Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Cancer Sci. 2006 Dec;97(12):1388-95. doi: 10.1111/j.1349-7006.2006.00333.x. Epub 2006 Oct 9.


The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ET(A)R expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ET(A)R represents a new target in NPC treatment, we tested the therapeutic role of ET(A)R in NPC. Cell proliferation was inhibited by the ET(A)R-selective antagonist ABT-627 in two ET(A)R-positive NPC cells in a dose-dependent manner. Proliferation of ET(A)R-negative NPC cells was not decreased. ET(A)R blockade also resulted in sensitization to cisplatin and 5-fluorouracil-induced apoptosis. In nude mice, ABT-627 inhibited the growth of NPC cell xenografts. Combined treatment of ABT-627 with the cytotoxic drug cisplatin or 5-fluorouracil produced additive antitumor effects. The antitumor activity of ABT-627 was demonstrated finally on an experimental lung metastasis by a reduction in the number of tumors. These results support the rationale of combining ABT-627 with current standard chemotherapy to further improve the therapeutic ratio in the treatment of NPC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Atrasentan
  • Cell Proliferation / drug effects
  • Cisplatin / therapeutic use
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Endothelin A Receptor Antagonists*
  • Endothelin B Receptor Antagonists
  • Endothelin-1 / metabolism
  • Fluorouracil / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology
  • Pyrrolidines / therapeutic use
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin B / genetics
  • Receptor, Endothelin B / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Pyrrolidines
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Cisplatin
  • Fluorouracil
  • Atrasentan