The endothelin axis as therapeutic target in human malignancies: Present and future

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies.

Original languageEnglish
Pages (from-to)2720-2733
Number of pages14
JournalCurrent Pharmaceutical Design
Volume18
Issue number19
Publication statusPublished - Jun 2012

Fingerprint

Endothelins
Endothelin-1
Endothelin A Receptors
Neoplasms
Arrestin
Therapeutics
G-Protein-Coupled Receptors
Growth
Molecular Targeted Therapy
Epithelial-Mesenchymal Transition
Tumor Microenvironment
Cell Movement
Blood Vessels
Cell Death
Clinical Trials
Pharmaceutical Preparations

Keywords

  • β-arrestin
  • Cancer therapy
  • Chemoresistance
  • Endothelin
  • Endothelin receptor
  • Epithelial-mesenchymal transition

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

The endothelin axis as therapeutic target in human malignancies : Present and future. / Bagnato, Anna.

In: Current Pharmaceutical Design, Vol. 18, No. 19, 06.2012, p. 2720-2733.

Research output: Contribution to journalArticle

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