Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice

  • Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.

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Author:Helga Weber, Pamela Leal-Rojas, Stefan Stein, Hana Kunkel, Patricia García, Carolina Bizama, Jaime A. Espinoza, Ismael Riquelme, Bruno Nervi, Juan C. Araya, Manuel Grez, Juan Carlos Roa
URN:urn:nbn:de:hebis:30:3-412871
DOI:https://doi.org/10.18632/oncotarget.5047
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/26397134
Parent Title (English):Oncotarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Date of Publication (online):2016/08/24
Date of first Publication:2015/11/09
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/08/24
Tag:WYE-354; gallbladder cancer; gallbladder cancer xenografts; mTOR inhibitors; rapamycin
Volume:6
Issue:31
Page Number:12
First Page:31877
Last Page:31888
Note:
Licensed under a Creative Commons Attribution 3.0 License.
HeBIS-PPN:399893490
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0