A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis.
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.
Laboratoire de Cancérologie et Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Annelise
A
Carvalho
Department of Biochemistry, McGill University, Montreal, Québec, Canada.
Jennifer
J
Chu
Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), Université de Namur, Namur, Belgium.
Céline
C
Meinguet
Laboratoire de Cancérologie et Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Robert
R
Kiss
Laboratory for the Structure and Function of Biological Membranes, Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium.
Guy
G
Vandenbussche
Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), Université de Namur, Namur, Belgium.
Bernard
B
Masereel
Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), Université de Namur, Namur, Belgium.
Johan
J
Wouters
Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX 78666, USA.
Alexander
A
Kornienko
Department of Biochemistry, McGill University, Montreal, Québec, Canada.
Jerry
J
Pelletier
Laboratoire de Cancérologie et Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: vemathie@ulb.ac.be.
Véronique
V
Mathieu
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006247:Harmine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D006247:Harmine
Beta-carboline; Cancer; Harmine; Protein synthesis; Translation initiation