| Popis: |
BACKGROUND We have previously demonstrated the anti-tumor activity of a nitric oxide-donor, nitrosylcobalamin (NO-Cbl), mediated by increased expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. OBJECTIVE The specific aim of this study was to examine the effects of nitric oxide (NO) on nuclear factor kappa B (NF-kB) and determine whether nitric oxide could sensitize drug-resistant melanomas to Apo2L/TRAIL via inhibition of NF-kB or Inhibitor kappa B kinase (IKK). METHODS Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL. The activation status of NF-kB was established by assaying luciferase reporter activity, the phosphorylation status of IkBa, and in vitro IKK activity. RESULTS NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. NO-Cbl suppressed Apo2L/TRAIL- and TNF-a-mediated activation of a transfected NF-kB-driven luciferase reporter. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IkBa. CONCLUSIONS NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination based on current anti-TNF-super family clinical strategies. CLINICALTRIAL n/a INTERNATIONAL REGISTERED REPORT RR2-10.1074/jbc.W119.011721 |
