The antiangiogenic agent linomide inhibits tumor necrosis factor-α secretion via inhibition of its synthesis

Ingrid B.J.K. Joseph, John T. Isaacs

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously reported that linomide, a quinoline-3-carboxamide, has antitumor effects against prostatic cancers in vivo through its ability to inhibit tumor angiogenesis. Subsequently, we reported that linomide inhibits several steps in the process of angiogenesis, including direct effects on endothelial cell proliferation and their chemotactic migration and invasion. Besides these direct effects, linomide's antiangiogenic activity also involves indirect effects secondary to inhibition of tumor infiltration of macrophages and their ability to secrete the angiogenic factor tumor necrosis factor-α (TNF-α). The current studies were conducted to gain insight into the mechanism by which linomide inhibits macrophage TNF-α secretion. The virally transformed RAW 264.7 mouse macrophage cell line was used as a model system. Chronic in vitro exposure (7 days) to 81-650 μM linomide is cytostatic to RAW cells. Such chronic exposure to linomide significantly decreased (P < 0.05) RAW cells' baseline ability to secrete TNF-α and also their ability to up-regulate TNF-α secretion in response to lipopolysaccharide (LPS) challenge. Ribonuclease protection assays demonstrated that linomide's ability to inhibit baseline and LPS-challenged TNF-α secretion is not functioning at the mRNA level, because steady-state levels of TNF-α mRNA do not change in response to linomide. Linomide's ability to inhibit TNF-α secretion is not associated with an increase in cell-associated TNF-α levels. Immunoprecipitation experiments demonstrated that linomide did not inhibit the normal proteolytic processing of the initial 26 kDa plasma membrane-bound TNF-α to the secreted 17 kDa soluble form. These results demonstrate that linomide inhibits TNF-α secretion by inhibition of the synthesis of the TNF-α protein. Linomide's ability to inhibit TNF-α protein synthesis is not due to an inhibition of general protein synthesis or secretion and is not mediated via a change in cyclic adenosine monophosphate levels.

Original languageEnglish (US)
Pages (from-to)183-190
Number of pages8
JournalProstate
Volume29
Issue number3
DOIs
StatePublished - Sep 1996

Keywords

  • TNF-α
  • angiogenesis
  • linomide
  • macrophage
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

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