Dataset Information
Preclinical evaluation of protein synthesis inhibitor omacetaxine in pediatric brainstem gliomas.
Ontology highlight
ABSTRACT: Background
Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as a highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development of novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated for its potential antitumor effects against preclinical DIPG models.Methods
We employed primary DIPG cultures to study omacetaxine's cytotoxicity and its impact on colony formation. Annexin V staining and flow cytometry assessed apoptosis. Wound healing assays evaluated migration, while western blotting determined inhibition of oncogenic proteins. We tested omacetaxine's therapeutic efficacy in an orthotopic DIPG model and assessed brain penetration using mass spectrometry.Results
We found a pronounced cytotoxic activity of omacetaxine against DIPG neurospheres, with low IC50 values of approximately 20 nM. Omacetaxine exerted its anti-proliferative effect by inhibiting protein synthesis and the induction of apoptotic pathways, evidenced by significant elevated levels of cleaved caspase 3 and cleaved PARP, both key markers of apoptosis. Omacetaxine effectively targeted oncogenic players such as PDGFRα and PI3K without additional effects on the mTOR signaling pathway. Furthermore, our study revealed the inhibitory effects of omacetaxine on cell migration, and a significant reduction in integrin/FAK signaling, which plays a crucial role in tumor progression and metastasis.Conclusions
Despite these promising in vitro effects, omacetaxine's efficacy in an orthotopic DIPG model was limited due to inadequate penetration across the blood-brain barrier. As such, further research and advancements are crucial to improve the drug's brain penetration, thus enhancing its overall therapeutic potential.
SUBMITTER: Chen Y
PROVIDER: S-EPMC10976909 | biostudies-literature | 2024 Jan-Dec
REPOSITORIES: biostudies-literature
Publications
Preclinical evaluation of protein synthesis inhibitor omacetaxine in pediatric brainstem gliomas.
Neuro-oncology advances 20240101 1
<h4>Background</h4>Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as a highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development of novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated for its potential antitumor effects against preclinical DIPG models.<h4>Methods</h4>We employed primary DIPG cultures to study omacetaxine's cyto ...[more]
