title: Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model.
abstract: The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology.
authors.affiliation: The 2nd Department of Medicine, Faculty of Medicine, Semmelweis University H-1088 Budapest, Szentkirályi Str. 46., Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nagy
authors.affiliation: The 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University H-1088 Budapest, Üllői Str. 26., Hungary.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: Laboratory of Proteomics, Biological Research Centre H-6726 Szeged, Temesvári Krt. 62., Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Hunyadi-Gulyás
authors.affiliation: The 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University H-1088 Budapest, Üllői Str. 26., Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Micsik
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University Szentkirályi Str. 46., H-1088 Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Nyírő
authors.affiliation: The 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University H-1088 Budapest, Üllői Str. 26., Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Rácz
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University Szentkirályi Str. 46., H-1088 Budapest, Hungary.
authors.forename: Henriett
authors.initials: H
authors.lastname: Butz
authors.affiliation: The 2nd Department of Medicine, Faculty of Medicine, Semmelweis University H-1088 Budapest, Szentkirályi Str. 46., Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Perge
authors.affiliation: The 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University H-1088 Budapest, Üllői Str. 26., Hungary.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.affiliation: Laboratory of Proteomics, Biological Research Centre H-6726 Szeged, Temesvári Krt. 62., Hungary.
authors.forename: Katalin F
authors.initials: KF
authors.lastname: Medzihradszky
authors.affiliation: The 2nd Department of Medicine, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Szentkirályi Str. 46., Hungary; Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Rácz
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary; "Lendület-2013" Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
authors.affiliation: The 2nd Department of Medicine, Faculty of Medicine, Semmelweis University H-1088 Budapest, Szentkirályi Str. 46., Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Igaz
keywords: 9-cis retinoic acid; Adrenocortical cancer; SET protein; circulating microRNA; mitotane; xenograft