A Harmine-derived Beta-carboline Displays Anti-cancer Effects in vitro by Targeting Protein Synthesis

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dc.contributor.authorDe Carvalho, Annelise
dc.contributor.authorChu, Jennifer
dc.contributor.authorMeinguet, Celine
dc.contributor.authorKiss, Robert
dc.contributor.authorVandenbussche, Guy
dc.contributor.authorMasereel, Bernard
dc.contributor.authorWouters, Johan
dc.contributor.authorKornienko, Alexander
dc.contributor.authorPelletier, Jerry
dc.contributor.authorMathieu, Veronique
dc.date.accessioned2020-04-03T15:19:52Z
dc.date.available2020-04-03T15:19:52Z
dc.date.issued2017-06
dc.description.abstractGrowing evidence indicates that protein synthesis is deregulated in cancer onset and progression and targeting this process might be a selective way to combat cancers. While harmine is known to inhibit DYRK1A and intercalate into the DNA, tri-substitution was shown previously to modify its activity profile in favor of protein synthesis inhibition. In this study, we thus evaluated the optimized derivative CM16 in vitro anti-cancer effects unfolding its protein synthesis inhibition activity. Indeed, the growth inhibitory profile of CM16 in the NCI 60-cancer-cell-line-panel correlated with those of other compounds described as protein synthesis inhibitors. Accordingly, CM16 decreased in a time- and concentration-dependent manner the translation of neosynthesized proteins in vitro while it did not affect mRNA transcription. CM16 rapidly penetrated into the cell in the perinuclear region of the endoplasmic reticulum where it appears to target translation initiation as highlighted by ribosomal disorganization. More precisely, we found that the mRNA expression levels of the initiation factors EIF1AX, EIF3E and EIF3H differ when comparing resistant or sensitive cell models to CM16. Additionally, CM16 induced eIF2α phosphorylation. Those effects could explain, at least partly, the CM16 cytostatic anti-cancer effects observed in vitro while neither cell cycle arrest nor DNA intercalation could be demonstrated. Therefore, targeting protein synthesis initiation with CM16 could represent a new promising alternative to current cancer therapies due to the specific alterations of the translation machinery in cancer cells as recently evidenced with respect to EIF1AX and eIF3 complex, the potential targets identified in this present study.
dc.description.departmentChemistry and Biochemistry
dc.description.versionThis is the accepted manuscript version of an article published in the European Journal of Pharmacology.
dc.formatText
dc.format.extent24 pages
dc.format.medium1 file (.pdf)
dc.identifier.citationCarvalho, A., Chu, J., Meinguet, C., Kiss, R., Vandenbussche, G., Masereel, B., Wouters, J., Kornienko, A., Pelletier, J., & Mathieu, V. (2017). A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis. European Journal of Pharmacology, 805, pp. 25–35.
dc.identifier.doihttps://doi.org/10.1016/j.ejphar.2017.03.034
dc.identifier.issn0014-2999
dc.identifier.urihttps://hdl.handle.net/10877/9576
dc.language.isoen
dc.publisherElsevier
dc.sourceEuropean Journal of Pharmacology, 2017, Vol. 805, pp. 25–35.
dc.subjectcancer
dc.subjectharmine
dc.subjectprotein synthesis
dc.subjecttranslation initiation
dc.subjectbeta-carboline
dc.subjectChemistry and Biochemistry
dc.titleA Harmine-derived Beta-carboline Displays Anti-cancer Effects in vitro by Targeting Protein Synthesis
dc.typeArticle

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