Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma

Our plain-English summary of Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma, by Z. Ahmad, B.A. Jacobson, M.W. McDonald, et al (Cancer Chemotherapy and Pharmacology, 2020).

The study

• Authors: Z. Ahmad, B.A. Jacobson, M.W. McDonald, N. Vattendahl Vidal, G. Vattendahl Vidal, S. Chen, M. Dillenburg, A.M. Okon, M.R. Patel, C.R. Wagner, R.A. Kratzke
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2020;85(2):425-432
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Activated cap-dependent translation promotes cancer by stimulating translation of mRNAs encoding malignancy-promoting proteins. The nucleoside monophosphate Protide, 4Ei-10, undergoes intracellular uptake and conversion by Hint1 to form 7-Cl-Ph-Ethyl-GMP. 7-Cl-Ph-Ethyl-GMP is an analog of cap and inhibits protein translation by binding and sequestering eIF4E thus blocking eIF4E from binding to the mRNA cap. The effects of inhibiting translation initiation by disruption of the eIF4F complex with 4Ei-10 were examined in malignant mesothelioma (MM). In a cell-free assay system, formation of the eIF4F complex was disabled in response to exposure to 4Ei-10. Treatment of MM with 4Ei-10 resulted in decreased cell proliferation, increased sensitivity to pemetrexed and altered expression of malignancy-related proteins. In light of these findings, suppression of translation initiation by small molecule inhibitors like 4Ei-10 alone or in combination with pemetrexed represents an encouraging strategy meriting further evaluation in the treatment of MM.

In plain English

This was a laboratory study of an experimental drug, 4Ei-10, tested on four human mesothelioma cell lines (H513, H2373, H2461 and H2596) grown in dishes. It did not involve patients, animals or asbestos exposure. 4Ei-10 is designed to block a step cells use to begin making certain proteins. The drug lowered cell viability in a dose-dependent way in all four lines. The effect was modest at 72 hours and larger at 96 hours for H513 and H2373. In cell extracts, the drug cut the amount of eIF4E protein captured on a cap-analogue by an average of 85.5%. In treated cells, cyclin D1 fell by an average of 82.5%. Bcl2 fell by an average of 38.6% in three lines but rose 22% in H2461. Combining 4Ei-10 with the chemotherapy drug pemetrexed lowered viability significantly more than either drug alone, except versus pemetrexed alone in H2461. The authors concluded this approach, alone or with pemetrexed, merits further evaluation. They noted modest differences in cell viability with the 4Ei-10 batch used in the combination test versus earlier experiments, and said differing cell-line sensitivity is not understood.

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) experiments on cultured mesothelioma cell lines and cell extracts; no human participants or animals
• Who was studied: four human mesothelioma cell lines (H513, H2373, H2461 and H2596) obtained from the American Type Culture Collection
• Exposure: no asbestos exposure was studied. Cells were treated with the experimental translation inhibitor 4Ei-10 at a range of concentrations, with pemetrexed, or with both (200 µM 4Ei-10 and 200 nM pemetrexed for 72 hours in the combination test). Cell extracts were treated with 400 µM 4Ei-10.
• Main results:
  • 4Ei-10 reduced cell viability in all four lines. The effect was modest at 72 hours, more substantial at 96 hours for H513 and H2373, and moderate at 96 hours for H2461 and H2596.
  • In cell extracts from the four lines, binding of eIF4E to the cap-analogue was reduced on average by 85.5% compared with untreated extracts.
  • Cyclin D1 decreased by an average of 82.5% across the four treated cell lines.
  • Bcl2 decreased by an average of 38.6% in three cell lines.
  • In H2461 cells, Bcl2 increased by 22% after treatment.
  • HSF1 fell to 58% of untreated levels in H2461 and to 33% in H2596. It did not markedly change in H2373.
  • HSF1 increased 1.77-fold in treated H513 cells.
  • CHOP was below detection in H513 and H2461. In H2373 it decreased to 0.005% of untreated levels (as printed). In H2596 it increased 50.4-fold.
  • The combination of 4Ei-10 and pemetrexed reduced viability significantly more than either drug alone (p less than 0.01) in each cell line, except compared with pemetrexed alone in H2461.
  • Adding 4Ei-10 reduced cell viability by an average of 18.6% compared with pemetrexed alone.
• The authors' conclusion: The authors concluded that suppressing translation initiation with small molecules such as 4Ei-10, alone or combined with pemetrexed, is an encouraging strategy that merits further evaluation for treating malignant mesothelioma.
• Limitations the authors state:
  • Captured eIF4G did not fall as much as eIF4E, which the authors could not explain.
  • Cell viability in the combination experiment, which used a particular batch of 4Ei-10, differed modestly from the earlier experiments.
  • The pemetrexed dose used for H2461 may have been too high, limiting the comparison.
  • The reason the cell lines differed in sensitivity to 4Ei-10 is not understood.

Topics

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

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

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