Journal
MOLECULAR CANCER THERAPEUTICS
Volume 8, Issue 8, Pages 2308-2318Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-09-0051
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Funding
- University of Pittsburgh
- Arnold and Mabel Beckman Scholar Award
- Lilly Summer Research Fellowship
- Averill Scholarship
- National Cancer Institute [R01 CA120792, CA78039]
- NIH [R01 GM35007]
- HHMI
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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]
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