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An endothelin receptor B antagonist inhibits growth and induces cell death in human melanoma cells in vitro and in vivo

Lahav, Ronit and Heffner, Garrett and Patterson, Paul H. (1999) An endothelin receptor B antagonist inhibits growth and induces cell death in human melanoma cells in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 96 (20). pp. 11496-11500. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:LAHpnas99

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Abstract

Activation of the endothelin receptor B (ETRB) in cultured melanocyte precursors promotes cell proliferation while inhibiting differentiation, two hallmarks of malignant transformation. We therefore tested whether ETRB has a similar role in malignant transformation of melanoma. When tested in culture, we find that the selective ETRB antagonist BQ788 can inhibit the growth of seven human melanoma cell lines, but not a human kidney cell line. This inhibition often is associated with increases in pigmentation and in the dendritic shape that is characteristic of mature melanocytes. In three cell lines we also observe a major increase in cell death. In contrast, the endothelin receptor A (ETRA) antagonist BQ123 does not have these effects, although all the cell lines express both ETRA and ETRB mRNA. Extending these studies in vivo, we find that administration of BQ788 significantly slows human melanoma tumor growth in nude mice, including a complete growth arrest in half of the mice treated systemically. Histological examination of tumor sections suggests that BQ788 also enhances melanoma cell death in vivo. Thus, ETRB inhibitors may be beneficial for the treatment of melanoma.


Item Type:Article
Additional Information:Copyright © 1999 by the National Academy of Sciences. Communicated by Norman Davidson, California Institute of Technology, Pasadena, CA, August 9, 1999 (received for review July 4, 1999). We thank D. McDowell for help with laboratory administration, J. Baer for help and advice with animal care, and D. Anderson for providing comments on the manuscript. R.L. is supported by a Human Frontier Science Program Long Term Fellowship, and G.H. was supported by a Caltech Summer Undergraduate Research Fellowship. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:INDUCED APOPTOSIS; C-KIT; EXPRESSION; GENE; PROLIFERATION; MELANOCYTES; STEEL; HEART
Record Number:CaltechAUTHORS:LAHpnas99
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LAHpnas99
Alternative URL:http://www.pnas.org/cgi/content/abstract/96/20/11496
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1589
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Feb 2006
Last Modified:26 Dec 2012 08:45

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