Up-regulation by ammonium trichloro(dioxoethylene-0,0') tellurate (AS101) of Fas/Apo-1 expression on B16 melanoma cells: implications for the antitumor effects of AS101.
It was recently reported that human and mouse melanoma cells express Fas ligand (FasL) but almost no Fas, which may contribute to their immune privilege. AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate), a synthetic immunomodulator with minimal toxicity, was found to have antitumor effects in various tumor models. Our present study shows that AS101 has direct and indirect effects on tumor cells; AS101 inhibits the clonogenicity of B16 melanoma cells in vitro. Moreover, wild-type P53 expression, which is required for induction of Apo-1 expression, increased significantly in AS101-treated cells. We therefore investigated Fas expression in AS101-treated B16 cells and found that Fas, but not FasL, expression was significantly increased; moreover, Fas receptors were functional. Longer incubation with AS101 resulted in spontaneous apoptosis triggered by the Fas-FasL system. To explore the relationship of these results to the antitumor effects of AS101, we injected B16-F10 mouse melanoma cells into syngeneic C57BL/6 mice carrying the lpr mutation in the Fas gene and to gld mutant mice that lack functional FasL. Tumor development in control groups was lowest in the lpr mice, while no difference was observed between gld and wild-type mice. Among the AS101-treated groups, the most pronounced effect appeared in the lpr mice, while the lowest was seen in the gld mutant mice. Our study suggests that AS101 may render melanoma tumor cells more sensitive to Fas/FasL-induced apoptosis and may therefore have clinical potential.
Cancer, AIDS, and Immunology Research Institute, Department of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Y
Y
Kalechman
G
G
Strassmann
M
M
Albeck
B
B
Sredni
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005030:Ethylenes / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005030:Ethylenes; D006131:Growth Inhibitors; D007106:Immune Sera; D019014:fas Receptor; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate