mHFE7A, a newly identified monoclonal antibody to Fas, induces apoptosis in human melanoma cells in vitro and delays the growth of melanoma xenotransplants.
The Fas receptor is a potentially valuable therapeutic target in cancer treatment. However, the clinical application of antibodies directed to this target is hindered by their serious side effects in vivo, including liver toxicity. One murine monoclonal antibody, mHFE7A, binds both to human Fas and murine Fas, without inducing any obvious side effects. However, the potential therapeutic effects of mHFE7A are unclear in human cancer cells or tumors. Here, we determined whether mHFE7A could induce apoptosis in vitro, and assessed its effects on major apoptotic pathways in a human melanoma cell line, MMN9. We also investigated its anti-cancer effects on transplanted melanoma MMN9 tumors in BALB/c nude mice. Treatment of mHFE7A cross-linking with Ig induced cell death similar to CH-11 treatment. Apoptosis induced by mHFE7A was defined by Hoechst 33342 DNA staining and DNA fragmentation assay. Furthermore, mHFE7A-mediated apoptosis was dependent on activation of a caspase signaling cascade involving caspases-8 and -3. Administration of mHFE7A also delayed the growth of melanoma xenografts. Thus, we provide the first evidence that the murine anti-Fas monoclonal antibody, mHFE7A, induces apoptosis of human malignant melanoma cells in vitro and is anti-tumorigenic in vivo.
Hiramoto
Kenichi
K
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. hiraken@clin.medic.mie-u.ac.jp
Inui
Madoka
M
Kamei
Takahiko
T
Okumura
Kenya
K
Nakase
Minoru
M
Tagawa
Toshiro
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D020169:Caspases