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Targeting melanoma with dual phosphoinosite 3-kinase/mammalian target of rapamycin inhibitors

Marone, Romina and Erhart, Dominik and Mertz, Ann C. and Bohnacker, Thomas and Schnell, Christian and Cmiljanovic, Vladimir and Stauffer, Frédéric and Garcia-Echeverria, Carlos and Giese, Bernd and Maira, Sauveur-Michel and Wymann, Matthias P.. (2009) Targeting melanoma with dual phosphoinosite 3-kinase/mammalian target of rapamycin inhibitors. Molecular Cancer Research, Vol. 7. pp. 601-613.

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Official URL: http://edoc.unibas.ch/dok/A5262596

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Abstract

Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein kinase pathways are often constitutively activated in melanoma and have thus been considered as promising drug targets. Exposure of melanoma cells to NVP-BAG956, NVP-BBD130, and NVP-BEZ235, a series of novel, potent, and stable dual PI3K/mammalian target of rapamycin (mTOR) inhibitors, resulted in complete G1 growth arrest, reduction of cyclin D1, and increased levels of p27(KIP1), but negligible apoptosis. In contrast, treatment of melanoma with the pan-class I PI3K inhibitor ZSTK474 or the mTORC1 inhibitor rapamycin resulted only in minor reduction of cell proliferation. In a syngeneic B16 mouse melanoma tumor model, orally administered NVP-BBD130 and NVP-BEZ235 efficiently attenuated tumor growth at primary and lymph node metastatic sites with no obvious toxicity. Metastatic melanoma in inhibitor-treated mice displayed reduced numbers of proliferating and significantly smaller tumor cells. In addition, neovascularization was blocked and tumoral necrosis increased when compared with vehicle-treated mice. In conclusion, compounds targeting PI3K and mTOR simultaneously were advantageous to attenuate melanoma growth and they develop their potential by targeting tumor growth directly, and indirectly via their interference with angiogenesis. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential in metastatic melanoma therapy.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Bioorganische Chemie (Giese)
03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P. and Giese, Bernd
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:AACR
ISSN:1541-7786
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:01
Deposited On:22 Mar 2012 14:10

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