Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

Celia A. Kanashiro, Andrew V Schally, Marta Zarandi, Brian D. Hammann, Jozsef L. Varga

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1019-1028
Number of pages10
JournalInternational Journal of Oncology
Volume30
Issue number4
StatePublished - Apr 1 2007

Fingerprint

Bombesin
Growth Hormone-Releasing Hormone
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Vascular Endothelial Growth Factor A
Gastrin-Releasing Peptide
Apoptosis
Vascular Endothelial Growth Factor Receptor
Down-Regulation
Therapeutics
Hormone Antagonists
Neoplasms
Peptide Hormones
Angiogenesis Inducing Agents
Growth
Heterografts
Nude Mice
Lung Neoplasms
Up-Regulation
Peptides

Keywords

  • Bax/Bcl-2
  • Bombesin/GRP antagonist
  • EGFR/HER
  • GHRH antagonists
  • VEGF/VEGF-R

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer. / Kanashiro, Celia A.; Schally, Andrew V; Zarandi, Marta; Hammann, Brian D.; Varga, Jozsef L.

In: International Journal of Oncology, Vol. 30, No. 4, 01.04.2007, p. 1019-1028.

Research output: Contribution to journalArticle

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abstract = "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.",
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