Received for publication September 23, 2005.
Revised December 8, 2005.
Accepted for publication December 8, 2005.

Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor, tipifarnib

Abstract

Protein farnesyltransferase inhibitors (FTIs) have shown clinical responses in hematologic malignancies, but the mechanisms are unclear. To better understand potential mechanisms of action, we have studied effects of the FTI, tipifarnib, on inflammatory responses in vitro and in vivo. In a human leukemia cell line, THP-1, tipifarnib inhibited LPS-induced transcription of chemokines (MCP-1, MCP?), cytokines (IL-1, IL-6, IFN), signaling pathway genes (MyD88, STAT-1), proteases (MMP-9) and receptors (urokinase receptor). Tipifarnib also inhibited LPS-induced secretion of MMP-9, IL-6, MCP-1 and IL-1 in THP-1 cells. In primary human PBMC, dose-dependent inhibition of LPS-induced TNF-, IL-6, MCP-1 and IL-1 by tipifarnib was observed, with no evidence of cytotoxicity. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pre-treatment with tipifarnib resulted in significant inhibition of TNF-, IL-6, MCP-1, IL-1, and MIP-1 production. Tipifarnib had no effect in vitro or in vivo on LPS-induced IL-8. Studies in THP-1 cells to address potential mechanism(s) showed that tipifarnib partially inhibited LPS-induced p38 phosphorylation. Tipifarnib significantly inhibited IB- degradation and p65 nuclear translocation induced by LPS, but not by TNF-, IL-1, or TLR2 ligand, suggesting that the target for inhibition of NF-B activation was exclusive to the LPS/TLR4 signal pathway. The extent of IB- degradation inhibition did not correlate with inhibition of Ras farnesylation, indicating that Ras was not the target for the observed anti-inflammatory activity of tipifarnib. Our findings differ from those for other FTIs, which may have relevance for their dissimilar activity in specific tumor repertoires.

Key words: NF-kappaB, chemokines, cytokines, farnesyltransferase, inflammation, lipopolysaccharide