Mechanistic Target of Rapamycin Small Interfering RNA and Rapamycin Synergistically Inhibit Tumour Growth in a Mouse Xenograft Model of Human Oesophageal Carcinoma

Abstract

OBJECTIVES:To investigate the effect of mechanistic target of rapamycin (mTOR)-specific small interfering RNA (siRNA) and rapamycin on tumour size and levels of hypoxia inducible factor 1a (HIF-1a), vascular endothelial growth factor (VEGF) and mTOR proteins, and mTOR mRNA, in a mouse xenograft model of human oesophageal carcinoma. METHODS: Tumours were induced in BALB/c nude mice using the human oesophageal squamous cell carcinoma cell line, EC1, injected subcutaneously. Animals were divided into four treatment groups (n = 5 per group) after 7 days: control (phosphate buffered saline, daily intraperitoneal [i.p.] injection); 50 µg/kg rapamycin, daily i.p. injection; 3 µg/kg mTOR siRNA, daily i.p. injection; combined mTOR siRNA and rapamycin, daily i.p. injections. Tumour volume was measured 21 days after xenograft. Levels of mTOR, VEGF and HIF-1a were assessed via immunohisto chemistry and in situ hybridization. RESULTS: mTOR siRNA and/or rapamycin significantly decreased tumour volume and levels of HIF-1a, VEGF and mTOR protein, and mTOR mRNA. Combination treatment was significantly more effective than either treatment alone. CONCLUSIONS: mTOR siRNA and/or rapamycin inhibited the growth of oesophageal carcinoma in vivo. This may represent a novel and effective treatment strategy for oesophageal carcinoma.

The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials

“…In a xenograft mouse model of oesophageal cancer both rapamycin induced and siRNA induced inhibition of mTOR were shown to decrease tumour size and mTOR expression [41] . The use of both agents was shown to have a greater anti-tumour effect than either agent alone.…”