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oai:repisalud.isciii.es:20.500.12105/202652024-11-28T16:39:44Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16958col_20.500.12105_16967

00925njm 22002777a 4500 dc Hugo Villar, Victor author Vögler, Oliver author Barcelo, Francisca author Martin-Broto, Javier author Martinez-Serra, Jordi author Ruiz-Gutierrez, Valentina author Alemany, Regina author 2016-05-24 Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA), being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR), in human soft tissue sarcoma cells. UA (5-50 mu M) strongly inhibited (up to 80%) the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6-9 h) strongly blocked the survival AKT/GSK3 beta/beta-catenin signalling pathway, which led to a concomitant reduction of the anti-apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10-15 mu M) enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR-induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS. Hugo Villar V, Vögler Bernhard O, Barcelo F, Martin-Broto J, Martinez Serra JJ, Ruiz-Gutierrez V, et al. Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma. PLoS One. 2016 May 24;11(5):e0155946. 10.1371/journal.pone.0155946 1932-6203 PloS One http://hdl.handle.net/20.500.13003/10359 27219337 L610516018 2-s2.0-84971572080 http://hdl.handle.net/20.500.12105/20265 376880700030 Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma