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The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

(2010) MOLECULAR CANCER THERAPEUTICS. 9(12). p.3145-3157
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Abstract
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.
Keywords
C-MYC, CENTRAL-NERVOUS-SYSTEM, ONCOGENE EXPRESSION, NEUROBLASTOMA, PHOSPHORYLATION, CAP-DEPENDENT TRANSLATION, SURVIVAL, ANTITUMOR-ACTIVITY, MEDULLOBLASTOMA, ACTIVATION

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Chicago
Castelletti, Deborah, Giulio Fiaschetti, Valeria Di Dato, Urs Ziegler, Candy Kumps, Katleen De Preter, Massimo Zollo, et al. 2010. “The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors.” Molecular Cancer Therapeutics 9 (12): 3145–3157.
APA
Castelletti, D., Fiaschetti, G., Di Dato, V., Ziegler, U., Kumps, C., De Preter, K., Zollo, M., et al. (2010). The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. MOLECULAR CANCER THERAPEUTICS, 9(12), 3145–3157.
Vancouver
1.
Castelletti D, Fiaschetti G, Di Dato V, Ziegler U, Kumps C, De Preter K, et al. The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. MOLECULAR CANCER THERAPEUTICS. 2010;9(12):3145–57.
MLA
Castelletti, Deborah, Giulio Fiaschetti, Valeria Di Dato, et al. “The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors.” MOLECULAR CANCER THERAPEUTICS 9.12 (2010): 3145–3157. Print.
@article{1176758,
  abstract     = {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.},
  author       = {Castelletti, Deborah and Fiaschetti, Giulio and Di Dato, Valeria and Ziegler, Urs and Kumps, Candy and De Preter, Katleen and Zollo, Massimo and Speleman, Franki and Shalaby, Tarek and De Martino, Daniela and Berg, Thorsten and Eggert, Angelika and Arcaro, Alexandre and Grotzer, Michael A},
  issn         = {1535-7163},
  journal      = {MOLECULAR CANCER THERAPEUTICS},
  keyword      = {C-MYC,CENTRAL-NERVOUS-SYSTEM,ONCOGENE EXPRESSION,NEUROBLASTOMA,PHOSPHORYLATION,CAP-DEPENDENT TRANSLATION,SURVIVAL,ANTITUMOR-ACTIVITY,MEDULLOBLASTOMA,ACTIVATION},
  language     = {eng},
  number       = {12},
  pages        = {3145--3157},
  title        = {The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors},
  url          = {http://dx.doi.org/10.1158/1535-7163.MCT-10-0539},
  volume       = {9},
  year         = {2010},
}

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