Antagonist of Growth Hormone-Releasing Hormone Receptor MIA-690 Suppresses the Growth of Androgen-Independent Prostate Cancers

• Published in: International journal of molecular sciences 2024-10, Vol.25 (20), p.11200
• Main Authors: Muñoz-Moreno, Laura, Gómez-Calcerrada, M Isabel, Arenas, M Isabel, Carmena, M José, Prieto, Juan C, Schally, Andrew V, Bajo, Ana M
• Format: Article
• Language: English
• Subjects: Androgen suppression therapy; Androgens; Angiogenesis; Animals; Cancer; Cancer therapies; Care and treatment; Cell adhesion & migration; Cell Adhesion - drug effects; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; Demographic aspects; Diagnosis; Drug Synergism; Drugs; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Extracellular matrix; Gefitinib - pharmacology; Growth Hormone-Releasing Hormone - antagonists & inhibitors; Growth Hormone-Releasing Hormone - metabolism; Growth hormones; Humans; Insulin-like growth factors; Kinases; Ligands; Male; Medical prognosis; Metastasis; Mice; Mice, Nude; Patient outcomes; PC-3 Cells; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Pyrroles - pharmacology; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Receptors, Neuropeptide - genetics; Receptors, Neuropeptide - metabolism; Receptors, Pituitary Hormone-Regulating Hormone - genetics; Receptors, Pituitary Hormone-Regulating Hormone - metabolism; Relapse; Sermorelin - analogs & derivatives; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252011200

The development of resistance remains the primary challenge in treating castration-resistant prostate cancer (CRPC). GHRH receptors (GHRH-R), which are coupled to G-proteins (GPCRs), can mediate EGFR transactivation, offering an alternative pathway for tumour survival. This study aimed to evaluate the effects of the GHRH-R antagonist MIA-690, in combination with the EGFR inhibitor Gefitinib, on cell viability, adhesion, gelatinolytic activity, and the cell cycle in advanced prostate cancer PC-3 cells. The findings demonstrate a synergistic effect between MIA-690 and Gefitinib, leading to the inhibition of cell viability, adhesion, and metalloprotease activity. Cell cycle analysis suggests that both compounds induce cell cycle arrest, both individually and in combination. Furthermore, similar effects of the GHRH-R antagonist MIA-690 combined with Gefitinib were observed in PC-3 tumours developed by subcutaneous injection in athymic nude mice 36 days post-inoculation. These results indicate that combined therapy with a GHRH-R antagonist and an EGFR inhibitor exerts a stronger antitumor effect compared to monotherapy by preventing transactivation between EGFR and GHRH-R in CRPC.