Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells

被引：84

作者：

Albert, Brian J. ^{[1
]}

McPherson, Peter A. ^{[2
]}

O'Brien, Kristine ^{[5
]}

Czaicki, Nancy L. ^{[1
]}

DeStefino, Vincent ^{[3
]}

Osman, Sami ^{[1
]}

Li, Miaosheng ^{[1
]}

Day, Billy W. ^{[1
,4
]}

Grabowski, Paula J. ^{[3
]}

Moore, Melissa J. ^{[5
]}

Vogt, Andreas ^{[2
]}

Koide, Kazunori ^{[1
]}

机构：

[1] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA

[4] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA

[5] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Dept Mol Pharmacol & Biochem, Worcester, MA 01605 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2009年 / 8卷 / 08期

关键词：

PRE-MESSENGER-RNA; ANTITUMOR SUBSTANCES; NATURAL-PRODUCT; DNA-DAMAGE; IN-VITRO; FR901464; TRANSCRIPTION; CANCER; P53; CYTOTOXICITY;

D O I：

10.1158/1535-7163.MCT-09-0051

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

FR901464 is a potent antitumor natural product that binds to the splicing factor 3b 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 with nontumorigenic human lung fibroblasts and retained picomolar growth-inhibitory activity against multidrug-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. [Mol Cancer Ther 2009;8(8):2308-18]

引用

页码：2308 / 2318

页数：11

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