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Int J Clin Exp Pathol. 2013 Sep 15;6(10):2082-91. eCollection 2013.

Systematic screen with kinases inhibitors reveals kinases play distinct roles in growth of osteoprogenitor cells.

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1
Department of Orthopedic Surgery, Jinling Hospital Affiliated to School of Medicine, Nanjing University Nanjing, Jiangsu Province, China.

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.

KEYWORDS:

Cancer treatment-related bone loss; kinases inhibitors screening; osteoprogenitor cells

PMID:
24133586
PMCID:
PMC3796230
[Indexed for MEDLINE]
Free PMC Article
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