Dimeric ansamycins--a new class of antitumor Hsp90 modulators with prolonged inhibitory activity
| Autor: | Hong, Zhang, Yong-Ching, Yang, Lin, Zhang, Junhua, Fan, Daun, Chung, Diana, Choi, Roy, Grecko, Gregg, Timony, Patricia, Karjian, Marcus, Boehm, Francis, Burrows |
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| Rok vydání: | 2006 |
| Předmět: |
Lung Neoplasms
Receptor ErbB-2 Lactams Macrocyclic Blotting Western Mice Nude Antineoplastic Agents Protein Serine-Threonine Kinases Flow Cytometry Xenograft Model Antitumor Assays Receptor IGF Type 1 Mice Rifabutin Benzoquinones Tumor Cells Cultured Animals Humans HSP90 Heat-Shock Proteins Dimerization Cell Proliferation |
| Zdroj: | International journal of cancer. 120(4) |
| ISSN: | 0020-7136 |
| Popis: | The geldanamycin derivative 17-allyamino-17-demethoxygeldanamycin (17-AAG) is a clinical stage ATP-competitive HSP90 inhibitor that induces degradation of HSP90 client proteins. 17-AAG contains 1 ansamycin moiety and is highly potent in conventional cell killing assays. Since active Hsp90 exists as a dimer, we hypothesized that dimeric compounds containing 2 ansamycin pharmacophores might inhibit Hsp90 function more efficiently than 17-AAG. Here, we show that monomeric and dimeric ansamycins exert their activity in distinct ways. Under conditions of continuous exposure, 17-AAG induced client degradation and cell growth inhibition more readily than the dimeric drugs CF237 and CF483. By contrast, 24 hr treatment of various tumor cells with 17-AAG followed by drug washout caused temporary client degradation and cell cycle arrest but minimal cell death, whereas both dimers induced massive apoptosis. CF237 remained bound to Hsp90 for days after drug withdrawal and, while both monomeric and dimeric compounds caused accumulation of the inactive intermediate Hsp90 complex, this effect disappeared following washout of 17-AAG but not CF237. The dimer was also retained for longer in tumor xenografts and displayed superior antitumor activity in vivo. These results indicate that monomeric and dimeric Hsp90 inhibitors have distinct biological profiles and work differentially toward target inhibition. |
| Databáze: | OpenAIRE |
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