Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer
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Helga Weber1,2,*, José R. Valbuena3,*, Mustafa A. Barbhuiya4, Stefan Stein5, Hana Kunkel5, Patricia García3,6, Carolina Bizama3,6, Ismael Riquelme1,2, Jaime A. Espinoza7, Stephen E. Kurtz8, Jeffrey W. Tyner8, Juan Francisco Calderon9, Alejandro H. Corvalán6,10, Manuel Grez5, Akhilesh Pandey4,11, Pamela Leal-Rojas1, Juan C. Roa3,6
1Center of Excellence in Traslational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
2Department of Pathology, Faculty of Medicine, Temuco, Chile
3Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
4McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
5Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
6Center for Investigation in Translational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
7SciLifeLab, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden
8Division of Hematology and Medical Oncology, Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
9Center for Genetics and Genomics, School of Medicine, Clínica Alemana de Santiago - Universidad del Desarrollo, Santiago, Chile
10Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
11Department of Biological Chemistry, Department of Oncology, Department of Pathology, The Johns Hopkins University School of Medicine Baltimore, MD, USA
*These authors contributed equally to this work
Juan C. Roa, email: firstname.lastname@example.org
Pamela Leal-Rojas, email: email@example.com
Keywords: gallbladder cancer, HSP90 inhibitors, geldanamycin, 17-AAG, gallbladder cancer xenografts
Received: October 13, 2016 Accepted: February 01, 2017 Published: February 16, 2017
Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.
In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.
In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).
The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).
Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
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