Journal Article

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

Seitz, Stephan, Schally, Andrew Victor, Weber, Florian, Engel, Jörg Bernhard, Hohla, Florian, Klinkhammer-Schalke, Monika, Inwald, Elisabeth C, Buchholz, Stefan, Ortmann, Olaf, Szalontay, Luca, Segerer, Sabine, Rick, Ferenc G, Kwok, Chui Wai, Perez, Roberto

2014

Overview

Background Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z. Methods 69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.). Results In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69). HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective. As compared to AEZS 108, the Disorazol Z – LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment. Conclusion The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.

• Publisher: BioMed Central
• Subject: Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line, Tumor / Cell Proliferation - drug effects / Doxorubicin - administration & dosage / Doxorubicin - analogs & derivatives / Doxorubicin - pharmacology / Female / Gonadotropin-Releasing Hormone - administration & dosage / Gonadotropin-Releasing Hormone - analogs & derivatives / Gonadotropin-Releasing Hormone - metabolism / Gonadotropin-Releasing Hormone - pharmacology / Health Promotion and Disease Prevention / Humans / Medicine/Public Health / Mice / Mice, Nude / Oncology / Oxazoles - administration & dosage / Oxazoles - pharmacology / Receptors, LHRH - genetics / Receptors, LHRH - metabolism / Research Article / Surgical Oncology / Translational oncology / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Xenograft Model Antitumor Assays