title: Vinorelbine-induced oxidative injury in human endothelial cells mediated by AMPK/PKC/NADPH/NF-κB pathways.
abstract: Vinorelbine tartrate (VNR), a semi-synthetic vinca alkaloid acquired from vinblastine, has extensively been used as an anticancer agent. However, VNR-induced oxidative damage may cause several side effects, such as venous irritation, vascular pain, and necrotizing vasculitis, thereby repressing clinical treatment efficiency. The molecular mechanisms underlying the induced oxidative stress in endothelial cells are still largely unknown. This study was designed to test the hypothesis that VNR induces oxidative injury through modulation of AMP-activated protein kinase (AMPK) and possible mechanisms were then explored. Human umbilical vein endothelial cells (HUVECs) were treated with VNR (5-0.625 μM) to produce oxidative damage. The VNR-mediated AMPK, PKC, and NADPH oxidase expressions were investigated by western blotting. Furthermore, several oxidative stress-induced oxidative damage markers as well as pro-inflammatory responses were also investigated. VNR treatment resulted in dephosphorylation of AMPK, which in turn led to an activation of NADPH oxidase by PKC; however, the phenomena were repressed by AICAR (an agonist of AMPK). Furthermore, VNR suppressed Akt/eNOS and enhanced p38 mitogen-activated protein kinase (MAPK), which in turn activated the NF-κB pathway. Furthermore, VNR facilitated several pro-inflammatory events, such as the adherence of monocytic THP-1 cells to HUVECs, pro-inflammatory cytokines release, and overexpression of adhesion molecular. Our results highlight a possible molecular mechanism for VNR-mediated endothelial dysfunction.
authors.affiliation: Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan No. 91, Shuch-Shih Road, Taichung 404, Taiwan.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Tsai
authors.forename: Tsan-Hung
authors.initials: TH
authors.lastname: Chiu
authors.forename: Mei-Hsueh
authors.initials: MH
authors.lastname: Tsai
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Chen
authors.forename: Hsiu-Chung
authors.initials: HC
authors.lastname: Ou
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D014747:Vinblastine; D019255:NADPH Oxidases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D000077235:Vinorelbine