The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms.
The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms.
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DOI：
10.1158/0008-5472.can-08-2037
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Mooberry SL
中科院分区：
文献类型：
--
作者：
Risinger AL;Jackson EM;Polin LA;Helms GL;LeBoeuf DA;Joe PA;Hopper-Borge E;Ludueña RF;Kruh GD;Mooberry SL
Taccalonolides是一类从Tacca chantrieri中分离的结构和机制不同的微管稳定剂。紫杉烷家族微管稳定剂的一个关键特征是其对细胞耐药机制的易感性，包括P-糖蛋白、MRP 7和微管蛋白βIII同种型的过表达。研究了四种他卡内酯A、E、B和N规避这些多药耐药机制的能力。Taccalonolides A、E、B和N在体外对过表达P-糖蛋白和MRP 7的细胞系有效。此外，他卡内酯A和E在体内对表达阿霉素和紫杉醇耐药Pgp的肿瘤Mam 17/ADR具有高度活性。产生表达微管蛋白的βIII同种型的等基因HeLa衍生细胞系以评估β III-微管蛋白对药物敏感性的影响。与亲代HeLa细胞相比，β III-微管蛋白过表达细胞系对紫杉醇、多西他赛、埃博霉素B和长春碱的敏感性较低。与此形成鲜明对比的是，β III-微管蛋白过表达细胞系对所有四种taccalonolides均表现出更高的敏感性。这些数据累积表明，他卡内酯类在规避多重耐药机制方面优于紫杉烷类。他卡隆内酯在体外和体内克服临床相关的耐药性机制的能力证实了他卡隆内酯代表了对具有临床潜力的微管稳定化合物家族的有价值的补充。
The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein, MRP7 and the βIII isotype of tubulin. The ability of four taccalonolides, A, E, B and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B and N were effective in vitro against cell lines that overexpress P-glycoprotein and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel- resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the βIII isotype of tubulin was generated to evaluate the effect of βIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the βIII-tubulin overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B and vinblastine. In striking contrast, the βIII-tubulin overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential.