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.
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Authors | 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 |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 32
Issue 4
Pg. 598-603
(Aug 2014)
ISSN: 1573-0646 [Electronic] United States |
PMID | 24711125
(Publication Type: Journal Article)
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Chemical References |
- Eukaryotic Initiation Factor-4E
- Eukaryotic Initiation Factor-4F
- Glutamates
- Oncogene Proteins
- Prodrugs
- RNA, Messenger
- Pemetrexed
- Guanine
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Topics |
- Cell Line, Tumor
- Cell Proliferation
(drug effects, genetics)
- Cell Survival
(drug effects, genetics)
- Eukaryotic Initiation Factor-4E
(antagonists & inhibitors)
- Eukaryotic Initiation Factor-4F
(antagonists & inhibitors)
- Glutamates
(pharmacology)
- Guanine
(analogs & derivatives, pharmacology)
- Humans
- Mesothelioma
(drug therapy, genetics)
- Oncogene Proteins
(antagonists & inhibitors, genetics)
- Pemetrexed
- Prodrugs
(pharmacology)
- Protein Biosynthesis
(drug effects, genetics)
- RNA, Messenger
(genetics)
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