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Clinical Cancer Research

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Cancer Therapy: Preclinical

Targeted Inhibition of Inducible Nitric Oxide Synthase Inhibits Growth of Human Melanoma In vivo and Synergizes with Chemotherapy

Andrew G. Sikora, Alexander Gelbard, Michael A. Davies, Daisuke Sano, Suhendan Ekmekcioglu, John Kwon, Yared Hailemichael, Padmini Jayaraman, Jeffrey N. Myers, Elizabeth A. Grimm and Willem W. Overwijk
Andrew G. Sikora
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Alexander Gelbard
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Michael A. Davies
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Daisuke Sano
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Suhendan Ekmekcioglu
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John Kwon
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Yared Hailemichael
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Padmini Jayaraman
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Jeffrey N. Myers
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Elizabeth A. Grimm
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Willem W. Overwijk
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DOI: 10.1158/1078-0432.CCR-09-3123 Published March 2010
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Abstract

Purpose: Aberrant expression of inflammatory molecules, such as inducible nitric oxide (NO) synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. Whereas iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and NO can have both protumor and antitumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model.

Experimental Design: We used an immunodeficient non-obese diabetic/severe combined immunodeficient xenograft model to test the susceptibility of two different human melanoma lines to the orally-given iNOS-selective small molecule antagonist N6-(1-iminoethyl)-l-lysine-dihydrochloride (L-nil) with and without cytotoxic cisplatin chemotherapy.

Results: L-nil significantly inhibited melanoma growth and extended the survival of tumor-bearing mice. L-nil treatment decreased the density of CD31+ microvessels and increased the number of apoptotic cells in tumor xenografts. Proteomic analysis of melanoma xenografts with reverse-phase protein array identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical antiapoptotic protein Bcl-2 was downregulated in vivo and in vitro after L-nil treatment, which was associated with increased susceptibility to cisplatin-mediated tumor death. Consistent with this observation, combination therapy with L-nil plus cisplatin in vivo was more effective than either drug alone, without increased toxicity.

Conclusions: These data support the hypothesis that iNOS and iNOS-derived NO support tumor growth in vivo and provide convincing preclinical validation of targeted iNOS inhibition as therapy for solid tumors. Clin Cancer Res; 16(6); 1834–44

Keywords
  • inducible nitric oxide synthase (iNOS)
  • targeted therapy

This article is featured in Highlights of This Issue, p. 1693

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received November 25, 2009.
  • Revision received January 22, 2010.
  • Accepted January 22, 2010.
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Clinical Cancer Research: 16 (6)
March 2010
Volume 16, Issue 6
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Targeted Inhibition of Inducible Nitric Oxide Synthase Inhibits Growth of Human Melanoma In vivo and Synergizes with Chemotherapy
Andrew G. Sikora, Alexander Gelbard, Michael A. Davies, Daisuke Sano, Suhendan Ekmekcioglu, John Kwon, Yared Hailemichael, Padmini Jayaraman, Jeffrey N. Myers, Elizabeth A. Grimm and Willem W. Overwijk
Clin Cancer Res March 15 2010 (16) (6) 1834-1844; DOI: 10.1158/1078-0432.CCR-09-3123

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Targeted Inhibition of Inducible Nitric Oxide Synthase Inhibits Growth of Human Melanoma In vivo and Synergizes with Chemotherapy
Andrew G. Sikora, Alexander Gelbard, Michael A. Davies, Daisuke Sano, Suhendan Ekmekcioglu, John Kwon, Yared Hailemichael, Padmini Jayaraman, Jeffrey N. Myers, Elizabeth A. Grimm and Willem W. Overwijk
Clin Cancer Res March 15 2010 (16) (6) 1834-1844; DOI: 10.1158/1078-0432.CCR-09-3123
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Clinical Cancer Research
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