Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells.
Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells.
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DOI：
10.1248/bpb.28.1979
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发表时间：
2005-10
影响因子：
2
通讯作者：
Feng-peng Wang;Li Wang;Jin-song Yang;M. Nomura;K. Miyamoto
中科院分区：
文献类型：
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作者：
Feng-peng Wang;Li Wang;Jin-song Yang;M. Nomura;K. Miyamoto
我们研究了部分合成的新化合物从fangchinoline和粉防己碱逆转P-糖蛋白（P-gp）依赖的多药耐药（MDR）在体外和体内的能力。所有化合物均增强0.1 μ M长春碱（VBL）对耐药细胞系P388/ADR的体外细胞毒性作用，其效力与10 μ M维拉帕米相同。通过取代大体积基团，组合效果趋于强，得到的5，14-二溴粉防己碱（化合物#9）显示出最强的效果。化合物#9增加P388/ADR细胞中的细胞内VBL积累，比维拉帕米强得多，以及细胞毒性组合效应。该机制可能抑制P-gp的功能，但不影响P-gp的表达。与VBL组合，该化合物还协同延长了携带P388/ADR的小鼠的寿命。双苄基异喹啉类生物碱及其衍生物有可能作为肿瘤化疗中的MDR调节剂。
We examined the ability of partially synthesized new compounds from fangchinoline and tetrandrine to reverse P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) in vitro and in vivo. All compound enhanced the in vitro cyctotoxic effect of vinblastin (VBL) at 0.1 microM as potent as 10 microM verapamil against the resistant cell line P388/ADR. The combination effect tended to be strong by substitution of bulky group, resulting 5,14-dibromotetrandrine (compound #9) showed the strongest effect. Compound #9 increased intracellular VBL accumulation in P388/ADR cells, much stronger than verapamil, as well as cytotoxic combined effect. This mechanism seems to inhibit the function of P-gp, but not the expression of P-gp. In combination with VBL, this compound also synergistically prolonged the life-span of P388/ADR-bearing mice. Bisbenzylisoquinoline alkaloids and their derivatives are possible to be good candidates as modifier of MDR in cancer chemotherapy.