Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model

Zoltán Nagy, Kornélia Baghy, E. Hunyadi-Gulyás, Tamás Micsik, Gábor Nyíro, Gergely Rácz, Henriett Butz, Pál Perge, I. Kovalszky, Katalin F. Medzihradszky, K. Rácz, A. Patócs, P. Igaz

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3645-3658
Number of pages14
JournalAmerican Journal of Cancer Research
Volume5
Issue number12
Publication statusPublished - 2015

Fingerprint

Mitotane
Heterografts
Adrenocortical Carcinoma
alitretinoin
Type 4 Cyclic Nucleotide Phosphodiesterase
Proteins
SCID Mice
MicroRNAs
Proteomics
Real-Time Polymerase Chain Reaction
Neoplasms

Keywords

  • 9-cis retinoic acid
  • Adrenocortical cancer
  • Circulating microRNA
  • Mitotane
  • SET protein
  • Xenograft

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model. / Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, E.; Micsik, Tamás; Nyíro, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, I.; Medzihradszky, Katalin F.; Rácz, K.; Patócs, A.; Igaz, P.

In: American Journal of Cancer Research, Vol. 5, No. 12, 2015, p. 3645-3658.

Research output: Contribution to journalArticle

Nagy, Zoltán ; Baghy, Kornélia ; Hunyadi-Gulyás, E. ; Micsik, Tamás ; Nyíro, Gábor ; Rácz, Gergely ; Butz, Henriett ; Perge, Pál ; Kovalszky, I. ; Medzihradszky, Katalin F. ; Rácz, K. ; Patócs, A. ; Igaz, P. / Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model. In: American Journal of Cancer Research. 2015 ; Vol. 5, No. 12. pp. 3645-3658.
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