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

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

Research output: Contribution to journalArticle

26 Scopus citations

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 μM 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.

Original languageEnglish (US)
Pages (from-to)14513-14518
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number39
DOIs
StatePublished - Sep 26 2006

Keywords

  • Chemotherapeutic substance
  • Cyclooxygenase-2
  • K-Ras
  • Non-small cell lung cancer
  • pAkt

ASJC Scopus subject areas

  • Genetics
  • General

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  • Cite this

    Hohla, F., Schally, A. V., Szepeshazi, K., Varga, J. L., Buchholz, S., Köster, F., Heinrich, E., Halmos, G., Rick, F. G., Kannadka, C., Datz, C., & Kanashiro, C. A. (2006). Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel. Proceedings of the National Academy of Sciences of the United States of America, 103(39), 14513-14518. https://doi.org/10.1073/pnas.0605309103