Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel.

Abstract

We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice. Treatment with MZ-J-7-138 or JV-1-92 inhibited orthotopic growth of H460 NSCLC by 52-65% (P < 0.001) and was associated with a significant decrease in protein expression of K-Ras, cyclooxygenase-2 (Cox-2) and phospho-Akt (pAkt). In other experiments, treatment with MZ-J-7-138 or docetaxel reduced tumor volume of s.c. xenografted H460 human NSCLC by 30-36% (P < 0.01). The combination of MZ-J-7-138 and docetaxel resulted in a synergistic growth inhibition of H460 NSCLC xenografts of 63%. MZ-J-7-138 alone or in combination with docetaxel significantly reduced protein levels of K-Ras, Cox-2, and pAkt by 56-63%. Docetaxel given singly diminished the protein levels only of Cox-2 and did not affect K-Ras and pAkt. High-affinity binding sites, mRNA, and protein expression of pituitary GHRH receptors and its splice variant (SV) 1 were found in H460. H460 NSCLC cells contained GHRH peptide, and its growth was significantly inhibited in vitro by 10 microM MZ-J-7-138 (P < 0.001). Serum insulin-like growth factor 1 (IGF1) was not reduced by either GHRH antagonists. These findings suggest that antiproliferative effects of GHRH antagonists in H460 NSCLC are associated with down-regulation of K-Ras, Cox-2, and pAkt. In conclusion, GHRH antagonists in combination with docetaxel synergistically inhibit growth of H460 NSCLC and the expression of K-ras, Cox-2, and pAkt, which might abrogate the signal transduction pathways for cell growth stimulation and therapeutic resistance.

• Authors: Florian Hohla, Andrew V Schally, Karoly Szepeshazi, Jozsef L Varga, Stefan Buchholz, Frank Köster, Elmar Heinrich, Gabor Halmos, Ferenc G Rick, Chandrika Kannadka, Christian Datz, Celia A Kanashiro
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 39 Pg. 14513-8 (Sep 26 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16983095 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Phosphoproteins
• RNA, Messenger
• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• Taxoids
• Docetaxel
• Insulin-Like Growth Factor I
• Growth Hormone-Releasing Hormone
• Cyclooxygenase 2
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins p21(ras)
• somatotropin releasing hormone receptor

Topics

• Alternative Splicing (genetics)
• Animals
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Body Weight (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Docetaxel
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Growth Hormone-Releasing Hormone (antagonists & inhibitors)
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Mice
• Mice, Nude
• Organ Size (drug effects)
• Phosphoproteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins p21(ras) (metabolism)
• RNA, Messenger (genetics, metabolism)
• Radioimmunoassay
• Receptors, Neuropeptide (genetics, metabolism)
• Receptors, Pituitary Hormone-Regulating Hormone (genetics, metabolism)
• Taxoids (therapeutic use)
• Transplantation, Heterologous