sermorelin and Carcinoma--Non-Small-Cell-Lung

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

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Female; Gene Expression; Growth Hormone-Releasing Hormone; Humans; Mice; Mice, Nude; Sermorelin; Signal Transduction; Small Cell Lung Carcinoma; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Topics: Alternative Splicing; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Female; Growth Hormone-Releasing Hormone; Humans; Mice; Mice, Nude; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; RNA Splicing; Sermorelin; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays

AMP-activated protein kinase (AMPK) regulates cellular proliferation, growth and metabolism. Targeted activation of AMPK is considered an important therapeutic strategy for cancer treatment. To evaluate the effect of growth hormone-releasing hormone (GHRH) and its antagonist MZ-5-156 on the phosphorylation of AMPK and other related regulatory intracellular proteins we employed human non-small cell lung cancer cell line A549, which expresses GHRH receptors. Treatment of A549 cells with GHRH antagonist decreased cell proliferation and activated AMPK as well as glycogen synthase kinase (GSK)3β. Furthermore, MZ-5-156 inhibited Akt, the mammalian target of rapamycin (mTOR) and its downstream target eIF4E which controls protein synthesis and cell growth. GHRH(1-29)NH2 counteracted all these effects. HeLa human endometrial cancer cells which do not express any GHRH receptors were used as a negative control and GHRH did not induce the AMPK activation in these cells. Our results demonstrate for the first time that GHRH antagonists can regulate the AMPK metabolic pathway, which is crucial for the growth of non-small cell lung cancer and other major cancers.

Topics: AMP-Activated Protein Kinases; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Eukaryotic Initiation Factor-4E; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Growth Hormone-Releasing Hormone; HeLa Cells; Humans; Ki-67 Antigen; Lung Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Sermorelin; TOR Serine-Threonine Kinases

New therapeutic strategies are necessary to improve the treatment of lung cancer. We investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonist, RC-3940-II, and growth hormone-releasing hormone (GHRH) antagonists, MZ-J-7-114 and MZ-J-7-118, on the expression of epidermal growth factor receptor (EGFR)/HER (-2, -3, and -4) family, angiogenic factors, VEGF-A and VEGF receptors (VEGF-R1 and VEGF-R2), and the apoptotic molecules Bax and Bcl-2, in H-460 and A-549 non-small cell lung carcinomas (NSCLC). Nude mice bearing xenografts of H-460 and A-549 NSCLC were treated daily with these peptide analogues for 4 weeks. The treatment resulted in growth inhibition of H-460 by 22-77% and A-549 NSCLCs by 64-84%. The inhibition of tumor growth was associated with a down-regulation of members of EGFR/HER family. A significant reduction of the levels of expression of EGFR/HER family on both tumors varied from 29-96%: the greatest inhibition being induced by RC-3940-II. Similarly, a significant decrease in the levels of VEGF-A in tumors by 19-60% and VEGF receptors (VEGF-R1, 24-74% and VEGF-R2, 25-50%) was detected after therapy. An up-regulation of Bax by 21-63% and a down-regulation of Bcl-2 by 23-39% was observed only for H-460 NSCLC. Our study demonstrates that human H-460 and A-549 NSCLC, express receptors for GHRH and bombesin/GRP, and respond to the respective antagonists. The antagonists of bombesin/GRP and GHRH could provide a new strategy for treatment of NSCLC through down-regulation of EGFR/HER family and an interference with the angiogenic and apoptotic pathways.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Bombesin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Down-Regulation; ErbB Receptors; Growth Hormone-Releasing Hormone; Humans; Lung Neoplasms; Mice; Neovascularization, Pathologic; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Receptors, Bombesin; Sermorelin; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model Antitumor Assays