ABC转运蛋白介导的外排的探针，以探索中药逆转MDR的机制。
