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

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

doi:10.1016/j.bcp.2012.06.015

Cited by 15 publications

(26 citation statements)

References 30 publications

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“…When RD ( 1 , 100 μ M) was oxidized by mushroom tyrosinase (25 U/ml) in the presence of NAcCys (200 μ M) at pH 6.8, the oxidation did not start until 15 min (Figure A). The reaction was then accelerated after 15 min to completion in 30 min; this strange time course is expected for the lag time when phenols are oxidized by tyrosinase (Ito et al., ; Ramsden and Riley, ). HPLC analysis indicated the production of 1 major and 3 minor compounds (Figure S1G).…”

Section: Resultsmentioning

confidence: 99%

“…In related studies to develop antimelanoma agents using tyrosinase substrates, we synthesized a number of derivatives of 4‐ S ‐cysteaminylphenol (4‐ S ‐CAP), a sulfur containing analog of L‐tyrosine (Alena et al., ), among which N ‐propionyl‐4‐ S ‐cysteaminylphenol (NPrCAP) was the most active in inhibiting the growth of melanoma cells in vitro and in vivo (Ishii‐Osai et al., ; Tandon et al., ). Our recent study showed that the phenol NPrCAP is activated by mushroom tyrosinase to an o ‐quinone that reacts rapidly with cysteine, GSH, and bovine serum albumin (Ito et al., ). The adduct formation with melanocytic proteins was confirmed in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosinase‐catalyzed oxidation of rhododendrol produces 2‐methylchromane‐6,7‐dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity

Ito

Ojika

Yamashita

et al. 2014

Pigment Cell Melanoma Res

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RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD) was used as a skin-whitening agent until it was reported to induce leukoderma in July 2013. To explore the mechanism underlying its melanocyte toxicity, we characterized the tyrosinase-catalyzed oxidation of RD using spectrophotometry and HPLC. Oxidation of RD with mushroom tyrosinase rapidly produced RD-quinone, which was quickly converted to 2-methylchromane-6,7-dione (RD-cyclic quinone) and RD-hydroxy-p-quinone through cyclization and addition of water molecule, respectively. RD-quinone and RD-cyclic quinone were identified as RD-catechol and RD-cyclic catechol after NaBH4 reduction. Autoxidation of RD-cyclic catechol produced superoxide radical. RD-quinone and RD-cyclic quinone quantitatively bound to thiols such as cysteine and GSH. These results suggest that the melanocyte toxicity of RD is caused by its tyrosinase-catalyzed oxidation through production of RD-cyclic quinone which depletes cytosolic GSH and then binds to essential cellular proteins through their sulfhydryl groups. The production of ROS through autoxidation of RD-cyclic catechol may augment the toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tyrosinase‐catalyzed oxidation of rhododendrol produces 2‐methylchromane‐6,7‐dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity

Ito

Ojika

Yamashita

et al. 2014

Pigment Cell Melanoma Res

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“…One possibility is the haptenation theory that was put forth to explain the molecular mechanism of monobenzone-induced skin depigmentation ( Figure 5 ) [ 26 , 77 ]. Phenolic substrates as prohaptens are oxidized by tyrosinase to produce o -quinones, which act as haptens that covalently bind to tyrosinase or other melanosomal (or melanocytic) proteins to generate possible neo-antigens [ 26 , 30 ]. These neo-antigens, in turn, can trigger an immunological response cascade that leads to melanocyte loss to produce depigmentation.…”

Section: Immunological Mechanismsmentioning

confidence: 99%

“…In related studies to develop antimelanoma agents using tyrosinase substrates, we synthesized a number of derivatives of 4- S -cysteaminylphenol (4- S -CAP), among which N -propionyl-4- S -cysteaminylphenol (NPrCAP) was the most active in inhibiting the growth of melanoma cells in vitro and in vivo [ 28 , 29 ]. Our study showed that the phenol NPrCAP is activated by mushroom tyrosinase to an o -quinone that reacts rapidly with CySH, GSH and BSA [ 30 ]. The adduct formation with melanocytic proteins was confirmed in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Mechanism of Rhododendrol-Induced Leukoderma

Ito

Wakamatsu

2018

IJMS

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RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))—a skin-whitening ingredient—was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products. Subsequently, we confirmed that human tyrosinase is able to oxidize both enantiomers of RD. We then showed that B16 cells exposed to RD produce high levels of RD-pheomelanin and protein-SH adducts of RD-quinone. Our recent studies showed that RD-eumelanin—an oxidation product of RD—exhibits a potent pro-oxidant activity that is enhanced by ultraviolet-A radiation. In this review, we summarize our biochemical findings on the tyrosinase-dependent metabolism of RD and related studies by other research groups. The results suggest two major mechanisms of cytotoxicity to melanocytes. One is the cytotoxicity of RD-quinone through binding with sulfhydryl proteins that leads to the inactivation of sulfhydryl enzymes and protein denaturation that leads to endoplasmic reticulum stress. The other mechanism is the pro-oxidant activity of RD-derived melanins that leads to oxidative stress resulting from the depletion of antioxidants and the generation of reactive oxygen radicals.

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“…NAcCys-NPrCAC is produced by the addition reaction of NAcCys (R-SH) with NPrCAQ. From Ito et al [47]. …”

Section: Figurementioning

confidence: 99%

Melanoma-Targeted Chemothermotherapy andIn SituPeptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles

Jimbow

Ishii-Osai

Itô

et al. 2013

Journal of Skin Cancer

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Exploitation of biological properties unique to cancer cells may provide a novel approach to overcome difficult challenges to the treatment of advanced melanoma. In order to develop melanoma-targeted chemothermoimmunotherapy, a melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP), sulfur-amine analogue of tyrosine, was conjugated with magnetite nanoparticles. NPrCAP was exploited from melanogenesis substrates, which are expected to be selectively incorporated into melanoma cells and produce highly reactive free radicals through reacting with tyrosinase, resulting in chemotherapeutic and immunotherapeutic effects by oxidative stress and apoptotic cell death. Magnetite nanoparticles were conjugated with NPrCAP to introduce thermotherapeutic and immunotherapeutic effects through nonapoptotic cell death and generation of heat shock protein (HSP) upon exposure to alternating magnetic field (AMF). During these therapeutic processes, NPrCAP was also expected to provide melanoma-targeted drug delivery system.

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

Cited by 15 publications

References 30 publications

Tyrosinase‐catalyzed oxidation of rhododendrol produces 2‐methylchromane‐6,7‐dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity

Tyrosinase‐catalyzed oxidation of rhododendrol produces 2‐methylchromane‐6,7‐dione, the putative ultimate toxic metabolite: implications for melanocyte toxicity

Biochemical Mechanism of Rhododendrol-Induced Leukoderma

Melanoma-Targeted Chemothermotherapy andIn SituPeptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles

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