Preclinical Study of AUY922, a Novel Hsp90 Inhibitor, in the Treatment of Esophageal Adenocarcinoma.
Journal Article (Journal Article)
Objective
To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo.Background
EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy.Methods
In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression.Results
In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control = 9.4%), increase in 9.1% (control = 37.5%), and stable disease in 54.5% (control = 43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90β, and CDK4, and upregulation of Hsp72.Conclusions
AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.Full Text
Duke Authors
Cited Authors
- Kosovec, JE; Zaidi, AH; Kelly, LA; Rotoloni, CL; Vytlacil, C; DiCarlo, C; Matsui, D; Komatsu, Y; Boyd, NH; Omstead, A; Kolano, EL; Biederman, RWW; Finley, G; Silverman, JF; Landreneau, RJ; Jobe, BA
Published Date
- August 2016
Published In
Volume / Issue
- 264 / 2
Start / End Page
- 297 - 304
PubMed ID
- 26445473
Electronic International Standard Serial Number (EISSN)
- 1528-1140
International Standard Serial Number (ISSN)
- 0003-4932
Digital Object Identifier (DOI)
- 10.1097/sla.0000000000001467
Language
- eng