Endocrine Abstracts

Growth hormone-releasing hormone (GHRH) is synthesized in hypothalamic neurons and regulates the secretion of growth hormone (GH) from the pituitary gland. GHRH also displays extra-pituitary activities in a variety of cells and organs expressing both GHRH, GHRH receptor (GHRH-R) and its splice variants (SVs). These include, among others, the retina, pancreas, kidney, skeletal muscle and heart. In the heart, we have demonstrated that GHRH(1-44)NH2 exerts survival and antihypertrophic effects in vitro in murine cardiomyocytes and human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, improves heart function and reduces myocardial infarction (MI) in isolated rat hearts. Moreover, we and others have shown that in murine and swine in vivo models, agonistic analogs of GHRH, such as MR-409, counteract maladaptive hypertrophy, improve heart function and protect against ischemic injury, suggesting potential therapeutic role in heart failure and regeneration after myocardial infarction. In tumors, GHRH acts as an autocrine/paracrine growth factor and stimulates growth of various cancers. In the last years, many antagonists of GHRH have been synthesized, with potent inhibitory effects on growth of various tumors, including breast, prostate, lung and gastric cancer. Our recent findings indicate that GHRH antagonists MIA602 and MIA690, either alone or in combination with chemotherapics, potently inhibit the growth of human malignant pleural mesothelioma (MPM) cell lines and primary mesothelioma cells in vitro, through induction of apoptosis and inhibition of proliferative and survival pathways. Thus, GHRH antagonists may be considered as additional tools for new therapeutic approaches in MPM, for which an effective therapy remains to be established.