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.

• Authors: Joaquin J Jimenez, Gina M DelCanto, Petra Popovics, Aymee Perez, Ailin Vila Granda, Irving Vidaurre, Ren-Zhi Cai, Ferenc G Rick, Ronan T Swords, Andrew V Schally
• Journal: British journal of haematology (Br J Haematol) Vol. 181 Issue 4 Pg. 476-485 (05 2018) ISSN: 1365-2141 [Electronic] England
• PMID: 29663325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• Sermorelin
• Proto-Oncogene Proteins c-akt
• somatotropin releasing hormone receptor

Topics

• Animals
• Apoptosis (drug effects)
• Drug Delivery Systems (methods)
• Female
• Humans
• K562 Cells
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Neuropeptide (antagonists & inhibitors)
• Receptors, Pituitary Hormone-Regulating Hormone (antagonists & inhibitors)
• Sermorelin (analogs & derivatives, pharmacology)
• Signal Transduction (drug effects)
• THP-1 Cells
• Xenograft Model Antitumor Assays