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Investigational New Drugs

, Volume 32, Issue 4, pp 598–603 | Cite as

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. KratzkeEmail author
PRECLINICAL STUDIES

Summary

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.

Keywords

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

Notes

Acknowledgments

We would like to thank Sabine Darling, Nate Rietvold and Ryan McDonald for their technical assistance.

Disclosure of Potential Conflicts of Interest

All other authors declare no potential conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Esther Z. Chen
    • 1
  • Blake A. Jacobson
    • 1
  • Manish R. Patel
    • 1
  • Aniekan M. Okon
    • 2
  • Shui Li
    • 2
  • Kerry Xiong
    • 1
  • Abhishek J. Vaidya
    • 1
  • Peter B. Bitterman
    • 1
  • Carston R. Wagner
    • 2
  • Robert A. Kratzke
    • 1
    • 3
    Email author
  1. 1.Department of MedicineUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Medicinal ChemistryUniversity of MinnesotaMinneapolisUSA
  3. 3.Division of Hematology, Oncology and TransplantationUniversity of Minnesota Medical SchoolMinneapolisUSA

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