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

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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
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

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docetaxel
Growth Hormone-Releasing Hormone
Non-Small Cell Lung Carcinoma
Cyclooxygenase 2
Carcinoma
Lung
Hormone Antagonists
Growth
Pituitary Hormone-Regulating Hormone Receptors
Somatomedins
Tumor Burden
Heterografts
Nude Mice
Growth Hormone
MZ-J-7-138
Signal Transduction
Carrier Proteins
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel. / Hohla, Florian; Schally, Andrew V; Szepeshazi, Karoly; Varga, Jozsef L.; Buchholz, Stefan; Köster, Frank; Heinrich, Elmar; Halmos, Gabor; Rick, Ferenc G.; Kannadka, Chandrika; Datz, Christian; Kanashiro, Celia A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 39, 26.09.2006, p. 14513-14518.

Research output: Contribution to journalArticle

Hohla, F, Schally, AV, Szepeshazi, K, Varga, JL, Buchholz, S, Köster, F, Heinrich, E, Halmos, G, Rick, FG, Kannadka, C, Datz, C & Kanashiro, CA 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, vol. 103, no. 39, pp. 14513-14518. https://doi.org/10.1073/pnas.0605309103
Hohla, Florian ; Schally, Andrew V ; Szepeshazi, Karoly ; Varga, Jozsef L. ; Buchholz, Stefan ; Köster, Frank ; Heinrich, Elmar ; Halmos, Gabor ; Rick, Ferenc G. ; Kannadka, Chandrika ; Datz, Christian ; Kanashiro, Celia A. / Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 39. pp. 14513-14518.
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AU - Datz, Christian

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