Endocrine Abstracts

Human malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm, arising from pleural mesothelial cells, generally due to asbestos exposure. Different growth factors are involved in the pathogenesis of MPM and in resistance to therapy; moreover, chemotherapy with cisplatin and antifolates, like pemetrexed (PEM), is the first-line treatment for inoperable MPM. Growth hormone-releasing hormone (GHRH), apart from stimulating GH secretion in the pituitary, exerts many extrapituitary functions, including stimulation of cell proliferation and survival. GHRH and GHRH receptor (GHRH-R) are expressed in different cancer cell types, where they modulate their proliferative effects. Moreover, GHRH-R antagonists were found to inhibit the proliferation of different cancer cells in vitro and in vivo; however, the role of GHRH antagonists in MPM remains unknown. Thus, in the present study, we investigated the effects of the GHRH antagonists MIA-602 and MIA-690 on survival, proliferation and apoptosis of human MPM cells. Our results show that MIA-602 and MIA-690 reduce survival and proliferation of MSTO-211H (biphasic) and REN (epithelioid) MPM cells, but have no effect in MeT-5A (human non-malignant mesothelial cells). Moreover, MIA-602 and MIA-690 promoted apoptosis and reduced the expression of the antiapoptotic protein Bcl-2 in MSTO-211H and REN cells. Cell cycle analysis of REN cells treated with GHRH antagonists showed an increase in the Sub-G1 apoptotic phase and a decrease in the G2 pre-mitotic phase. Furthermore, MIA-602 and MIA-690 inhibited cell migration in REN cells and increased the cytotoxic action of PEM in both MPM cell lines. These results suggest a novel therapeutic role for GHRH antagonists in the treatment of MPM, alone or in combination with standard therapies, by reducing the chemotherapy doses and their associated side effects.