mTOR inhibition by TAK-228 is effective against growth, survival and angiogenesis in preclinical retinoblastoma models.
Pharmacol Res Perspect
; 10(1): e00930, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-35142090
ABSTRACT
We and others have shown that aberrant activation of the mammalian target of rapamycin (mTOR) signalling is essential for retinoblastoma progression and has potential therapeutic value. TAK-228 is a potent inhibitor of mTOR1 and 2 with preclinical activity in a variety of cancers. In this study, we report that TAK-228 is a dual inhibitor of retinoblastoma and angiogenesis. TAK-228 inhibits growth and induces apoptosis in a panel of retinoblastoma cell lines, with IC50 at ~0.2 µM. Under the same experimental conditions, TAK-228 was less effective in inhibiting growth and survival in normal retinal and fibroblast cells than retinoblastoma cells. In addition, TAK-228 inhibited retinal endothelial cell capillary network formation, migration, growth and survival. We further demonstrate that TAK-228 inhibits retinoblastoma and retinal angiogenesis through inhibiting mTOR signalling. Rescue studies confirm that mTOR is the target of TAK-228 in both retinoblastoma and retinal endothelial cells. Finally, we confirm the inhibitory effects of TAK-228 on tumor and angiogenesis in retinoblastoma xenograft mouse model. Our findings provide a preclinical rationale to explore TAK-228 as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Retinoblastoma
/
Benzoxazóis
/
Neoplasias da Retina
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Pharmacol Res Perspect
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China