Inhibitory Effects of GHRH Antagonists on Human GH-Secreting Adenoma Tissue

Abstract

Experimental data indicate that antagonists of growth hormone-releasing hormone (GHRH) could be used clinically in disorders characterized by excessive GHRH/growth hormone (GH) secretion, but direct evidence for the effectiveness of GHRH antagonists on human pituitary tissue is still lacking. In this study, we investigated the inhibitory effect of our GHRH antagonists MZ-4-71 and JV-1-36 and the somatostatin (SST) analog RC-160 on superfused pituitary cells obtained from a human GH-secreting adenoma. Using Western blot analysis and immunohistochemistry, we demonstrated profuse expression of the GHRH receptor and its major splice variant SV1 and an increase in the expression of Gsa protein in the adenoma tissue. Exposure of the tumor cells to exogenous pulses of GHRH induced definite GH responses, causing a 3- to 5-fold elevation of the basal GH level. The antagonists MZ-4-71 and JV-1-36 did not alter basal GH secretion, indicating that the adenoma cells did not secrete GHRH in an autocrine manner. However, both antagonists prevented the stimulatory effect of exogenous GHRH. Similarly to the GHRH antagonists, neither SST-14 nor the SST analog RC-160 had an effect on the basal GH secretion of the tumor cells, but both peptides inhibited the stimulatory effect of exogenous GHRH, with RC-160 being more potent than SST. Our study provides direct evidence for the effectiveness of potent GHRH antagonists such as MZ-4-71 and JV-1-36 on human pituitary GH-secreting adenoma tissue and strongly suggests that these drugs could be used for therapy of GHRH-associated forms of acromegaly, particularly for those patients in whom surgery fails or is not an option.

Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling

“…Various studies have demonstrated the anticancer effect of early generation GHRH antagonists in rat and mouse pituitary GHRH-R and human tumoral GHRH-R [20,[22][23][24][25][26][27]. Furthermore, the role of GHRH antagonists of JV series in blocking GHRH actions was described in the same in vitro model of somatotroph adenoma used in this study, i.e., rat pituitary GH3 cells that were induced to express a functional human GHRH-R [23,33,43].…”

“…In fact, it has been demonstrated that GHRH antagonists, such as MZ-4-71 and MZ-5-156, suppressed GH and IGF-I secretion in transgenic mice overexpressing human GHRH gene, an animal model of acromegaly [20]. Furthermore, in a different study, MZ-4-71 and JV-1-36 prevented the stimulatory effect of exogenous GHRH on GH secretion in pituitary cells obtained from a human GH-secreting adenoma by blocking GHRH receptors (GHRH-Rs) [22]. The studies mentioned above were conducted with early generation antagonists, whereas the analogs of MIAMI (MIA) series, such as MIA-602 and MIA-690, synthesized more recently, possessed greatly increased anticancer activity and higher receptor binding affinity but showed only weak inhibitory activity on GH/IGF-I axis [17].…”

“…Many studies demonstrated that GHRH antagonists can also strongly inhibit the stimulatory activity of exogenous and endogenous GHRH on GH secretion, suggesting that they could be used for the treatment of diseases caused by excessive production of GHRH or GH, such as acromegaly and diabetic retinopathy [20][21][22][23][24][25][26][27]. In fact, it has been demonstrated that GHRH antagonists, such as MZ-4-71 and MZ-5-156, suppressed GH and IGF-I secretion in transgenic mice overexpressing human GHRH gene, an animal model of acromegaly [20].…”

Growth Hormone‐Releasing Hormone and Its Analogues: Significance for MSCs‐Mediated Angiogenesis

“…This provides us a novel approach to treat cancer with GHRH antagonists. For the past 25 years the antitumor properties of GHRH antagonists have been studied on cancer cell lines from breast, prostate, pancreas, colon, lung, ovarian, brain, and lymphocyte [ 23 , 24 , 37 – 42 ]. GHRH was shown to cause MAPK activation in MDA-MB-231 breast cancer cells via phosphorylation of Ras and Raf, and the GHRH antagonists MZ-J-7-138 and JV-1-92 were shown to block this pathway and suppress lung carcinoma growth in a manner that correlated with Ras inhibition [ 40 , 48 ].…”

A Case of Ectopic Growth Hormone Releasing Hormone (GHRH) from Pancreatic Neuroendocrine Tumor Resistant to Therapy

“…Together with the fact that such tumors not only produced GHRH but the GHRH-receptor as well [22] support the hypothesis that GH hypersecretion in ectopic GHRH syndrome requires GHRH receptor occupancy and make the GHRH antagonists attractive tool to study the potential involvement of endogenous GHRH in acromegaly. Szalontay et al study provides direct evidence for effectiveness of GHRH antagonists on human pituitary GH-secreting adenoma tissue and strongly suggests their usefulness in other forms of acromegaly or for those who failed surgery [23].…”