The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors.
The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.
Castelletti
Deborah
D
Department of Oncology, University Children's Hospital of Zurich, Switzerland.
Fiaschetti
Giulio
G
Di Dato
Valeria
V
Ziegler
Urs
U
Kumps
Candy
C
De Preter
Katleen
K
Zollo
Massimo
M
Speleman
Frank
F
Shalaby
Tarek
T
De Martino
Daniela
D
Berg
Thorsten
T
Eggert
Angelika
A
Arcaro
Alexandre
A
Grotzer
Michael A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D036702:Quassins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016196:S Phase / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C556906:NBT 272; D016271:Proto-Oncogene Proteins c-myc; D036702:Quassins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases