N-propionyl-4-S-cysteaminylphenol induces apoptosis in B16F1 cells and mediates tumor-specific T-cell immune responses in a mouse melanoma model

作者：Ishii Osai Yasue; Yamashita Toshiharu^*; Tamura Yasuaki; Sato Noriyuki; Ito Akira; Honda Hiroyuki; Wakamatsu Kazumasa; Ito Shosuke; Nakayama Eiichi; Okura Masae; Jimbow Kowichi

来源：Journal of Dermatological Science, 2012, 67(1): 51-60.

DOI：10.1016/j.jdermsci.2012.04.009

• N-propionyl-4-S-cysteaminylphenol
• Melanogenesis
• Apoptosis
• Reactive oxygen species
• Tumor suppression
• Tyrosinase-related protein

Background: N-propionyl-4-S-cysteaminylphenol (NPr-4-S-CAP) is selectively incorporated into melanoma cells and degrades them. However, it remains unclear whether NPr-4-S-CAP can induce cell death associated with the induction of host immune responses and tumor suppression in vivo. %26lt;br%26gt;Objective: To examine the molecular mechanism of NPr-4-S-CAP-mediated cytotoxicity toward melanoma cells and to test whether NPr-4-S-CAP can suppress transplanted primary and secondary B16F1 melanomas. %26lt;br%26gt;Methods: Cytotoxicity and apoptosis of melanoma cells were assessed by cell counting, flow cytometry, and detection of reactive oxygen species (ROS) and apoptotic molecules. NPr-4-S-CAP-associated host immunity was studied using a B16F1 mouse melanoma model through the application of CD4- and CD8-specific antibodies and tetramer assay. %26lt;br%26gt;Results: NPr-4-S-CAP suppressed growth of pigmented melanoma cells associated with an increase of intracellular ROS, activation of caspase 3 and DNA fragmentation, suggesting that NPr-4-S-CAP mediated ROS production, eliciting apoptosis of melanoma cells. Growth of transplanted B16F1 melanomas was inhibited after the consecutive intratumoral injections of NPr-4-S-CAP, and the tumor growth after rechallenge of B16F1 was significantly suppressed in the treated mice. This suppression occurred when the treated mice were given the anti-CD4 antibody, but not the anti-CD8 antibody. Tetramer assay demonstrated increased TYRP-2-specific CD8(+) T cells in the lymph node and spleen cells prepared from NPr-4-S-CAP-treated B16F1-bearing mice. %26lt;br%26gt;Conclusions: These suggest that NPr-4-S-CAP induces apoptosis in melanoma cells through ROS production and generates CD8(+) cell immunity resulting in the suppression of rechallenged B16F1 melanoma.

• 出版日期2012-7