RKTS-33, an epoxycyclohexenone derivative that specifically inhibits Fas ligand-dependent apoptosis in CTL-mediated cytotoxicity

Tomokazu Mitsui, Yasunobu Miyake, Hideaki Kakeya, Yujiro Hayashi, Hiroyuki Osada, Takao Kataoka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Cytotoxic T lymphocytes (CTLs) eliminate virus-infected cells and tumor cells by two distinct killing pathways, mediated by lytic granules containing perform and by Fas ligand (FasL). ECH [(2R,3R,4S)-2,3-epoxy-4-hydroxy-5- hydroxymethyl-6-(1E)-propenyl-cyclohex-5-en-1-one] has been shown to inhibit FasL-dependent apoptosis or the killing pathway in short-term culture. However, since ECH exhibited cell toxicity in long-term culture, we attempted the synthesis of less toxic epoxycyclohexenone derivatives. In the present study, we found that RKTS-33 [(2R,3R,4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-cyclohex-5- en-1-one] has cell toxicity lower than ECH in long-term culture, and further investigated the inhibitory effect of RKTS-33 on CTL-mediated killing pathways. RKTS-33 did not affect cell-surface expression of FasL upon CD3 stimulation, but profoundly inhibited the FasL-dependent killing pathway mediated by CD4 + and CD8+ CTLs, indicating that RKTS-33 specifically blocks target cell apoptosis but not CTL function. By contrast, RKTS-33 did not affect the perforin-dependent killing pathway in CD8+ CTLs. These results indicate that RKTS-33 is a specific inhibitor of the FasL-dependent killing pathway in CTL-mediated cytotoxicity.

Original languageEnglish
Pages (from-to)1923-1928
Number of pages6
JournalBioscience, Biotechnology and Biochemistry
Volume69
Issue number10
DOIs
Publication statusPublished - 2005 Oct 23
Externally publishedYes

Keywords

  • (2R,3R,4S)-2,3-epoxy-4-hydroxy-5- hydroxymethyl-6-(1E)-propenyl-cyclohex-5-en-1-one (ECH)
  • (2R,3R,4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-cyclohex-5-en-1-one (RKTS-33)
  • Apoptosis
  • Cytotoxic T lymphocyte (CTL)
  • Fas ligand

ASJC Scopus subject areas

  • Biotechnology
  • Analytical Chemistry
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Organic Chemistry

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