Endothelin-A receptor in gastric cancer and enhanced antitumor activity of trastuzumab in combination with the endothelin-A receptor antagonist ZD4054.

Abstract

Endothelin-A receptor (ETAR) is overexpressed in cancers and can function through transactivation of the epidermal growth factor receptor. We explored ETAR in gastric cancer and investigated the antitumor effect of trastuzumab in combination with the ETAR antagonist ZD4054. The expression of ETAR was significantly correlated with the expression of vascular endothelial growth factor. Univariate and multivariate analyses further showed that ETAR expression correlated with reduced survival in gastric cancer patients. In vitro, ZD4054 increased the antiproliferative effect of trastuzumab in gastric cancer cell lines. Moreover, the addition of ZD4054 to trastuzumab significantly increased apoptosis in gastric cancer cell lines. In vivo, tumor growth was considerably inhibited by treatment with ZD4054 and trastuzumab, and the tumor volume in the trastuzumab and ZD4054 combination group was smaller than in the other groups. The detection of ETAR could help predict the prognosis of gastric cancer patients. Additionally, this study provides support for the therapeutic use of the combination of ZD4054 and trastuzumab as an anticancer treatment, especially for gastric cancer.

• Authors: Weisong Shen, Hongqing Xi, Chenyang Li, Shibo Bian, Haidong Cheng, Jianxin Cui, Ning Wang, Bo Wei, Xiaohui Huang, Lin Chen
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1448 Issue 1 Pg. 30-41 (07 2019) ISSN: 1749-6632 [Electronic] United States
• PMID: 30937921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 New York Academy of Sciences.

Chemical References

• Antineoplastic Agents, Immunological
• Endothelin A Receptor Antagonists
• Pyrrolidines
• Receptor, Endothelin A
• ZD4054
• EGFR protein, human
• ErbB Receptors
• Trastuzumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Endothelin A Receptor Antagonists (pharmacology)
• ErbB Receptors (metabolism)
• Female
• Gastric Mucosa (pathology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Pyrrolidines (pharmacology)
• Receptor, Endothelin A (genetics, metabolism)
• Stomach Neoplasms (drug therapy, genetics)
• Trastuzumab (pharmacology)
• Xenograft Model Antitumor Assays