Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer.

Abstract

The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.

• Authors: Diana Rita Szabó, Kornélia Baghy, Peter M Szabó, Adrienn Zsippai, István Marczell, Zoltán Nagy, Vivien Varga, Katalin Éder, Sára Tóth, Edit I Buzás, András Falus, Ilona Kovalszky, Attila Patócs, Károly Rácz, Peter Igaz
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 71 Issue 5 Pg. 917-32 (Mar 2014) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 23807211 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Gonadal Steroid Hormones
• Alitretinoin
• Tretinoin

Topics

• Adrenal Cortex Neoplasms (drug therapy)
• Alitretinoin
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Computational Biology (methods)
• Gene Expression Regulation, Neoplastic (drug effects, immunology, physiology)
• Gonadal Steroid Hormones (metabolism)
• Humans
• Mice
• Mice, Nude
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, physiology)
• Tretinoin (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays