4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer.
Invest New Drugs
; 39(3): 636-643, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-33230623
ABSTRACT
In order to suppress 5' cap-mediated translation a highly available inhibitor of the interaction between the 5' mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5'-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.
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Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
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Carcinoma Pulmonar de Células não Pequenas
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Fator de Iniciação 4E em Eucariotos
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Neoplasias Pulmonares
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Antineoplásicos
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Nucleotídeos
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article