{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:58:14Z","timestamp":1760147894609,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T00:00:00Z","timestamp":1678320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health and Labor Sciences Research Grant-in-Aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) is a substrate for tyrosinase, which is a melanin biosynthesis enzyme and has been shown to be selectively incorporated into melanoma cells. It was found to cause selective cytotoxicity against melanocytes and melanoma cells after selective incorporation, resulting in the induction of anti-melanoma immunity. However, the underlying mechanisms for the induction of anti-melanoma immunity remain unclear. This study aimed to elucidate the cellular mechanism for the induction of anti-melanoma immunity and clarify whether N-Pr-4-S-CAP administration could be a new immunotherapeutic approach against melanoma, including local recurrence and distant metastasis. A T cell depletion assay was used for the identification of the effector cells responsible for N-Pr-4-S-CAP-mediated anti-melanoma immunity. A cross-presentation assay was carried out by using N-Pr-4-S-CAP-treated B16-OVA melanoma-loaded bone marrow-derived dendritic cells (BMDCs) and OVA-specific T cells. Administration of N-Pr-4-S-CAP induced CD8+ T cell-dependent anti-melanoma immunity and inhibited the growth of challenged B16F1 melanoma cells, indicating that the administration of N-Pr-4-S-CAP can be a prophylactic therapy against recurrence and metastasis of melanoma. Moreover, intratumoral injection of N-Pr-4-S-CAP in combination with BMDCs augmented the tumor growth inhibition when compared with administration of N-Pr-4-S-CAP alone. BMDCs cross-presented a melanoma-specific antigen to CD8+ T cells through N-Pr-4-S-CAP-mediated melanoma cell death. Combination therapy using N-Pr-4-S-CAP and BMDCs elicited a superior anti-melanoma effect. These results suggest that the administration of N-Pr-4-S-CAP could be a new strategy for the prevention of local recurrence and distant metastasis of melanoma.<\/jats:p>","DOI":"10.3390\/ijms24065235","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T03:03:23Z","timestamp":1678331003000},"page":"5235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Sulfur Containing Melanogenesis Substrate, N-Pr-4-S-CAP as a Potential Source for Selective Chemoimmunotherapy of Malignant Melanoma"],"prefix":"10.3390","volume":"24","author":[{"given":"Yasuaki","family":"Tamura","sequence":"first","affiliation":[{"name":"Department of Pathology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8556, Hokkaido, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Chemical Systems Engineering, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-9001","authenticated-orcid":false,"given":"Kazumasa","family":"Wakamatsu","sequence":"additional","affiliation":[{"name":"Institute for Melanin Chemistry, Fujita Health University, 1-98 Degakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9463-5917","authenticated-orcid":false,"given":"Toshihiko","family":"Torigoe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8556, Hokkaido, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9182-5144","authenticated-orcid":false,"given":"Shosuke","family":"Ito","sequence":"additional","affiliation":[{"name":"Institute for Melanin Chemistry, Fujita Health University, 1-98 Degakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kowichi","family":"Jimbow","sequence":"additional","affiliation":[{"name":"Institute of Dermatology & Cutaneous Sciences, 1-27 Odori West 17, Chuo-ku, Sapporo 060-0042, Hokkaido, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.mayocp.2014.02.002","article-title":"Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma","volume":"89","author":"Shah","year":"2014","journal-title":"Mayo Clin. Proc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1007\/s10147-018-1246-y","article-title":"Recent advances in therapeutic strategies for unresectable or metastatic melanoma and real-world data in Japan","volume":"24","author":"Uhara","year":"2019","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hida, T., Kamiya, T., Kawakami, A., Ogino, J., Sohma, H., Uhara, H., and Jimbow, K. (2020). Elucidation of melanogenesis cascade for identifying pathophysiology and therapeutic approach of pigmentary disorders and melanoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176129"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/00008390-200010010-00002","article-title":"Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity","volume":"10","author":"Gili","year":"2000","journal-title":"Melanoma Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wakamatsu, K., Ito, A., Tamura, Y., Hida, T., Kamiya, T., Torigoe, T., Honda, H., Ito, S., and Jimbow, K. (2022). Molecular events in the melanogenesis cascade as novel melanoma-targeted small molecules: Principle and development. Cancers, 14.","DOI":"10.3390\/cancers14225588"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1001\/archderm.1991.01680090092011","article-title":"N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma","volume":"127","author":"Jimbow","year":"1991","journal-title":"Arch. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231S","DOI":"10.1038\/jid.1993.82","article-title":"Exploitation of pigment biosynthesis pathway as a selective chemotherapeutic approach for malignant melanoma","volume":"100","author":"Jimbow","year":"1993","journal-title":"J. Investig. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0006-2952(98)00090-2","article-title":"Synthesis and antitumour effect of the melanogenesis-based antimelanoma agent N-propionyl-4-S-cysteaminylphenol","volume":"55","author":"Tandon","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1046\/j.1523-1747.1999.00781.x","article-title":"Selective incorporation and specific cytocidal effect as the cellular basis for the antimelanoma action of sulphur containing tyrosine analogs","volume":"113","author":"Thomas","year":"1999","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/BF00417318","article-title":"Synthesis of cysteinylphenol, cysteaminylphenol, and related compounds, and in vivo evaluation of antimelanoma effect","volume":"279","author":"Miura","year":"1987","journal-title":"Arch. Dermatol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/1523-1747.ep12470098","article-title":"The cytotoxicity of cysteinylcatechols and related compounds to human melanoma cells in vitro","volume":"88","author":"Yamada","year":"1987","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/0006-2952(90)90287-U","article-title":"Mechanism of growth inhibition of melanoma cells by 4-S-cysteaminylphenol and its analogues","volume":"39","author":"Inoue","year":"1990","journal-title":"Biochem. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jdermsci.2012.04.009","article-title":"N-propionyl-4-S-cysteaminylphenol induces apoptosis in B16F1 cells and mediates tumor-specific T-cell immune responses in a mouse melanoma model","volume":"67","author":"Yamashita","year":"2012","journal-title":"J. Dermatol. Sci."},{"key":"ref_14","first-page":"3278","article-title":"Selective cytotoxicity of 4-S-cysteaminylphenol on follicular melanocytes of the black mouse: Rational basis for its application to melanoma chemotherapy","volume":"47","author":"Ito","year":"1987","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1042\/bj2800721","article-title":"Tyrosine transport in a human melanoma cell line as a basis for selective transport of cytotoxic analogues","volume":"280","author":"Pankovich","year":"1991","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/j.1600-0749.1990.tb00279.x","article-title":"4-S-cysteaminylphenol and its analogues as substrates for tyrosinase and monoamine oxidase","volume":"3","author":"Pankovich","year":"1990","journal-title":"Pigment Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.bcp.2012.06.015","article-title":"Mechanism of putative neo-antigen formation from N-propionyl-4-S-cysteaminylphenol, a tyrosinase substrate, in melanoma models","volume":"84","author":"Ito","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"457936","DOI":"10.1155\/2009\/457936","article-title":"Growth inhibition of re-challenge B16 melanoma transplant by conjugates of melanogenesis substrate and magnetite nanoparticles as the basis for developing melanoma-targeted chemo-thermo-immunotherapy","volume":"2009","author":"Takada","year":"2009","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1038\/jid.2009.39","article-title":"N-propionyl-cysteaminylphenol-magnetite conjugate (NPrCAP\/M) is a nanoparticle for the targeted growth suppression of melanoma cells","volume":"129","author":"Sato","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s00262-005-0049-y","article-title":"Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: A novel concept of \u201cheat-controlled necrosis\u201d with heat shock protein expression","volume":"55","author":"Ito","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1111\/j.1349-7006.2010.01623.x","article-title":"Melanoma-targeted chemo-thermo-immuno (CTI)-therapy using N-propionyl-4-S-cysteaminylphenol-magnetite nanoparticles elicits CTL response via heat shock protein-peptide complex release","volume":"101","author":"Sato","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tamura, Y., Ito, A., Wakamatsu, K., Kamiya, T., Torigoe, T., Honda, H., Yamashita, T., Uhara, H., Ito, S., and Jimbow, K. (2022). Immunomodulation of melanoma by chemo-thermo-immunotherapy using conjugates of melanogenesis substrate NPrCAP and magnetite nanoparticles: A Review. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202205.0037.v1"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"742925","DOI":"10.1155\/2013\/742925","article-title":"Melanoma-targeted chemothermotherapy and in situ peptide immunotherapy through HSP production by using melanogenesis substrate, NPrCAP, and magnetite nanoparticles","volume":"2013","author":"Jimbow","year":"2013","journal-title":"J. Skin. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.278.5335.117","article-title":"Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations","volume":"278","author":"Tamura","year":"1997","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S1074-7613(00)80570-1","article-title":"Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world","volume":"8","author":"Srivastava","year":"1998","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0952-7915(01)00297-7","article-title":"Roles of heat-shock proteins in antigen presentation and cross-presentation","volume":"14","author":"Li","year":"2002","journal-title":"Curr. Opin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s00262-002-0335-x","article-title":"Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles","volume":"52","author":"Ito","year":"2003","journal-title":"Cancer Immunol. Immunother"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/j.1349-7006.2003.tb01438.x","article-title":"Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma","volume":"94","author":"Ito","year":"2003","journal-title":"Cancer Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1097\/CMR.0000000000000359","article-title":"Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland","volume":"27","author":"Mangana","year":"2017","journal-title":"Melanoma Res."},{"key":"ref_30","first-page":"2661","article-title":"Selective in vivo accumulation of N-acetyl-4-S-cysteaminylphenol in B16F10 murine melanoma and enhancement of its in vitro and in vivo antimelanoma effect by combination of buthionine sulfoximine","volume":"54","author":"Alena","year":"1994","journal-title":"Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5235\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:51:39Z","timestamp":1760122299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,9]]},"references-count":30,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065235"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065235","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,3,9]]}}}