Endocrine Abstracts

Human malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm, arising from pleural mesothelial cells, generally due exposure to asbestos. Of note, different growth factors and their receptors are involved in the pathogenesis of MPM and resistance to therapy. Chemotherapy with cisplatin (cis) and antifolates, like pemetrexed (PEM), is the first-line treatment for inoperable MPM. Growth hormone-releasing hormone (GHRH), besides stimulating GH secretion in the anterior pituitary, exerts many peripheral functions, such as stimulation of cell proliferation and survival. GHRH and GHRH receptors (GHRH-Rs) are expressed in different cancer cell types, where they modulate their proliferative effects. Conversely, GHRH-R antagonists were found to inhibit the proliferation of different cancer cells in vitro and in vivo. Moreover, we recently demonstrated the antitumor activity of GHRH antagonists MIA-602 and MIA-690, in both in vitro and in in vivo models of MPM. However, the antitumor functions of GHRH-antagonists in combination with cis and PEM (cis/PEM) remain to be elucidated. Thus, in the present study, we assessed the antitumor effects of MIA-690 in combination with cis/PEM in vitro, in human biphasic MPM cell line MSTO-211H, and in vivo, in mice bearing MPM xenografts. In vitro, MIA-690 showed synergistic inhibitory activity with cis/PEM, by reducing cell survival and proliferation at 48 h in MSTO-211H and increasing the chemotherapy-induced apoptosis. In vivo, subcutaneous administration of MIA-690, at the dose of 5 μg/d for 4 weeks, potentiated the antitumor activity of cis/PEM by strongly inhibiting the growth of MPM xenografts, as demonstrated by the reduction of tumor volume and weight and inhibition of survival/proliferative markers, as revealed by immunohistochemistry analysis. MIA-690 also influenced the expression levels of cell cycle regulators (cyclinB1, D1 and D2), cell migration effectors (MMP-2 and MMP-9) and epithelial-mesenchymal transition markers (E-cadherin, N-cadherin, and vimentin), compared with cis/PEM treatment alone. Moreover, mice treated with both MIA-690 and cis/PEM showed increased expression of apoptotic molecules, along with a reduction of tumor insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in tumor xenografts. Collectively, these results further confirm the antitumor role of GHRH antagonists in MPM and suggest the potential therapeutic efficacy of these molecules in combination with chemotherapy, by potentially reducing anticancer drug doses and associated side effects.