A new approach to the treatment of acute myeloid leukaemia targeting the receptor for growth hormone‐releasing hormone

Abstract

Growth hormone-releasing hormone (GHRH) is secreted by the hypothalamus and acts on the pituitary gland to stimulate the release of growth hormone (GH). GHRH can also be produced by human cancers, in which it functions as an autocrine/paracrine growth factor. We have previously shown that synthetic antagonistic analogues of GHRH are able to successfully suppress the growth of 60 different human cancer cell lines representing over 20 cancers. Nevertheless, the expression of GHRH and its receptors in leukaemias has never been examined. Our study demonstrates the presence of GHRH receptor (GHRH-R) on 3 of 4 human acute myeloid leukaemia (AML) cell lines-K-562, THP-1, and KG-1a-and significant inhibition of proliferation of these three cell lines in vitro following incubation with the GHRH antagonist MIA-602. We further show that this inhibition of proliferation is associated with the upregulation of pro-apoptotic genes and inhibition of Akt signalling in leukaemic cells. Treatment with MIA-602 of mice bearing xenografts of these human AML cell lines drastically reduced tumour growth. The expression of GHRH-R was further confirmed in 9 of 9 samples from patients with AML. These findings offer a new therapeutic approach to this malignancy and suggest a possible role of GHRH-R signalling in the pathology of AML.

Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1

“…GHRH receptors are present in many tumors [ 1 , 2 , 27 - 33 ]. In order to determine whether GHRH agonist, MR-409, has an effect on the expression of IGF-1 in cancer cells, 16 human cancer cell lines were examined.…”

“…This inhibitory action of GHRH antagonists on IGF-1 levels in serum has been demonstrated by our group in nude mice bearing various human cancers [ 1 , 27 , 31 , 43 - 46 ]. Nevertheless, the main inhibitory effect of GHRH antagonists on tumor growth appears to be exerted through GHRH receptors which are present in various human cancers [ 1 , 2 , 27 - 33 ].…”

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

“…MIA-602 and MIA-690 are part of the latest MIA series of GHRH antagonists with potent antitumor activity in different cancers, including lung cancer (16–25); however, their inhibitory effects in MPM remain to be investigated. This study shows that MIA-602 and MIA-690 can potently—and to a similar extent—inhibit the growth of human MPM cell lines and primary MPM cells in vitro and display antitumor effects in vivo in MPM xenografts.…”

“…Recently, new GHRH antagonists of the Miami (MIA) series have been synthetized, such as MIA-602 and MIA-690, with greatly increased anticancer activity, higher binding affinity, and low endocrine effect on the GH/insulin-like growth factor I (IGF-I) axis. These analogs display potent inhibitory actions in thyroid, lung, gastric, renal, prostate, and endometrial cancer, as well as in glioblastoma, colorectal adenocarcinoma, lymphoma, and retinoblastoma (16–25). To date, however, the role of GHRH antagonists in MPM remains to be determined.…”

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

“…Cancer cells can produce hormones, such as growth hormone-releasing hormone (GHRH), to stimulate the pituitary gland and then the release of growth hormone (132,133). In a previous study, a GHRH antagonist was synthesized to inhibit proliferation in AML cell lines, including K562, THP-1 and KG-1a cells (134). Follicle stimulating hormone (FSH), for which the circulating level is increased by leptin, serves an important role in the initiation and the proliferation of the ovarian cancer cells (135).…”