Inhibition of experimental small‐cell and non‐small‐cell lung cancers by novel antagonists of growth hormone‐releasing hormone

Abstract

We investigated the effects of novel antagonists of growth hormone releasing hormone (GHRH)-MIA602 and MIA690-on three human small cell lung cancer (SCLC) lines (H446, DMS53 and H69) and two non-SCLC (NSCLC) lines (HCC827 and H460). In vitro exposure of cancer cells to these GHRH antagonists significantly inhibited cell viability, increased cell apoptosis, decrease cellular levels of cAMP and reduced cell migration. In vivo, the antagonists strongly inhibited tumor growth in xenografted nude mice models. Subcutaneous administration of MIA602 at the dose of 5 μg/day for 4-8 weeks reduced the growth of HCC827, H460 and H446 tumors by 69.9%, 68.3% and 53.4%, respectively, while MIA690 caused a reduction of 76.8%, 58.3% and 54.9%, respectively. Western blot and qRT-PCR analyses demonstrated a downregulation of expression of the pituitary-type GHRH-R and its splice-variant, cyclinD1/2, cyclin-dependent kinase4/6, p21-activated kinase-1, phosphorylation of activator of transcription 3 and cAMP response element binding protein; and an upregulation of expression of E-cadherin, β-catenin and P27 in cancer cells and in xenografted tumor tissues. The study demonstrates the involvement of GHRH antagonists in multiple signaling pathways in lung cancers. Our findings suggest the merit of further investigation with these GHRH antagonists on the management of both SCLC and NSCLC.

Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

“…However, in vivo, when MR409 was administered to nude mice bearing HCC827, H460, and H446 lung tumors, a significant suppression of tumor growth was observed. The doses applied were similar to those previously used in our study with the GHRH antagonists MIA602 and MIA690 in the same lung tumor models (28). The rate of inhibition of tumor growth by the agonist MR409 in vivo was comparable to that observed with the antagonists (28).…”

“…5B). The reduction of GHRH-Rs in these tumors was similar to that in animals treated with GHRH antagonists (28). Immunohistochemistry analyses confirmed the down-regulation of GHRH-Rs in the tumors treated with MR409 ( Fig.…”

“…Conversely, various studies have documented that antagonistic analogs of GHRH inhibit cancer cell proliferation, act as autocrine/paracrine inhibitors of growth factors, and suppress the growth of tumors through GHRH-Rs expressed on cancer cells (1-4, 28, 31-34). Recently, we demonstrated that our GHRH antagonists MIA602 and MIA690 inhibit significantly the growth of human lung cancers, including NSCLC (HCC827 and H460) and SCLC (H446), in vitro and in vivo (28). The study also revealed the involvements of multiple cell signaling pathways in the action of GHRH antagonists on lung cancer cells and tumors (28).…”

“…Recently, we demonstrated that our GHRH antagonists MIA602 and MIA690 inhibit significantly the growth of human lung cancers, including NSCLC (HCC827 and H460) and SCLC (H446), in vitro and in vivo (28). The study also revealed the involvements of multiple cell signaling pathways in the action of GHRH antagonists on lung cancer cells and tumors (28). In the present study, we report that in the in vitro assays, the GHRH agonist MR409 promoted cell proliferation and reduced cell apoptosis in the HCC827 adenocarcinoma lung cancer cell line, the H460 LCLC cell line, and the H446 SCLC cell line, which is similar to its effect in nonmalignant cells.…”

“…The animals bearing H460 tumors were treated similarly for 4 wk. This dose and duration of treatment were the same as in our previous study with GHRH antagonists (28). Paradoxically, the treatment with the GHRH agonist MR409 suppressed the growth of the three tumors in nude mice.…”