Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth.

Abstract

The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.

• Authors: Christophe Couderc, Gilles Poncet, Karine Villaume, Martine Blanc, Nicolas Gadot, Thomas Walter, Florian Lepinasse, Valérie Hervieu, Martine Cordier-Bussat, Jean-Yves Scoazec, Colette Roche
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 1 Pg. 336-44 (Jan 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21224070 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Chromones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Antibiotics, Antineoplastic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Carcinoma, Neuroendocrine (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromones (therapeutic use)
• Intestinal Neoplasms (drug therapy, enzymology, pathology)
• Mice
• Morpholines (therapeutic use)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (therapeutic use)
• Sirolimus (therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)