Reversal of anticancer multidrug resistance by the ardeemins
Reversal of anticancer multidrug resistance by the ardeemins
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DOI：
10.1073/pnas.95.14.8369
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发表时间：
1998-07-07
影响因子：
11.1
通讯作者：
Danishefsky, SJ
中科院分区：
文献类型：
--
作者：
Chou, TC;Depew, KM;Danishefsky, SJ
在表现多药耐药(MDR)表型的细胞中，5-N-乙酰基-8-脱甲基吲哚和5-N-乙酰基-8-脱甲基吲哚生物碱作为逆转剂被评价为逆转剂。这些Ardeemins(I)在体外对长春花碱(VBL)或紫杉醇的耐药性逆转达700倍；(Ii)作为单一药物在高浓度下比各自的亲本野生型细胞更有效地杀死MDR细胞；(Iii)与阿霉素(DX)和VBL显示出很强的协同作用，抑制MDR肿瘤细胞的生长，但对亲本野生型细胞的影响较小。机理研究表明，[H-3]叠氮多宾对P-糖蛋白(Pgp)的光亲和标记受到Ardeemins的竞争性抑制。20MU-M可使MDR-[Pgp(+)和MD相关蛋白(MRP)(+)]、MDR-Pgp(+)、表达肺耐药蛋白(LRP)(+)和野生型肺癌细胞对DX的耐药性分别逆转110~200倍、50~66倍、7~15倍和0.9~3倍。此外，这些化合物还增加了VBL在细胞内的蓄积，并显著减少了其外流。最后，体内联合研究表明，无毒剂量的青蒿素与DX显著提高了对DX耐药的B6D2F(1)小鼠和裸鼠MX-I乳腺癌移植瘤的化疗效果。上述特征表明，ardeemins可能在肿瘤的治疗中有应用价值。
Two "reverse prenyl" hexahydropyrroloindole alkaloids, 5-N-acetylardeemin and 5-N-acetyl-8-demethylardeemin, were evaluated as reversal agents in cells exhibiting a multidrug resistant (MDR) phenotype. These ardeemins (i) reversed drug resistance to vinblastine (VBL) or to taxol as much as 700-fold at relatively noncytotoxic concentrations in vitro; (ii) as a single agent at high concentrations killed MDR cells more efficaciously than the respective parent wild-type cells; and (iii) exhibited strong synergistic effects with doxorubicin (DX) and VBL against the growth of MDR neoplastic cells, and to a lesser extent, of the parent wild-type cells. Mechanistic studies showed that photoaffinity labeling of P-glycoprotein (Pgp) with [H-3] azidopine was competitively inhibited by the ardeemins. Resistance to DX in MDR-[Pgp(+) and MD-associated protein (MRP)(+)], MDR-Pgp(+), lung resistance protein (LRP)(+)-expressing, and wild-type lung cancer cells were reversed 110- to 200-fold, 50- to 66-fold, 7- to 15-fold, and 0.9- to 3-fold, respectively, by 20 mu M of the ardeemins. Moreover, these compounds increased the intracellular accumulation of VBL and markedly decreased its efflux. Finally, in vivo combination studies demonstrated that nontoxic doses of the ardeemins with DX significantly improved the chemotherapeutic effects in B6D2F(1) mice bearing DX-resistant P388 leukemia, and nude mice bearing human MX-I mammary carcinoma xenografts. The above features indicate that the ardeemins may have utility in the therapy of cancer.