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Qiuhua Zhang, Jordan Toutounchian, Charles Yates, Matthew Wilson, Jena Steinle; KZ-41 prevents melphalan-induced intercellular adhesion molecule-1 (ICAM-1) upregulation and apoptosis in retinal endothelial cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1259.
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To determine whether a novel NF-κB inhibitor, KZ-41, can inhibit melphalan’s actions on retinal endothelial cells (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79).
REC were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 μM KZ-41, following treatment with 4 μg/ml melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and cell death ELISA. REC were also transfected with or without NF-κB siRNA before melphalan treatment to determine the involvement of NF-κB in REC apoptosis and ICAM-1 levels. Cell lysates were processed for ICAM-1 levels and cell death ELISA. Western blotting was done to verify NF-κB knockdown following both NF-κB siRNA transfection and KZ-41 treatment. Phospho-P38MAPK inhibitor was also treated before KZ-41 and melphalan treatment and cell lysates were tested for ICAM-1 levels and REC cell death. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and antibiotics and performed a cell death ELISA after melphalan + KZ-41 treatment to verify that the treatments did not alter melphalan’s ability to promote cell death of Y79 cells.
KZ-41 could inhibit melphalan-induced ICAM-1 levels and REC apoptosis. KZ-41 blocked increased ICAM-1 levels through p38MAPK activation and NF-κB inhibition; and decreased REC apoptosis likely through p38MAPK activation. KZ-41 did not alter melphalan’s effects on Y79 cells.
Use of KZ-41 to block NF-κB and activate P38MAPK protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis.
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