Research Papers:

The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

Klara Fodor, Nikoletta Dobos, Andrew Schally, Zita Steiber, Gabor Olah, Eva Sipos, Lorant Szekvolgyi and Gabor Halmos _

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Oncotarget. 2020; 11:175-187. https://doi.org/10.18632/oncotarget.27431

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Klara Fodor1, Nikoletta Dobos1, Andrew Schally2,3, Zita Steiber4, Gabor Olah1, Eva Sipos1, Lorant Szekvolgyi5 and Gabor Halmos1,2

1 University of Debrecen, Department of Biopharmacy, Debrecen, Hungary

2 Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Insitute, Miami, FL, USA

3 University of Miami, Miller School of Medicine, Department of Pathology and Department of Medicine, Divisions of Oncology and Endocrinology, Sylvester Comprehensive Center, Miami, FL, USA

4 University of Debrecen, Department of Ophthalmology, Debrecen, Hungary

5 University of Debrecen, Faculty of Medicine, Department of Biochemistry and Molecular Biology, MTA-DE Momentum, Genome Architecture and Recombination Research Group, Debrecen, Hungary

Correspondence to:

Gabor Halmos,email: [email protected]

Keywords: uveal melanoma; luteinizing hormone-releasing hormone (LHRH) receptor; angiogenesis; MASPIN/SERPINB5; AEZS-108 (AN-152/Zoptarelin Doxorubicin Acetate)

Received: December 05, 2019     Accepted: December 29, 2019     Published: January 14, 2020


Uveal melanoma (UM) is the most common malignant tumor of the eye. Recently, we have established that 46% of UM specimens express LHRH receptors. This finding supports the idea of a LHRH receptor-targeted therapy of UM patients. Cytotoxic analog of LHRH, AEZS-108 exhibits effective anti-cancer activity in LHRH-receptor positive cancers. AEZS-108 is a hybrid molecule, composed of a synthetic peptide carrier and the cytotoxic doxorubicin (DOX). In the present study, we investigated AEZS-108 induced cytotoxicity and the altered mRNA expression profile of regulatory factors related to angiogenesis and metastasis in LHRH receptor positive OCM3 cells. Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression. In order to investigate the mechanism of the induction of MASPIN by AEZS-108, OCM3 cells were treated with free DOX, D-Lys6 LHRH analog, or AEZS-108. qRT- PCR analysis revealed in OCM3 cells that AEZS-108 is a more potent inducer of MASPIN than free DOX. In conclusion, we show for the first time that AEZS-108 has a major impact in the regulation of angiogenesis thus plays a potential role in tumor suppression. Taken together, our results support the development of novel therapeutic strategies for UM focusing on LHRH receptors.

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