title: Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma.
abstract: 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 μM) 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/GSK3β/β-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 μM) 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.
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Victor Hugo
authors.initials: VH
authors.lastname: Villar
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vögler
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Barceló
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.|Department of Oncology, University Hospital Virgen del Rocío and Biomedicine Institute of Sevilla (IBIS), Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín-Broto
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.|Department of Hematology, University Hospital Son Espases, Palma de Mallorca, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Martínez-Serra
authors.affiliation: Instituto de la Grasa, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain.|CIBER:CB06/03 Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud, Carlos III (ISCIII), Spain.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ruiz-Gutiérrez
authors.affiliation: Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.|CIBER:CB06/03 Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud, Carlos III (ISCIII), Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Alemany
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D014315:Triterpenes; D000097245:Ursolic Acid