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Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Montgomery, Jennifer P. and Patterson, Paul H. (2008) Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor. BMC Cancer, 8 . p. 354. ISSN 1471-2407. PMCID PMC2613414. doi:10.1186/1471-2407-8-354.

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Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes.

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Additional Information:Copyright © 2008 Montgomery and Patterson; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Published: 28 November 2008. Received: 14 November 2007. Accepted: 28 November 2008. This work is supported by the Kenneth and Eileen Norris Foundation, the Dana Foundation Clinical Hypotheses in Neuroscience Research, and the Millard and Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology. JPM was the recipient of an Alumnae Association of Barnard College Fellowship. We thank the Caltech Flow Cytometry Facility and Rochelle Diamond for her technical expertise and Benjamin Deverman and Fraser Moss for their helpful comments on the manuscript. We also are grateful to Abbott Laboratories for providing A-192621.
Funding AgencyGrant Number
Abbott LaboratoriesA-192621
Kenneth and Eileen Norris FoundationUNSPECIFIED
Dana Foundation Clinical Hypotheses in Neuroscience ResearchUNSPECIFIED
Caltech Millard and Muriel Jacobs Genetics and Genomics LaboratoryUNSPECIFIED
Subject Keywords:human glioblastoma cells; ovarian-carcinoma cells; in-vitro; human meningiomas; kinase-activity; melanoma-cells; growth-factor; DNA-damage; expression; apoptosis
PubMed Central ID:PMC2613414
Record Number:CaltechAUTHORS:MONbmcc08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13569
Deposited By: Tony Diaz
Deposited On:08 May 2009 21:16
Last Modified:08 Nov 2021 22:38

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