Combined targeting of endothelin a receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity

Laura Rosanò, Valeriana Di Castro, Francesca Spinella, Giampaolo Tortora, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Ovarian carcinomas overexpress endothelin A receptors (ETAR) and epidermal growth factor (EGF) receptor (EGFR). In these cells, endothelin-1 (ET-1) triggers mitogenic and invasive signaling pathways that are in part mediated by EGFR transactivation. Combined targeting of ETAR, by the specific ETAR antagonist ZD4054, and of EGFR by the EGFR inhibitor gefitinib (IRESSA), may offer improvements in ovarian carcinoma treatment. In HEY and OVCA 433 ovarian carcinoma cells, ET-1 or EGF induced rapid activation of EGFR, p42/44 mitogen-activated protein kinase (MAPK), and AKT. ZD4054 was able to reduce the ET-1-induced EGFR transactivation. Gefitinib significantly inhibited EGF- and ET-1-induced EGFR phosphorylation, but incompletely reduced the ET-1-induced activation of downstream targets. ZD4054 plus gefitinib resulted in a greater inhibition of EGFR, MAPK, and AKT phosphorylation, indicating the critical role of these interconnected signaling proteins. ZD4054 effectively inhibited cell proliferation, invasiveness, and vascular endothelial growth factor (VEGF) secretion. Concomitantly, ZD4054 enhanced apoptosis and E-cadherin promoter activity and expression. In both cell lines, the drug combination resulted in a significant decrease in cell proliferation (65%), invasion (52%), and VEGF production (50%), accompanied by a 2-fold increase in apoptosis. The coadministration of ZD4054 enhanced the efficacy of gefitinib leading to partial (82%) or complete tumor regression on HEY ovarian carcinoma xenografts. Antitumor effects were paralleled by biochemical and immunohistologic evidence of decreased vascularization, Ki-67, matrix metalloproteinase-2 (MMP-2), VEGF, MAPK and EGFR, and enhanced E-cadherin expression. The cross-signaling between the EGFR/ETAR pathways provides a rationale to combine EGFR inhibitors with ETAR antagonists, identifying new effective therapeutic opportunities for ovarian cancer.

Original languageEnglish
Pages (from-to)6351-6359
Number of pages9
JournalCancer Research
Volume67
Issue number13
DOIs
Publication statusPublished - Jul 1 2007

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Endothelin Receptors
Epidermal Growth Factor Receptor
Ovarian Neoplasms
Endothelin-1
Endothelin A Receptors
Vascular Endothelial Growth Factor A
Carcinoma
Cadherins
Mitogen-Activated Protein Kinases
Epidermal Growth Factor
Transcriptional Activation
Phosphorylation
Cell Proliferation
Apoptosis
Mitogen-Activated Protein Kinase 1
Matrix Metalloproteinase 2
Drug Combinations
Heterografts
ZD4054

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combined targeting of endothelin a receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. / Rosanò, Laura; Di Castro, Valeriana; Spinella, Francesca; Tortora, Giampaolo; Nicotra, Maria Rita; Natali, Pier Giorgio; Bagnato, Anna.

In: Cancer Research, Vol. 67, No. 13, 01.07.2007, p. 6351-6359.

Research output: Contribution to journalArticle

Rosanò, Laura ; Di Castro, Valeriana ; Spinella, Francesca ; Tortora, Giampaolo ; Nicotra, Maria Rita ; Natali, Pier Giorgio ; Bagnato, Anna. / Combined targeting of endothelin a receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. In: Cancer Research. 2007 ; Vol. 67, No. 13. pp. 6351-6359.
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