Abstract
Growing 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.
| Language | English |
|---|---|
| Pages | 25-35 |
| Number of pages | 11 |
| Journal | European Journal of Pharmacology |
| Volume | 805 |
| DOIs | |
| Publication status | Published - 15 Jun 2017 |
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Keywords
- Beta-carboline
- Cancer
- Harmine
- Protein synthesis
- Translation initiation
- Humans
- Ribosomes/drug effects
- Antineoplastic Agents/chemistry
- RNA, Messenger/genetics
- Biological Transport
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Protein Biosynthesis/drug effects
- Harmine/chemistry
Cite this
}
A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis. / Carvalho, Annelise; Chu, Jennifer; Meinguet, Céline; Kiss, Robert; Vandenbussche, Guy; Masereel, Bernard; Wouters, Johan; Kornienko, Alexander; Pelletier, Jerry; Mathieu, Véronique.
In: European Journal of Pharmacology, Vol. 805, 15.06.2017, p. 25-35.Research output: Contribution to journal › Article
TY - JOUR
T1 - A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis
AU - Carvalho, Annelise
AU - Chu, Jennifer
AU - Meinguet, Céline
AU - Kiss, Robert
AU - Vandenbussche, Guy
AU - Masereel, Bernard
AU - Wouters, Johan
AU - Kornienko, Alexander
AU - Pelletier, Jerry
AU - Mathieu, Véronique
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Growing 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.
AB - Growing 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.
KW - Beta-carboline
KW - Cancer
KW - Harmine
KW - Protein synthesis
KW - Translation initiation
KW - Humans
KW - Ribosomes/drug effects
KW - Antineoplastic Agents/chemistry
KW - RNA, Messenger/genetics
KW - Biological Transport
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Protein Biosynthesis/drug effects
KW - Harmine/chemistry
UR - http://www.scopus.com/inward/record.url?scp=85015783857&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2017.03.034
DO - 10.1016/j.ejphar.2017.03.034
M3 - Article
VL - 805
SP - 25
EP - 35
JO - European Journal of Pharmacology
T2 - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
ER -