Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 1; pp. 216 - 226
• Main Authors: Chan, Carmel T., Paulmurugan, Ramasamy, Gheysens, Olivier S., Kim, Joungnam, Chiosis, Gabriela, Gambhir, Sanjiv Sam
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2008
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzodioxoles - pharmacology; Benzoquinones - chemistry; Biological and medical sciences; Cell Line, Tumor; Drug Screening Assays, Antitumor - methods; Genes, Reporter - genetics; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic - chemistry; Luciferases, Renilla - analysis; Luciferases, Renilla - genetics; Medical sciences; Mice; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - metabolism; Mutation; Pharmacology. Drug treatments; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - metabolism; Protein Interaction Mapping - methods; Purines - metabolism; Purines - pharmacology; Renilla; Tumors; Xenograft Model Antitumor Assays; Human; Medical imagery; Inhibitor; Treatment efficiency; Heat shock protein; Heat shock protein 90
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-2268

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 kidney cancer 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 efficacy of 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. [Cancer Res 2008;68(1):216–26]