GHRH Antagonist MZ-5-156 Inhibits FAK and Decreases VEGF in Human Lung Cancer Cells

Lung cancers with increased vascularization and high microvessel density are associated with high metastatic potential and poor prognosis. Current therapies often fall short in effectively targeting these aggressive features. Growth hormone-releasing hormone (GHRH) antagonists have emerged as promising anticancer agents, demonstrating efficacy in lung cancer tumor models without significant adverse events. This study explores the specific molecular mechanisms by which the GHRH antagonist MZ-5-156 influences key pathways involved in angiogenesis and invasion, such as FAK activity and VEGF expression, to better understand its therapeutic potential.

Researchers investigated the in vitro effects of the GHRH antagonist, MZ-5-156, on human lung cancer cells. The study utilized A549 non-small cell lung cancer (NSCLC) cells and H727 bronchial carcinoid cells. The primary endpoints included assessing focal adhesion kinase (FAK) activity, the expression levels of MMP-2 and MMP-9 metalloproteinases, and vascular endothelial growth factor (VEGF) levels. A control arm involved treatment with GHRH itself to observe counteracting effects, providing insight into the specific action of the antagonist.

The GHRH antagonist MZ-5-156 demonstrated significant inhibitory effects on key cancer-promoting pathways in both A549 NSCLC and H727 bronchial carcinoid cells. For the first time, this study showed that MZ-5-156 effectively inhibits FAK signaling, a crucial pathway involved in cell adhesion, migration, and survival. Furthermore, the antagonist decreased the expression of MMP-2 and MMP-9 metalloproteinases, which are known to facilitate tumor invasion and metastasis.

MZ-5-156 also significantly reduced vascular endothelial growth factor (VEGF) levels, a critical factor in angiogenesis, thereby potentially limiting tumor blood supply and growth. In contrast to the antagonist's effects, treatment with GHRH itself was found to counteract these beneficial actions, suggesting a direct and specific mechanism of action for MZ-5-156. These findings underscore the role of GHRH antagonists in modulating multiple factors involved in cancer progression.