title: Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma.
abstract: Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its anti-tumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.
authors: a Department of Orthopedics; The Affiliated Jiangyin Hospital of Medical College of Southeast University ; Jiangyin City , Jiangsu , China.
authors: Yun-Rong
authors: YR
authors: Zhu
authors: Han
authors: H
authors: Min
authors: Jian-Feng
authors: JF
authors: Fang
authors: Feng
authors: F
authors: Zhou
authors: Xiong-Wei
authors: XW
authors: Deng
authors: Yun-Qing
authors: YQ
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D058539:Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: MEK/Erk and chemo-resistance; NVP-BEZ235; PI3K-Akt-mTOR signaling; mTOR complex 1 (mTORC1); mTOR complex 2 (mTORC2); mammalian target of rapamycin (mTOR); osteosarcoma; phosphatidylinositol 3-kinase (PI3K); phosphoinositide-dependent protein kinase-1 (PDK1); receptor tyrosine kinases (RTKs)