Enhanced therapeutic effects on the multi-drug resistant human leukemia cells in vitro and xenograft in mice using the stealthy liposomal vincristine plus quinacrine
Enhanced therapeutic effects on the multi-drug resistant human leukemia cells in vitro and xenograft in mice using the stealthy liposomal vincristine plus quinacrine
复制标题
DOI：
10.1111/j.1472-8206.2008.00613.x
复制
发表时间：
2008-08-01
影响因子：
2.9
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Liang, Gong-Wen;Lu, Wan-Liang;Zhang, Qiang
多药耐药（multi-drug resistance，MDR）可能是由于三磷酸腺苷结合盒转运蛋白（adenosine triphosphate binding cassette transporter，如P-糖蛋白）的过度表达，从而导致抗癌药物从细胞外排而引起的。本研究定义了一种抗耐药隐形脂质体长春新碱+奎纳克林。包括人慢性髓性白血病K562和MDR K562细胞用于比较。在具有MDR K562细胞异种移植物的雌性BALB/c裸鼠中进行抗肿瘤活性研究。结果表明，奎纳克林可逆转K562细胞的耐药性，并增强长春新碱的抗肿瘤作用。随着奎纳克林剂量的增加，K562和K562 MDR细胞中caspase-9和caspase-3的活性增加。长春新碱隐形脂质体联合奎纳克林对耐药K562细胞移植瘤有明显的抗肿瘤作用。奎纳克林增强长春新碱对耐药/非耐药K562细胞的抗肿瘤作用可能是由于长春新碱通过激活起始型caspase-9和随后激活效应型caspase-3而产生的直接损伤和增强凋亡效应以及隐形脂质体的长循环效应。长春新碱和奎纳克林的隐形脂质体包封有望成为治疗耐药白血病的一种新方法。
The multi-drug resistance (MDR) could be caused by the over-expression of adenosine triphosphate binding cassette transporters such as p-glycoprotein, thereby resulting in the efflux of anti-cancer drugs from the cells. An anti-resistant stealthy liposomal vincristine plus quinacrine was defined in this study. Human chronic myelogenous leukemia K562 and MDR K562 cells were included for comparisons. Anti-tumor activity studies were performed on female BALB/c nude mice with MDR K562 cell xenografts. Results showed that quinacrine was effective in reversing the resistance in the MDR K562 cells, and enhanced the anti-tumor effect of vincristine in K562 cells. The caspase-9 and -3 activities in the MDR K562 and K562 cells were increased with the dose rise of quinacrine. In the MDR K562 cell xenografts in mice, the anti-resistant tumor effect of the stealthy liposomal vincristine plus quinacrine was evidently observed. The enhanced anti-tumor effects of vincristine by quinacrine in the resistant/non-resistant K562 cells could be because of the direct injury and the potentiating apoptotic effect of vincristine via activating the initiator caspase-9 and subsequently the effector caspase-3, and the long circulatory effect of stealthy liposomes. The stealthy liposomal encapsulation of vincristine plus quinacrine could be a potential therapeutic approach for resistant human leukemia.