Abstract
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]
- FR901464
- meayamycin
- pre-mRNA splicing
- alternative splicing
- multidrug resistance
- reversibility
- p53
- apoptosis
- high content cellular analysis
Footnotes
Grant support: Graduate Excellence Fellowship from the University of Pittsburgh (B.J. Albert); the Arnold and Mabel Beckman Scholar Award, the Lilly Summer Research Fellowship, and the Averill Scholarship (N.L. Czaicki); National Cancer Institute grants R01 CA120792 (K. Koide) and CA 78039 (A. Vogt); and NIH grants R01 GM35007 and HHMI (M.J. Moore).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received January 27, 2009.
- Revision received May 5, 2009.
- Accepted May 5, 2009.
- © 2009 American Association for Cancer Research.
This OnlineFirst version was published on August 11, 2009
doi: 10.1158/1535-7163.MCT-09-0051
