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

Abstract

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.

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.

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.

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.

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.

• Authors: Yasue Ishii-Osai, Toshiharu Yamashita, Yasuaki Tamura, Noriyuki Sato, Akira Ito, Hiroyuki Honda, Kazumasa Wakamatsu, Shosuke Ito, Eiichi Nakayama, Masae Okura, Kowichi Jimbow
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 67 Issue 1 Pg. 51-60 (Jul 2012) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 22622238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antibodies
• Antineoplastic Agents
• Melanins
• N-propionyl-4-S-cysteaminylphenol
• Phenols
• Reactive Oxygen Species
• Casp3 protein, mouse
• Caspase 3
• Intramolecular Oxidoreductases
• dopachrome isomerase
• Cystamine

Topics

• Animals
• Antibodies (administration & dosage)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cystamine (analogs & derivatives, pharmacology)
• DNA Fragmentation
• Dose-Response Relationship, Drug
• Enzyme Activation
• Female
• Flow Cytometry
• Humans
• Immunity, Cellular (drug effects)
• Intramolecular Oxidoreductases (metabolism)
• Melanins (biosynthesis)
• Melanoma, Experimental (drug therapy, immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• NIH 3T3 Cells
• Phenols (pharmacology)
• Reactive Oxygen Species (metabolism)
• Time Factors
• Tumor Burden (drug effects)