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

Am J Pathol. 2011 Jan;178(1):336-44. doi: 10.1016/j.ajpath.2010.11.023. Epub 2010 Dec 23.

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.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / enzymology
  • Carcinoma, Neuroendocrine / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / therapeutic use*
  • Intestinal Neoplasms / drug therapy*
  • Intestinal Neoplasms / enzymology
  • Intestinal Neoplasms / 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*

Substances

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