Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells

Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3β and Src kinase pathways were shown to be acti...

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Published in:British journal of cancer 2013-09, Vol.109 (5), p.1214-1222
Main Authors: VAN OOSTERWIJK, J. G, VAN RULER, M. A. J. H, BRIAIRE-DE BRUIJN, I. H, HERPERS, B, GELDERBLOM, H, VAN DE WATER, B, BOVEE, J. V. M. G
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adolescent
Adult
Aged
Aged, 80 and over
AKT protein
Antibiotics, Antineoplastic - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis
Apoptosis - drug effects
Biological and medical sciences
Bone Neoplasms - drug therapy
Bone tumors
Cancer therapies
Cartilage
Cell Line, Tumor
Cell lines
Cell migration
Cell Movement - drug effects
Chemoresistance
Chemotherapy
Chondrosarcoma
Chondrosarcoma - drug therapy
Dasatinib
Diseases of the osteoarticular system
Doxorubicin
Doxorubicin - therapeutic use
Drug Resistance, Neoplasm
Drug Synergism
Female
Fyn protein
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
HeLa Cells
Humans
Immunohistochemistry
Indoles - pharmacology
Kinases
Male
MCF-7 Cells
Medical research
Medical sciences
Metastases
Metastasis
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutation
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-fyn - drug effects
Pyrimidines - pharmacology
Radiation therapy
Signal transduction
Signal Transduction - drug effects
src-Family Kinases - antagonists & inhibitors
src-Family Kinases - metabolism
Thiazoles - pharmacology
Translational Therapeutics
Tumor Suppressor Protein p53 - genetics
Tumors
Tumors of striated muscle and skeleton
Young Adult
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Summary:Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3β and Src kinase pathways were shown to be activated in chondrosarcoma cell lines. Our aim was to investigate the role of these kinases in chemoresistance and migration in chondrosarcoma in relation to TP53 mutation status. We used five conventional and three dedifferentiated chondrosarcoma cell lines and investigated the effect of PI3K/AKT/GSK3β pathway inhibition (enzastaurin) and Src pathway inhibition (dasatinib) in chemoresistance using WST assay and live cell imaging with AnnexinV staining. Immunohistochemistry on tissue microarrays (TMAs) containing 157 cartilaginous tumours was performed for Src family members. Migration assays were performed with the RTCA xCelligence System. Src inhibition was found to overcome chemoresistance, to induce apoptosis and to inhibit migration. Cell lines with TP53 mutations responded better to combination therapy than wild-type cell lines (P=0.002). Tissue microarray immunohistochemistry confirmed active Src (pSrc) signalling, with Fyn being most abundantly expressed (76.1%). These results strongly indicate Src family kinases, in particular Fyn, as a potential target for the treatment of inoperable and metastatic chondrosarcomas, and to sensitise for doxorubicin especially in the presence of TP53 mutations.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2013.451