Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / therapeutic use
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Atrasentan
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Cell Proliferation / drug effects
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Cisplatin / therapeutic use
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Disease Models, Animal
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Drug Therapy, Combination
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Endothelin A Receptor Antagonists*
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Endothelin B Receptor Antagonists
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Endothelin-1 / metabolism
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Fluorouracil / therapeutic use
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nasopharyngeal Neoplasms / drug therapy*
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology
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Pyrrolidines / therapeutic use
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Receptor, Endothelin A / genetics
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Receptor, Endothelin A / metabolism
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Receptor, Endothelin B / genetics
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Receptor, Endothelin B / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents
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Endothelin A Receptor Antagonists
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Endothelin B Receptor Antagonists
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Endothelin-1
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Pyrrolidines
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RNA, Messenger
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RNA, Neoplasm
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Receptor, Endothelin A
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Receptor, Endothelin B
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Cisplatin
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Fluorouracil
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Atrasentan