Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells.
Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells.
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DOI：
10.1158/1535-7163.mct-09-0051
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Koide K
中科院分区：
文献类型：
--
作者：
Albert BJ;McPherson PA;O'Brien K;Czaicki NL;Destefino V;Osman S;Li M;Day BW;Grabowski PJ;Moore MJ;Vogt A;Koide K
FR 901464是一种有效的抗肿瘤天然产物，可与SF 3b复合物结合并抑制前体mRNA剪接。它的类似物，美亚霉素，是两个数量级更有效的抗增殖剂对人类乳腺癌MCF-7细胞。在这里，我们报告了皮摩尔的meayamycin对各种癌细胞系和多药耐药细胞的抗增殖活性。时间依赖性研究表明，meayamycin可能与其靶蛋白形成共价键。Meayamycin抑制HEK-293细胞中的前体mRNA剪接，但不抑制神经元系统中的选择性剪接。与非致瘤性人肺成纤维细胞相比，美亚霉素对人肺癌细胞具有特异性，并保留了对多药耐药细胞的皮摩尔生长抑制活性。这些数据表明，meayamycin是一个有用的化学探针，研究前mRNA剪接在活细胞中，是一个有前途的铅作为抗癌剂。
FR901464 is a potent antitumor natural product that binds to the SF3b complex and inhibits pre-mRNA splicing. Its analogue, meayamycin, is two orders of magnitude more potent as an antiproliferative agent against human breast cancer MCF-7 cells. Here, we report the picomolar antiproliferative activity of meayamycin against various cancer cell lines and multidrug resistant cells. Time-dependence studies implied that meayamycin may form a covalent bond with its target protein(s). Meayamycin inhibited pre-mRNA splicing in HEK-293 cells but not alternative splicing in a neuronal system. Meayamycin exhibited specificity toward human lung cancer cells compared to non-tumorigenic human lung fibroblasts and retained picomolar growth inhibitory activity against multi-drug resistant cells. These data suggest that meayamycin is a useful chemical probe to study pre-mRNA splicing in live cells and is a promising lead as an anticancer agent.