Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance
Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance
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DOI：
10.1007/s00280-003-0742-5
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发表时间：
2004-04-01
影响因子：
3
通讯作者：
Pan, QC
中科院分区：
文献类型：
--
作者：
Fu, LW;Liang, YJ;Pan, QC
多药耐药（Multidrug resistance，MDR）是肿瘤化疗的主要障碍之一。解决这一问题的一种有希望的方法是利用能够逆转MDR的无毒且有效的调节剂，其与抗癌药物组合增加抗癌效果。进行实验以检查粉防己碱（泰特）作为MDR逆转剂的潜力。用2.5 μ mol/L的泰特孵育72 h的细胞存活率超过90%。2.5 μ mol/l的泰特几乎完全逆转了KBv 200细胞对长春新碱（VCR）的耐药性。泰特在0.625 μ mol/l浓度下可使KB细胞的MDR逆转7.6倍，但对KB细胞的体外敏感性无影响。在裸鼠KBv 200细胞异种移植模型中，泰特和VCR均未抑制肿瘤生长。然而，VCR和泰特联合使用在三个独立的实验环境中抑制肿瘤生长的比例分别为45.7%、61.2%和55.7%。在裸鼠KB细胞异种移植模型中，泰特不抑制肿瘤生长，但VCR和VCR与泰特联合用药分别抑制肿瘤生长40.6%和41.6%。机制研究表明，泰特可抑制[H-3]azidopine对P-gp的光亲和标记，并以浓度依赖性方式增加VCR在MDR KBv 200细胞中的蓄积。结果表明，泰特是一种有效的体外和体内MDR逆转剂。其作用机制是通过与P-gp直接结合，增加细胞内VCR蓄积。
Multidrug resistance (MDR) is one of the main obstacles in tumor chemotherapy. A promising approach to solving this problem is to utilize a nontoxic and potent modulator able to reverse MDR, which in combination with anticancer drugs increases the anticancer effect. Experiments were carried out to examine the potential of tetrandrine (Tet) as a MDR-reversing agent. Survival of cells incubated with Tet at 2.5 mumol/l for 72 h was over 90%. Tet at 2.5 mumol/l almost completely reversed resistance to vincristine (VCR) in KBv200 cells. Tet at a concentration as low as 0.625 mumol/l produced a 7.6-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive KB cells in vitro. In the KBv200 cell xenograft model in nude mice, neither Tet nor VCR inhibited tumor growth. However, VCR and Tet combined inhibited tumor growth by 45.7%, 61.2% and 55.7% in three independent experimental settings. In the KB cell xenograft model in nude mice, Tet did not inhibit tumor growth, but VCR and the combination of VCR and Tet inhibited tumor growth by 40.6% and 41.6%, respectively. Mechanism studies showed that Tet inhibited [H-3]azidopine photoaffinity labeling of P-gp and increased accumulation of VCR in MDR KBv200 cells in a concentration-dependent manner. The results suggest that Tet is a potent MDR-reversing agent in vitro and in vivo. Its mechanism of action is via directly binding to P-gp and increasing intracellular VCR accumulation.