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

Abstract

BackgroundTriple 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.Methods69 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.).ResultsIn 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.ConclusionThe 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.

Cetrorelix and Triptorelin active immunization influences follicle development and receptor expressions of ovaries in mice

“…GnRH exerts its actions through specific GnRH receptors (GnRHR), which not only exist in the pituitary gland, but also in healthy tissue of male and female reproductive organs (Seitz et al, 2014). Contrary to GnRHa, GnRHant is a competitive inhibitor of GnRH binding to GnRHR (Coccia et al, 2004) and has different receptor occupancy from GnRHa with high affinity.…”

Potentiating effects of GHRH analogs on the response to chemotherapy

“…Among the affected pathways are the PI3K/AKT and inflammatory cytokine pathways that regulate EMT. 18,25,37 This reduction as described above in the expression of the multidrug resistance (MDRI) gene, the drug resistance regulator, NANOG, and the suppression of efflux pump function produced by GHRH antagonists in doxorubicintreated HCC1806 and MX-1 breast cancers was similar to those obtained in many cancers employing other therapies targeted to peptide receptors of tumors, using, for example, cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH), AN-152 or AN-207, [38][39][40][41][42] or other targeted cytotoxic analogs including AN-162 and AN-238 [43][44][45][46] which are based on somatostatin. 47,48 In both circumstances of therapy with GHRH antagonists or other targeted analogs these findings clearly demonstrate a more efficacious chemotherapeutic result by the mechanism of disabling of the efflux pumps and the reduction in resulting resistance to chemotherapy.…”

Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma

“…Over the past decade, a direct receptor-mediated antiproliferative effect of LH-RH-analogs on tumor cells was proposed (14,16,17,19–21). The receptors for LH-RH (LH-RH-R) on human tumors can also serve as targets for LH-RH analogs linked to various cytotoxic agents (15–17,22,23). In our previous study, it was demonstrated that a high percentage (47%) of human UMs express the type-I receptor for LH-RH (24).…”