Brian J Albert,
Peter A McPherson,
Kristine O'Brien,
Nancy L Czaicki, Vincent Destefino,
Sami Osman,
Miaosheng Li,
Billy W Day,
Paula J Grabowski,
Melissa J Moore,
Andreas Vogt,
Kazunori Koide
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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.
Molecular Cancer Therapeutics 09/2009; 8(8):2308-18. · 5.23 Impact Factor
