sermorelin and Neoplasm-Metastasis

New approaches are needed to the therapy of advanced prostate cancer. This study determined the effect of growth hormone-releasing hormone (GHRH) antagonists, JMR-132 and JV-1-38 on growth of PC3 tumors as well as on angiogenesis and metastasis through the evaluation of various factors that contribute largely to the progression of prostate cancer. Human PC3 androgen-independent prostate cancer cells were injected subcutaneously into nude mice. The treatment with JMR-132 (10 μg/day) or JV-1-38 (20 μg/day) lasted 41 days. We also evaluated the effects of JMR-132 and JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of GHRH receptors and its splice variants, GHRH, vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF)-1α, metalloproteinases (MMPs) -2 and -9, β-catenin and E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3 tumors. After treatment with these analogues, we found an increase in expression of GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both VEGF and HIF-1α expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated β-catenin and a significant decline in E-cadherin. These results support that the blockade of GHRH receptors can modulate elements involved in angiogenesis and metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of androgen-independent prostate cancer.

Topics: Animals; Antineoplastic Agents; beta Catenin; Cadherins; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Growth Hormone-Releasing Hormone; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Prostatic Neoplasms; Random Allocation; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Vascular Endothelial Growth Factors; Xenograft Model Antitumor Assays

We investigated the effect of a GHRH antagonist, MIA-602on the metastatic cascade in vitro of three human cancers, DBTRG-05 glioblastoma, MDA-MB-468 estrogen-independent breast, and ES-2 clear cell ovarian cancer. GHRH receptors and their main splice variant, SV1 were detected on all three cell lines. After treatment with MIA-602, the cell viability decreased significantly, significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased. The attachment of cancer cells to fibronectin and matrigel was severely hindered. Wound-healing experiments demonstrated a reduced cellular motility in all three cell lines. The upregulation of caveolin-1 and E-cadherin,and thepowerful downregulation of NF-kappaB and beta-catenin was detected. Our study suggests that the clinical application of highly potent GHRH antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well.

Topics: Blotting, Western; Cell Adhesion; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Female; Growth Hormone-Releasing Hormone; Humans; Immunoblotting; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Protein Isoforms; Sermorelin

To determine whether antagonists of growth hormone-releasing hormone (GHRH) and bombesin/gastrin-releasing peptide (BN/GRP) can inhibit the orthotopic and metastatic growth of PC-3 human androgen-independent prostate cancers.. The effects of administration of GHRH antagonist MZ-J-7-118, BN/GRP antagonist RC-3940-II, and their combination on the growth and metastatic spread of PC-3 tumors implanted orthotopically into nude mice were evaluated. The efficacy of this treatment on PC-3 tumors implanted intratibially and s.c. was also determined.. Treatment with MZ-J-7-118, RC-3940-II, or their combination significantly inhibited the growth of PC-3 tumors implanted orthotopically, intraosseously, and s.c. The combination of the two antagonists had the greatest effect, inhibiting orthotopic tumor growth by 77%, intratibially implanted tumors by 86%, and s.c. tumors by 86%. The therapy with BN/GRP and GHRH antagonists, especially in combination, also reduced the local tumor spread and distant metastases in animals bearing orthotopic tumors. Combination therapy was likewise the most effective in reducing the incidence and severity of tibial osteolytic lesions and pathologic fractures in intraosseously implanted tumors. High-affinity binding sites for BN/GRP and GHRH were found in s.c. and orthotopic PC-3 tumor samples. MZ-J-7-118, RC-3940-II, and the combination of both compounds inhibited in vitro growth of PC-3 cells.. Our findings show the efficacy of BN/GRP antagonists and GHRH antagonists for the treatment of advanced prostate cancer in preclinical metastatic models. As BN/GRP antagonists are already in clinical trials and GHRH antagonists are effective in androgen-independent prostate cancer models, these analogues could be considered for the management of advanced prostate carcinoma.

Topics: Animals; Bombesin; Cell Line, Tumor; Cell Proliferation; Clinical Trials as Topic; Growth Hormone-Releasing Hormone; Humans; In Vitro Techniques; Male; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Peptide Fragments; Peptides; Prostatic Neoplasms; Protein Binding; Sermorelin; Time Factors