RKTS-33, an Epoxycyclohexenone Derivative That Specifically Inhibits Fas Ligand-Dependent Apoptosis in CTL-Mediated Cytotoxicity

• MITSUI Tomokazu

  Center for Biological Resources and Informatics, Tokyo Institute of Technology

• MIYAKE Yasunobu

  Center for Biological Resources and Informatics, Tokyo Institute of Technology Antibiotics Laboratory, Discovery Research Institute, RIKEN

• KAKEYA Hideaki

  Antibiotics Laboratory, Discovery Research Institute, RIKEN

• HAYASHI Yujiro

  Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science

• OSADA Hiroyuki

  Antibiotics Laboratory, Discovery Research Institute, RIKEN

• KATAOKA Takao

  Center for Biological Resources and Informatics, Tokyo Institute of Technology

Abstract

Cytotoxic T lymphocytes (CTLs) eliminate virus-infected cells and tumor cells by two distinct killing pathways, mediated by lytic granules containing perforin 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.

Journal

• Bioscience, Biotechnology, and Biochemistry

  Bioscience, Biotechnology, and Biochemistry 69 (10), 1923-1928, 2005

  Japan Society for Bioscience, Biotechnology, and Agrochemistry

Keywords

• apoptosis
• cytotoxic T lymphocyte (CTL)
• (<I>2R</I>,<I>3R</I>,<I>4S</I>)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-6-(<I>1E</I>)-propenyl-cyclohex-5-en-1-one (ECH)
• Fas ligand
• (<I>2R</I>,<I>3R</I>,<I>4S</I>)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-cyclohex-5-en-1-one (RKTS-33)

Details

• CRID: 1390282681453052416
• NII Article ID: 130000030524
• NII Book ID: AA10824164
• DOI: 10.1271/bbb.69.1923
• ISSN: 13476947
• ISSN: 09168451
• NDL BIB ID: 7679053
• PubMed: 16244443
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I7679053
• Web Site: http://www.tandfonline.com/doi/pdf/10.1271/bbb.69.1923
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed