Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.

Beuvink, Iwan and Boulay, Anne and Fumagalli, Stefano and Zilbermann, Frederic and Ruetz, Stephan and O'Reilly, Terence and Natt, Francois and Hall, Jonathan and Lane, Heidi A and Thomas, George (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell, 120 (6). pp. 747-759. ISSN 0092-8674

Abstract

Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.

Item Type: Article
Related URLs:
Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Related URLs:
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8076

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.