title: 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.affiliation: INSERM, U865, Faculté Laënnec, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Couderc
authors.forename: Gilles
authors.initials: G
authors.lastname: Poncet
authors.forename: Karine
authors.initials: K
authors.lastname: Villaume
authors.forename: Martine
authors.initials: M
authors.lastname: Blanc
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.forename: Florian
authors.initials: F
authors.lastname: Lepinasse
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Colette
authors.initials: C
authors.lastname: Roche
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000627:therapeutic use*; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000903:Antibiotics, Antineoplastic; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus