Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin
| Autor: | Junke Liu, Francis G. Fang, Silvio Campagna, Edward M. Suh, Veronique Marceau, Ye Yao, James J. Kowalczyk, Shawn Schiller, Hongsheng Cheng, Galina Kuznetsov, Karen TenDyke, Bruce A. Littlefield, Hu Yang, Murray J. Towle, Christina J. Shaffer, Mark Spyvee, Joanne Marsh, Boris M. Seletsky |
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| Rok vydání: | 2009 |
| Předmět: |
G2 Phase
Cancer Research Poly ADP ribose polymerase Mitosis Antineoplastic Agents Apoptosis macromolecular substances Photoaffinity Labels Spindle Apparatus Antimitotic Agents Cleavage (embryo) Vinblastine Microtubules chemistry.chemical_compound Piperidines In vivo Tubulin Cell Line Tumor medicine Animals Humans Seawater Biological Products Natural product biology In vitro Spindle apparatus Porifera Oncology Biochemistry chemistry biology.protein Cattle Oligopeptides medicine.drug |
| Zdroj: | Molecular cancer therapeutics. 8(10) |
| ISSN: | 1538-8514 |
| Popis: | E7974 is a synthetic analogue of the marine sponge natural product hemiasterlin. Here, we show that E7974, such as parental hemiasterlin, acts via a tubulin-based antimitotic mechanism. E7974 inhibits polymerization of purified tubulin in vitro with IC50 values similar to those of vinblastine. In cultured human cancer cells, E7974 induces G2-M arrest and marked disruption of mitotic spindle formation characteristic of tubulin-targeted anticancer drugs. Extensive hypodiploid cell populations are seen in E7974-treated cells, indicating initiation of apoptosis after prolonged G2-M blockage. Consistent with this observation, E7974 induces caspase-3 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis. Only a short cellular exposure to E7974 is sufficient to induce maximum mitotic arrest, suggesting that E7974's antitumor effects in vivo may persist even after blood levels of the drug decrease after drug administration. Interactions of E7974 with purified tubulin were investigated using two synthetic tritiated photoaffinity analogues incorporating a benzophenone photoaffinity moiety at two different positions of the E7974 scaffold. Both analogues preferentially photolabeled α-tubulin, although minor binding to β-tubulin was also detected. E7974 thus seems to share a unique, predominantly α-tubulin–targeted mechanism with other hemiasterlin-based compounds, suggesting that, unlike many tubulin-targeted natural products and related drugs, the hemiasterlins evolved to mainly target α-tubulin, not β-tubulin subunits. [Mol Cancer Ther 2009;8(10):2852–60] |
| Databáze: | OpenAIRE |
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