Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer

Simple item page
dc.contributor.authorWeber, Helga
dc.contributor.authorValbuena, Jose R.
dc.contributor.authorBarbhuiya, Mustafa A
dc.contributor.authorStein, Stefan
dc.contributor.authorKunkel, Hana
dc.contributor.authorGarcia, Patricia
dc.contributor.authorBizama, Carolina
dc.contributor.authorRiquelme, Ismael
dc.contributor.authorEspinoza, Jaime
dc.contributor.authorKurtz, Stephen
dc.contributor.authorTyner, Jeffrey
dc.contributor.authorCalderón, Juan Francisco
dc.contributor.authorCorvalan, Alejandro
dc.contributor.authorGrez, Manuel
dc.contributor.authorPandey, Akhilesh
dc.contributor.authorLeal-Rojas, Pamela
dc.contributor.authorRoa, Juan C.
dc.date.accessioned2017-09-05T15:48:44Z
dc.date.available2017-09-05T15:48:44Z
dc.date.issued2017
dc.description.abstractGallbladder 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.
dc.description.versionVersión Publicada
dc.format.extent16
dc.identifier.citationWeber 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. Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer. Oncotarget. 2017 Apr 18;8(16):26169-26184. doi: 10.18632/oncotarget.15410.
dc.identifier.urihttp://hdl.handle.net/11447/1647
dc.identifier.urihttp://dx.doi.org/10.18632/oncotarget.15410
dc.language.isoen_US
dc.publisherImpact Journals
dc.sourceOncotarget
dc.subject17-AAG
dc.subjectHSP90 inhibitors
dc.subjectgallbladder cancer
dc.subjectgallbladder cancer xenografts
dc.subjectgeldanamycin
dc.titleSmall molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer
dc.typeArtículo

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Weber...Calderon...Roa Oncotarget 2017.pdf
Size:
9.53 MB
Format:
Adobe Portable Document Format
Description:
Texto completo
Download

Collections

Artículos Medicina y Ciencias de la Salud

Implementado por OpenGeek Services