Direct Stimulation of Apoptotic Signaling by Soluble Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Leads to Selective Killing of Glioma Cells

摘要: Apo2 ligand tumor necrosis factor-related apoptosis-inducing (Apo2L/TRAIL) is a member of the factor family that interacts with cell surface "death receptors" (DR4 and DR5) to initiate programmed death. Apo2L/TRAIL also binds "decoy" receptors (DcR1 DcR2) can antagonize its interaction DR4 DR5. In recent studies, has been noted produce selective toxicity toward certain neoplastic cells versus normal cells. The decoy may in part contribute this selectivity, because they are expressed various tissues but present at low or undetectable levels types current study, we examined potential therapeutic applicability recombinant soluble by investigating effects vitro vivo against series lines derived from malignant gliomas, which often resistant conventional treatment modalities. proliferation assays, produced striking decrease numbers, median inhibitory concentration 30-100 ng/ml, TP53 wild-type high-grade glioma U87 A172, TP53-mutated T98G, TP53-deleted LN-Z308. contrast, no significant were observed non-neoplastic astrocytes concentrations up 3000 ng/ml. Clonogenic assays showed exposure Apo2L time-dependent viability glioma-derived lines. This correlated induction apoptosis as assessed terminal transferase-catalyzed situ end-labeling assay. Pretreatment caspase inhibitors Acetyl-Asp-Glu-Val-L-aspartic acid aldehyde Acetyl-Tyr-Val-Ala-Asp-chlormethylketone (200 microM) largely eliminated Apo2L/TRAIL. Administration (0.3, 1, 3, 10, 30 mg/kg/day for 7 days via i.p. infusion) nude mice harboring established intracranial xenografts significant, dose-dependent prolongation survival control animals. Survival group was 27 +/- 1.7 days, compared more than 50 each groups (P < 0.001). At mg/kg dose level, 100% animals survived 120 without evidence tumor, substantial improvement comparison lower 0.01). No overt apparent even highest dose. We conclude effective inducing vitro. Because appears exhibit cytotoxicity demonstrates activity when administered systemically an otherwise uniformly fatal central nervous system model system, constitute useful agent these challenging tumors.