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

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.

• Authors: Helga Weber, Pamela Leal, Stefan Stein, Hana Kunkel, Patricia García, Carolina Bizama, Jaime A Espinoza, Ismael Riquelme, Bruno Nervi, Juan C Araya, Manuel Grez, Juan C Roa
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 31877-88 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26397134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• wye
• Guanine
• Sirolimus

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Therapy, Combination
• Gallbladder Neoplasms (drug therapy, pathology)
• Guanine (analogs & derivatives, pharmacology)
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays