4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

Blake A. Jacobson, Zeeshan Ahmad, Sierra Chen, Gabriella Waldusky, Maxwell Dillenburg, Emilia Stoian, Daniel A. Cambron, Anil J. Patel, Manish R. Patel, Carston R. Wagner, Robert A. Kratzke

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)636-643
Number of pages8
JournalInvestigational New Drugs
Volume39
Issue number3
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
The work was supported by the John Skoglund Fund for Lung Cancer Research at the University of Minnesota.

Keywords

  • 4Ei-10
  • Cap-dependent translation
  • Non-small cell lung cancer
  • ProTide
  • eIF4E
  • eIF4G

PubMed: MeSH publication types

  • Journal Article

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