title: The novel atypical retinoid ST5589 down-regulates Aurora Kinase A and has anti-tumour activity in lymphoma pre-clinical models.
abstract: Despite the marked improvements in the treatment of lymphomas, there is still a need for new therapeutic agents. Synthetic retinoids represent a class of compounds with anti-cancer activity. Here, we report the preclinical activity of a new member of this class, the ST1926-derivative ST5589, in lymphomas. ST5589 presented a dose-dependent anti-proliferative activity in almost all of the 25 lymphoma cell lines analysed, with a median 50% inhibitory concentration of 433 nM. Apoptosis was observed in 8/11 cell lines. ST5589 induced changes in the gene expression profiles of the cell lines, including the down-regulation of Aurora Kinase A (AURKA). Specific gene expression signatures were associated with a higher sensitivity to the compound and combination of ST5589 with carfilzomib revealed the importance of proteasome activity in mediating the anti-tumour activity of ST5589. In conclusion, we have identified a new mechanism of action of atypical retinoids as anti-cancer compounds, and the encouraging results obtained with the new ST1926-derivative ST5589 provide the basis for further developments of the compound.
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.|SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tarantelli
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Afua Adjeiwaa
authors.initials: AA
authors.lastname: Mensah
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stathis
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.affiliation: Research & Development, Sigma-Tau, Pomezia, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.affiliation: Research & Development, Sigma-Tau, Pomezia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D012176:Retinoids / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D012176:Retinoids; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: MYC; ST1926; aurora kinase; lymphomas; new drugs for lymphoma; retinoids