Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy.
Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy.
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DOI：
10.1158/1078-0432.ccr-09-3123
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发表时间：
2010-03-15
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影响因子：
--
通讯作者：
Overwijk WW
中科院分区：
文献类型：
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作者：
Sikora AG;Gelbard A;Davies MA;Sano D;Ekmekcioglu S;Kwon J;Hailemichael Y;Jayaraman P;Myers JN;Grimm EA;Overwijk WW
Aberrant expression of inflammatory molecules, such as inducible nitric oxide synthase (iNOS), has been linked to cancer, suggesting that their inhibition is a rational therapeutic approach. While iNOS expression in melanoma and other cancers is associated with poor clinical prognosis, in vitro and in vivo studies suggest that iNOS and nitric oxide (NO) can have both pro-and anti-tumor effects. We tested the hypothesis that targeted iNOS inhibition would interfere with human melanoma growth and survival in vivo in a preclinical model. We used an immunodeficient NOD/SCID xenograft model to test the susceptibility of two different human melanoma lines to the orally-administered iNOS-selective small molecule antagonist N6-(1-Iminoethyl)-L-lysine-dihydrochloride (L-nil)with and without cytotoxic cisplatin chemotherapy. 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 (RPPA) identified alterations in the expression of multiple cell signaling and survival genes after L-nil treatment. The canonical anti-apoptotic 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. 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.
