Dual mTORC1/2 inhibition by INK-128 results in antitumor activity in preclinical models of osteosarcoma.
Biochem Biophys Res Commun
; 468(1-2): 255-61, 2015.
Article
em En
| MEDLINE
| ID: mdl-26514724
Existing evidence has shown that mammalian target of rapamycin (mTOR) overactivation is an important contributor of osteosarcoma (OS) progression. Here, we studied the potential anti-OS activity of a potent mTOR kinase inhibitor: INK-128 (MLN0128). We demonstrated that INK-128 induced potent cytotoxic effects against several human OS cell lines (U2OS, MG-63 and SaOs-2), yet same INK-128 treatment was safe (non-cytotoxic) to OB-6 human osteoblastic cells and MLO-Y4 human osteocytic cells. INK-128 induced caspase-dependent apoptosis in OS cells, but not in MLO-Y4/OB-6 cells. The caspase-3 specific inhibitor (z-DVED-fmk) or the pan caspase inhibitor (z-VAD-fmk) dramatically attenuated INK-128-exerted cytotoxicity against OS cells. Molecularly, INK-128 inhibited activation of mTORC1 (S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser-473 phosphorylation), without affecting AKT Thr-308 phosphorylation in U2OS cells. Significantly, AKT inhibition by MK-2206 (an AKT inhibitor), or AKT1/2 stable knockdown by targeted-shRNA, remarkably sensitized INK-128-induced activity in OS cells. In vivo, oral administration of INK-128 potently inhibited U2OS xenograft growth in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation in xenograft tumors was also suppressed with INK-128 administration. In summary, we show that INK-128 exerts potent anti-OS activity in vitro and in vivo. INK-128 might be further investigated as a novel anti-OS agent.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Benzoxazóis
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Neoplasias Ósseas
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Osteossarcoma
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Complexos Multiproteicos
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Serina-Treonina Quinases TOR
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
China