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

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

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number847
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - Nov 19 2014

Keywords

  • AEZS 108
  • AEZS 125
  • LHRH- receptor
  • Targeted therapy
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125'. Together they form a unique fingerprint.

  • Cite this

    Seitz, S., Buchholz, S., Schally, A. V., Weber, F., Klinkhammer-Schalke, M., Inwald, E. C., Perez, R., Rick, F. G., Szalontay, L., Hohla, F., Segerer, S., Kwok, C. W., Ortmann, O., & Engel, J. B. (2014). Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125. BMC Cancer, 14(1), [847]. https://doi.org/10.1186/1471-2407-14-847