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


Castelletti, D; Fiaschetti, G; Di Dato, V; Ziegler, U; Kumps, C; De Preter, K; Zollo, M; Speleman, F; Shalaby, T; De Martino, D; Berg, T; Eggert, A; Arcaro, A; Grotzer, M A (2010). The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. Molecular Cancer Therapeutics, 9(12):3145-3157.

Abstract

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort to 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 anti-proliferative 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 the eukaryotic 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 two main pro-proliferative signaling pathways, i.e. the AKT and the MEK/extracellular signal-regulated kinase (ERK) 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 anti-tumor 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.

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort to 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 anti-proliferative 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 the eukaryotic 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 two main pro-proliferative signaling pathways, i.e. the AKT and the MEK/extracellular signal-regulated kinase (ERK) 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 anti-tumor 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Microscopy and Image Analysis
04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 October 2010
Deposited On:14 Jan 2011 14:13
Last Modified:15 Jun 2016 19:15
Publisher:American Association for Cancer Research
ISSN:1535-7163
Publisher DOI:https://doi.org/10.1158/1535-7163.MCT-10-0539
PubMed ID:20889731
Permanent URL: https://doi.org/10.5167/uzh-38849

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