Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas.
Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC(50) growth inhibitory values between 30-100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine. -
Van Goietsenoven
Gwendoline
G
Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
Hutton
Jenna
J
Becker
Jean-Paul
JP
Lallemand
Benjamin
B
Robert
Francis
F
Lefranc
Florence
F
Pirker
Christine
C
Vandenbussche
Guy
G
Van Antwerpen
Pierre
P
Evidente
Antonio
A
Berger
Walter
W
Prévost
Martine
M
Pelletier
Jerry
J
Kiss
Robert
R
Kinzy
Terri Goss
TG
Kornienko
Alexander
A
Mathieu
Véronique
V
D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D019668:Liliaceae / Q000737:chemistry*; D008545:Melanoma; D051379:Mice; D008958:Models, Molecular; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism
D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; C094814:EEF1A1 protein, human; D006912:Hydroxyquinolines; D020648:Peptide Elongation Factor 1; D010617:Phenanthridines; D015363:Quinolones; C010753:narciclasine; C010064:carbostyril