Tumor cell-specific inhibition of inducible nitric oxide synthase activation by tiazofurin

The effects of tiazofurin (TR) on proliferation and cytokine-induced nitric oxide (NO) production in the L929 fibrosarcoma cell line and murine embryo nic fibroblasts were investigated. Treatment with TR inhibited the growth o f nonconfluent L929 cells in a dose-dependent manner. TR, at concentrations not affecting cell viability or proliferation, markedly decreased IFN-gamm a + LPS-induced expression of inducible NO synthase (iNOS) mRNA and, subseq uently. NO production in confluent L929 cultures. However, TR did not inter fere with the IFN-gamma -triggered expression of mRNA for IRF-1, an importa nt iNOS transcription factor, implying that TR interferes with some other i ntracellular pathway involved in iNOS induction triggered by IFN-gamma + LP S. In contrast to the results obtained in L929 cells, iNOS mRNA expression induced by IFN-gamma + LPS in murine embryonic fibroblasts was resistant to TR, indicating a tumor-selective action of this agent. (C) 2001 Elsevier S cience B.V. All rights reserved.