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

Our plain-English summary of Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells, by E.Z. Chen, B.A. Jacobson, M.R. Patel, et al (Investigational New Drugs, 2014).

The study

• Authors: E.Z. Chen, B.A. Jacobson, M.R. Patel, A.M. Okon, S. Li, K. Xiong, A.J. Vaidya, P.B. Bitterman, C.R. Wagner, R.A. Kratzke
• Journal: Investigational New Drugs
• Published: 2014;32(4):598-603
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a laboratory study of human mesothelioma cell lines grown in dishes. It involved no patients and no asbestos exposure. The authors tested 4Ei-1, an experimental prodrug that is converted into a compound (7Bn-GMP) that competitively inhibits the protein eIF4E from binding to the cap on messenger RNA, reducing cap-dependent protein production. In all three cell lines tested, 4Ei-1 reduced colony formation in a dose-dependent way, with approximate EC50 values of 10 to 25 micromolar. Combining 4Ei-1 with the chemotherapy drug pemetrexed reduced colonies more than either drug alone. In the H2373 line, each drug alone cut colonies by about 25% and the combination by about 70%. 4Ei-1 also reduced cell viability after 72 hours of treatment, but higher amounts were needed than for colony formation. In extracts of four cell lines, 4Ei-1 lowered the eIF4E bound to a cap mimic by an average of 56% and eIF4G by 42.5%. The authors concluded that 4Ei-1 reduced mesothelioma cell growth and sensitized the cells to pemetrexed. They said they could not explain why the two protein decreases were unequal.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) study of a drug on human mesothelioma cell lines
• Who was studied: Four human mesothelioma cell lines (H513, H2373, H2461, H2596) obtained from the American Type Culture Collection. Three lines were used in each colony and viability test, and all four in the cap-binding test. No patients were studied.
• Exposure: No asbestos exposure was studied. Cells were treated with the experimental prodrug 4Ei-1 alone, with the chemotherapy drug pemetrexed alone, or with both, and were compared with untreated cells. 4Ei-1 is described as a prodrug of 7Bn-GMP, which competitively inhibits eIF4E binding to the mRNA cap and negatively regulates cap-dependent translation.
• Main results:
  • 4Ei-1 reduced colony formation in a dose-dependent way in all three mesothelioma cell lines tested, with approximate EC50 values of 10 to 25 μM.
  • In all cell lines, combining pemetrexed and 4Ei-1 reduced colony formation more than either drug alone.
  • In the H2373 cell line, 4Ei-1 alone and pemetrexed alone each reduced colonies by about 25%, and the combination reduced them by about 70%.
  • After 72 hours, 4Ei-1 reduced cell viability in a dose-dependent way in all three cell lines tested, with H2373 more affected than H2461 or H2596.
  • Higher levels of 4Ei-1 were needed to inhibit proliferation than to repress colony formation.
  • In extracts from four mesothelioma cell lines exposed to 4Ei-1 (600 μM), eIF4E bound to the cap-analogue fell by an average of 56%, and eIF4G bound to eIF4E fell by an average of 42.5%.
• The authors' conclusion: The authors concluded that in mesothelioma cells 4Ei-1 reduced colony formation, suppressed formation of the cap-binding complex in vitro, diminished cell proliferation, and sensitized cells to pemetrexed.
• Limitations the authors state:
  • The authors could not explain why the decreases in eIF4E and eIF4G in the cap-binding assay were unequal, although they expected them to be equivalent.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pemetrexed (Alimta).

Related studies

• Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma — Z. Ahmad, B.A. Jacobson, et al. (2020)
• 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma — A. De, B.A. Jacobson, et al. (2018)
• Novel role of c-jun N-terminal kinase in regulating the initiation of cap-dependent translation — M.R. Patel, A.A. Sadiq, et al. (2012)
• Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1 — S. Grosso, E. Pesce, et al. (2011)
• Expression of Clara cell secretory protein in the lungs of rats exposed to silicon carbide whisker in vivo — Y. Morimoto, L. Ding, et al. (2003)
• CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells — S. Jamal, V.T. Cheriyan, et al. (2014)

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