title: Systematic screen with kinases inhibitors reveals kinases play distinct roles in growth of osteoprogenitor cells.
abstract: Cancer treatment-related bone loss has become growing problematic, especially in breast and prostate cancer treated with hormone/endocrine therapy, chemotherapy and radiotherapy. However, bone loss caused by targeted therapy in cancer patients is largely unknown yet. In present study, a kinase inhibitors screen was applied for MC3T3-E1, a murine osteoprogenitor cell line, and seven kinase inhibitors (GSK1838705A, PF-04691502, Dasatinib, Masitinib, GDC-0941, XL880 and Everolimus) were found to suppress the cell viability with dose- and time-dependent manner. The most interesting is that many kinase inhibitors (such as lapatinib, erlotinib and sunitinib) can promote MC3T3-E1 cell proliferation at 0.01 μM. 4 out of 7 inhibitors were selected to perform the functional study and found that they lead to cell cycle dysregulation, treatments of PF-04691502 (AKT inhibitor), Dasatinib (Src inhibitor) and Everolimus (mTOR inhibitor) lead to G1 arrest of MC3T3-E1 cells via downregulation of cyclin D1 and p-AKT, whereas XL880 (MET and VEGFR inhibitor) treatment results in increase of sub-G1 and G2/M phase by upregulation of p53 protein. Our work provides important indications for the comprehensive care of cancer patients treated with some targeted drugs.
authors.affiliation: Department of Orthopedic Surgery, Jinling Hospital Affiliated to School of Medicine, Nanjing University Nanjing, Jiangsu Province, China.
authors.forename: Ni-Rong
authors.initials: NR
authors.lastname: Bao
authors.forename: Meng
authors.initials: M
authors.lastname: Lu
authors.forename: Fan-Wen
authors.initials: FW
authors.lastname: Bin
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Chang
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Zhou
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.forename: Jian-Ning
authors.initials: JN
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D010011:Osteocytes / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Cancer treatment-related bone loss; kinases inhibitors screening; osteoprogenitor cells