title: FIM-A, a phosphorus-containing sirolimus, inhibits the angiogenesis and proliferation of osteosarcomas.
abstract: The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1alpha. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.
authors.affiliation: The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Wei-Nan
authors.initials: WN
authors.lastname: Liu
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Lin
authors.forename: Yuan-Rong
authors.initials: YR
authors.lastname: Cheng
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Zhao-Yang
authors.initials: ZY
authors.lastname: Wu
authors.forename: Fa-Sheng
authors.initials: FS
authors.lastname: Wang
authors.forename: Sheng-Gui
authors.initials: SG
authors.lastname: Xu
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Lin
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Lan
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Yang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy*; D010758:Phosphorus; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D010758:Phosphorus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus