Involvement of superoxide and nitric oxide in BRAFV600E inhibitor PLX4032-induced growth inhibition of melanoma cells

摘要: The BRAF(V600E) inhibitor PLX4032 (Vemurafenib) is an FDA-approved new drug for the treatment of metastatic melanomas, which specifically inhibits RAS/MEK/ERK signaling pathway to control cell proliferation and adhesion. However, no study has been carried out investigate role intracellular oxidative balance in PLX4032-induced tumor growth inhibition. Herein, first time, superoxide (O2˙(-)) nitric oxide (NO) generated from PLX4032-challenged melanoma cells were monitored using electrochemical sensors conventional fluorescein staining techniques. Impacts dismutase (SOD) NG-monomethyl-L-arginine monoacetate (L-NMMA), a synthase inhibitor, also examined demonstrate specificity ROS/NO generation its biological consequences. triggers production O2˙(-) NO mutant A375 cells. SOD L-NMMA could abolish increase production, thereby rescuing BRAF (A375(BRAFV600E)). In addition, decrease mitochondrial membrane potential A375(BRAFV600E) results suggest that can selectively cause ROS depolarization membranes, potentially initiating apoptosis inhibition PLX4032-sensitive This work not only proposes mechanism inhibition, but highlights applications biosensors biology screening.