RRC ID 52125
Author Weber H, Valbuena JR, Barbhuiya MA, Stein S, Kunkel H, García P, Bizama C, Riquelme I, Espinoza JA, Kurtz SE, Tyner JW, Calderon JF, Corvalán AH, Grez M, Pandey A, Leal-Rojas P, Roa JC.
Title Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.
Journal Oncotarget
Abstract 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.
Volume 8(16)
Pages 26169-26184
Published 2017-4-18
DOI 10.18632/oncotarget.15410
PII 15410
PMID 28412732
PMC PMC5432248
MeSH Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects Benzoquinones / pharmacology* Cell Cycle Checkpoints / drug effects Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Cell Survival / drug effects Disease Models, Animal Drug Discovery* / methods Drug Screening Assays, Antitumor* / methods Gallbladder Neoplasms HSP90 Heat-Shock Proteins / antagonists & inhibitors* High-Throughput Screening Assays Humans Lactams, Macrocyclic / pharmacology* Mice Small Molecule Libraries Xenograft Model Antitumor Assays
Resource
Human and Animal Cells G-415(RCB2640) TGBC1TKB(RCB1129) TGBC2TKB(RCB1130) TGBC24TKB(RCB1196)