TY - JOUR
T1 - The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors
AU - Castelletti, Deborah
AU - Fiaschetti, Giulio
AU - Dato, Valeria Di
AU - Ziegler, Urs
AU - Kumps, Candy
AU - Preter, Katleen De
AU - Zollo, Massimo
AU - Speleman, Frank
AU - Shalaby, Tarek
AU - Martino, Daniela De
AU - Berg, Thorsten
AU - Eggert, Angelika
AU - Arcaro, Alexandre
AU - Grotzer, Michael A.
PY - 2010/12
Y1 - 2010/12
N2 - 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 G1/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.
AB - 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 G1/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.
UR - https://www.scopus.com/pages/publications/78650496926
U2 - 10.1158/1535-7163.MCT-10-0539
DO - 10.1158/1535-7163.MCT-10-0539
M3 - Article
C2 - 20889731
AN - SCOPUS:78650496926
SN - 1535-7163
VL - 9
SP - 3145
EP - 3157
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -