Mechanism of putative neo-antigen formation from N-propionyl-4-S- cysteaminylphenol, a tyrosinase substrate, in melanoma models

Shosuke Ito, Akira Nishigaki, Yasue Ishii-Osai, Makoto Ojika, Kazumasa Wakamatsu, Toshiharu Yamashita, Yasuaki Tamura, Akira Ito, Hiroyuki Honda, Eiichi Nakayama, Kowichi Jimbow

研究成果: Contribution to journalArticle査読

10 被引用数 (Scopus)

抄録

Metastatic melanoma is resistant to conventional therapies. N-propionyl-4-S-cysteaminylphenol (NPrCAP), an N-protected sulfur-amine analog of tyrosine, is a good substrate for tyrosinase and is selectively incorporated into melanoma cells, causing cytotoxicity in vitro and in vivo. We have recently shown that intratumoral injections of NPrCAP suppress not only the growth of primary B16F1 melanoma tumors but also of secondary, re-challenged tumors. The participation of CD8 + T cells has been suggested for the NPrCAP-mediated anti-B16 melanoma immunity. In this study, the molecular mechanism of the NPrCAP cytotoxicity and immunogenicity was examined. The phenol NPrCAP was shown to be activated by mushroom tyrosinase to the ortho-quinone N-propionyl-4-S-cysteaminyl-1,2-benzoquinone (NPrCAQ), and the structure was confirmed by reducing it to the corresponding catechol. NPrCAQ reacted rapidly with biologically relevant sulfhydryl compounds such as cysteine, glutathione and bovine serum albumin. The NPrCAQ-thiol adduct formation was proven with a model thiol N-acetylcysteine by spectroscopic methods. The production and release of NPrCAQ-protein adducts was verified in B16F1 melanoma cells in vitro and in B16F1 melanoma-bearing mice in vivo through the detection of 5-S-cysteaminyl-3-S-cysteinylcatechol after acid hydrolysis of the protein fraction. These results suggest that the phenol NPrCAP, acting as a prohapten, can be activated in melanoma cells by tyrosinase to the quinone-hapten NPrCAQ, which binds to melanosomal proteins through their cysteine residues to form possible neo-antigens, thus triggering the immunological response. NPrCAP thus represents a potential new approach to immunotherapy against metastatic melanoma.

本文言語英語
ページ(範囲)646-653
ページ数8
ジャーナルBiochemical Pharmacology
84
5
DOI
出版ステータス出版済み - 9 1 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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