Oncotarget

Research Papers:

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

Helga Weber, Pamela Leal, Stefan Stein, Hana Kunkel, Patricia García, Carolina Bizama, Jaime A. Espinoza, Ismael Riquelme, Bruno Nervi, Juan C. Araya, Manuel Grez and Juan C. Roa _

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Oncotarget. 2015; 6:31877-31888. https://doi.org/10.18632/oncotarget.5047

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Abstract

Helga Weber1,*, Pamela Leal1,*, Stefan Stein2, Hana Kunkel2, Patricia García3, Carolina Bizama3, Jaime A. Espinoza3, Ismael Riquelme1, Bruno Nervi4, Juan C. Araya1, Manuel Grez2,*, Juan C. Roa3,*

1Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile

2Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany

3Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

4Department of Hematology Oncology, UC-Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

*These authors have contributed equally to this work

Correspondence to:

Juan C. Roa, e-mail: jcroas@gmail.com

Manuel Grez, e-mail: grez@em.uni-frankfurt.de

Keywords: gallbladder cancer, mTOR inhibitors, gallbladder cancer xenografts, rapamycin, WYE-354

Received: May 12, 2015     Accepted: September 01, 2015     Published: September 11, 2015

ABSTRACT

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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