Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjects Journal Article
| Authors: | Chan, C. T.; Paulmurugan, R.; Gheysens, O. S.; Kim, J.; Chiosis, G.; Gambhir, S. S. |
| Article Title: | Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjects |
| Abstract: | Heat shock protein 90α (Hsp90α)/p23 and Hsp90β/p23 interactions are crucial for proper folding of proteins involved in cancer and neurodegenerative diseases. Small molecule Hsp90 inhibitors block Hsp90α/p23 and Hsp90β/p23 interactions in part by preventing ATP binding to Hsp90. The importance of isoform-selective Hsp90α/p23 and Hsp90β/p23 interactions in determining the sensitivity to Hsp90 was examined using 293T human kidneycancer cells stably expressing split Renilla luciferase (RL) reporters. Interactions between Hsp90α/p23 and Hsp90β/p23 in the split RL reporters led to complementation of RL activity, which was determined by bioluminescence imaging of intact cells in cell culture and living mice using a cooled charge-coupled device camera. The three geldanamycin-based and seven purine-scaffold Hsp90 inhibitors led to different levels of inhibition of complemented RL activities (10-70%). However, there was no isoform selectivity to both classes of Hsp90 inhibitors in cell culture conditions. The most potent Hsp90 inhibitor, PU-H71, however, led to a 60% and 30% decrease in RL activity (14 hr) in 293T xenografts expressing Hsp90α/p23 and Hsp90β/p23 split reporters respectively, relative to carrier control-treated mice. Molecular imaging of isoform-specific Hsp90α/p23 and Hsp90β/p23 interactions and efficacyof different classes of Hsp90 inhibitors in living subjects have been achieved with a novel genetically encoded reporter gene strategy that should help in accelerating development of potent and isoform-selective Hsp90 inhibitors. ©2008 American Association for Cancer Research. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; mutation; drug efficacy; nonhuman; antineoplastic agents; methodology; antineoplastic agent; protein function; protein analysis; mouse; animal; metabolism; animals; mice; drug inhibition; enzyme inhibition; protein protein interaction; animal model; drug screening; drug screening assays, antitumor; xenograft model antitumor assays; enzyme activity; molecular imaging; cell line, tumor; drug selectivity; drug specificity; chemistry; drug antagonism; cell culture; cancer cell; tumor cell line; reporter gene; phosphoproteins; heat shock protein 90 inhibitor; pu h71; heat shock protein 90; hsp90 heat-shock proteins; benzodioxoles; purines; genes, reporter; purine derivative; kidney cancer; protein interaction mapping; bioluminescence; isoprotein; phosphoprotein; benzoquinones; lactams, macrocyclic; renilla luciferin 2 monooxygenase; geldanamycin; benzoquinone derivative; macrocyclic lactam; chaperone; molecular chaperones; 1,3 benzodioxole derivative; pu 24fcl; pu 3; camera; protein p23; pudz 7; pudz 8; puh 58; puh 71; pul 66; hsp90ab1 protein, human; tebp protein, human; luciferases, renilla |
| Journal Title: | Cancer Research |
| Volume: | 68 |
| Issue: | 1 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-01-01 |
| Start Page: | 216 |
| End Page: | 226 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-07-2268 |
| PUBMED: | 18172314 |
| PROVIDER: | scopus |
| PMCID: | PMC4146344 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus" |
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