Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A.
Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A.
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DOI：
10.1158/1535-7163.mct-08-1026
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
Littlefield BA
中科院分区：
文献类型：
--
作者：
Kuznetsov G;Xu Q;Rudolph-Owen L;Tendyke K;Liu J;Towle M;Zhao N;Marsh J;Agoulnik S;Twine N;Parent L;Chen Z;Shie JL;Jiang Y;Zhang H;Du H;Boivin R;Wang Y;Romo D;Littlefield BA
我们在这里报告，des-methyl，des-amino pateamine A（DMDA-PatA），海洋天然产物pateamine A的结构简化的类似物，对各种各样的人类癌细胞系具有有效的抗增殖活性，同时显示相对较低的细胞毒性对非增殖，静止的人成纤维细胞。DMDA-PatA在对紫杉醇显著耐药的P-糖蛋白过表达MES-SA/D×5-R×1人子宫肉瘤细胞中保留了几乎全部的体外效力，表明DMDA-PatA不是P-糖蛋白介导的药物外排的底物。用DMDA-PatA处理增殖细胞会导致细胞周期S期的DNA合成迅速停止。无细胞研究表明，DMDA-PatA在体外直接抑制DNA聚合酶α和γ，尽管浓度远高于抑制细胞增殖的浓度。DMDA-PatA在裸鼠的几种人癌症异种移植模型中显示出有效的抗癌活性，包括在LOX和MDA-MB-435黑色素瘤模型中观察到的显著消退。因此，DMDA-PatA代表了一种有前途的基于天然产物的抗癌剂，值得进一步研究。
We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/D×5-R×1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.