Assessment of GSK1904529A as a promising anti-osteosarcoma agent

The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells,...

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Bibliographic Details
Published in:Oncotarget 2017-07, Vol.8 (30), p.49646-49654
Main Authors: Fei, Hao-Dong, Yuan, Qi, Mao, Li, Chen, Feng-Li, Cui, Zhao-Hui, Tao, Sha, Ji, Feng
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Caspase 3
Cell Cycle - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Disease Models, Animal
Gene Knockdown Techniques
Humans
Imidazoles - pharmacology
Male
Mice
Osteosarcoma - drug therapy
Osteosarcoma - metabolism
Osteosarcoma - pathology
Pyridines - pharmacology
Receptor, IGF Type 1 - antagonists & inhibitors
Receptor, IGF Type 1 - genetics
Receptor, IGF Type 1 - metabolism
Research Paper
Signal Transduction - drug effects
Xenograft Model Antitumor Assays
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Summary:The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells, treatment with GSK1904529A (at nM concentrations) significantly inhibited cell proliferation. At the molecular level, GSK1904529A almost completely blocked IGF1R activation in OS cells, and inhibited downstream AKT-ERK activation. IGF1R silence by targeted shRNA also inhibited AKT-ERK activation and Saos-2 cell proliferation. Significantly, GSK1904529A was unable to further inhibit proliferation of IGF1R-silenced Saos-2 cells. In vivo, GSK1904529A administration orally inhibited Saos-2 tumor growth in nude mice. Together, these results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.17911