Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells

Esther Z. Chen, Blake A Jacobson, Manish R Patel, Aniekan M. Okon, Shui Li, Kerry Xiong, Abhishek J. Vaidya, Peter B Bitterman, Carston R Wagner, Robert A Kratzke

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Deranged cap-mediated translation is implicated in the genesis, maintenance and progression of many human cancers including mesothelioma. In this study, disrupting the eIF4F complex by antagonizing the eIF4E-mRNA-cap interaction is assessed as a therapy for mesothelioma. Mesothelioma cells were treated with 4Ei-1, a membrane permeable prodrug that when converted to the active drug, 7-benzyl guanosine monophosphate (7Bn-GMP) displaces capped mRNAs from the eIF4F complex. Colony formation was measured in mesothelioma treated with 4Ei-1 alone or combined with pemetrexed. Proliferation was examined in cells treated with 4Ei-1. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation in lysates exposed to 4Ei-1. 4Ei-1 treatment resulted in a dose dependent decrease in colony formation and cell viability. Combination therapy of 4Ei-1 with pemetrexed further reduced colony number. Formation of eIF4F cap-complex decreased in response to 4Ei-1 exposure. 4Ei-1 is a novel prodrug that reduces proliferation, represses colony formation, diminishes association of eIF4F with the mRNA cap, and sensitizes mesothelioma cells to pemetrexed.

Original languageEnglish (US)
Pages (from-to)598-603
Number of pages6
JournalInvestigational New Drugs
Volume32
Issue number4
DOIs
StatePublished - Jan 1 2014

Fingerprint

Mesothelioma
Protein Biosynthesis
Pemetrexed
Prodrugs
Messenger RNA
Guanosine Monophosphate
Cell Survival
Maintenance
Membranes
Therapeutics
Pharmaceutical Preparations
Neoplasms

Keywords

  • 4Ei-1
  • 7-benzyl guanosine monophosphate
  • Cap-dependent translation
  • Mesothelioma
  • eIF4E

Cite this

Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells. / Chen, Esther Z.; Jacobson, Blake A; Patel, Manish R; Okon, Aniekan M.; Li, Shui; Xiong, Kerry; Vaidya, Abhishek J.; Bitterman, Peter B; Wagner, Carston R; Kratzke, Robert A.

In: Investigational New Drugs, Vol. 32, No. 4, 01.01.2014, p. 598-603.

Research output: Contribution to journalArticle

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