Suppression of the proliferation of human U-87 MG glioblastoma cells by new antagonists of growth hormone-releasing hormone in vivo and in vitro.

Five-year survival of patients afflicted with glioblastoma multiforme (GBM) is rare, making this cancer one of the most feared malignancies. Previously, we reported that growth hormone-releasing hormone (GHRH) is a potent growth factor in cancers. The present work evaluated the effects of two antagonistic analogs of GHRH (MIA-604 and MIA-690) on the proliferation of U-87 MG GBM tumors, in vivo as well as in vitro. Both analogs were administered subcutaneously and dose-dependently inhibited the growth of tumors transplanted into nude mice (127 animals in seven groups). The analogs also inhibited cell proliferation in vitro, decreased cell size, and promoted apoptotic and autophagic processes. Both antagonists stimulated contact inhibition, as indicated by the expression of the E-cadherin-β-catenin complex and integrins, and decreased the release of humoral regulators of glial growth such as FGF, PDGFβ, and TGFβ, as revealed by genomic or proteomic detection methods. The GHRH analogs downregulated other tumor markers (Jun-proto-oncogene, mitogen-activated protein kinase-1, and melanoma cell adhesion molecule), upregulated tumor suppressors (p53, metastasis suppressor-1, nexin, TNF receptor 1A, BCL-2-associated agonist of cell death, and ifκBα), and inhibited the expression of the regulators of angiogenesis and invasion (angiopoetin-1, VEGF, matrix metallopeptidase-1, S100 calcium binding protein A4, and synuclein-γ). Our findings indicate that GHRH antagonists inhibit growth of GBMs by multiple mechanisms and decrease both tumor cell size and number.