Authors: Martin Smollich,; Pia Wulfing,

Source: Current Vascular Pharmacology, Volume 5, Number 3, July 2007 , pp. 239-248(10)

Publisher: Bentham Science Publishers

Abstract:

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ETAR and ETBR, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ETAR, activation of ETBR prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers.

Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ETAR by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ETAR promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy.

The outstanding role of ET-1 and ETAR in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ETAR antagonists on the one hand and inhibitors of the endothelinconverting enzyme (ECE) on the other. Targeting the ET axis via ETAR or ECE blockade seems to be a promising approach in the treatment of female malignancies.

Keywords: ET axis; ETAR; atrasentan; ZD4054; breast cancer

Document Type: Research article

DOI: http://dx.doi.org/10.2174/157016107781024082

Publication date: 2007-07-01

More about this publication?

• Vascular disease is the commonest cause of death in Westernized countries and its incidence is on the increase in developing countries. It follows that considerable research is directed at establishing effective treatment for acute vascular events. Long-term treatment has also received considerable attention (e.g. for symptomatic relief). Furthermore, effective prevention, whether primary or secondary, is backed by the findings of several landmark trials.
  
  Vascular disease is a complex field with primary care physicians and nurse practitioners as well as several specialties involved. The latter include cardiology, vascular and cardio thoracic surgery, general medicine, radiology, clinical pharmacology and neurology (stroke units). Current Vascular Pharmacology will publish reviews to update all those concerned with the treatment of vascular disease. For example, reviews commenting on recently published trials or new drugs will be included. In addition to clinically relevant topics we will consider 'research-based' reviews dealing with future developments and potential drug targets. Therefore, another function of Current Vascular Pharmacology is to bridge the gap between clinical practice and ongoing research.
  
  Debates will also be encouraged in the correspondence section of this journal.

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