Cyclophosphamide enhances TNF-alpha-induced apoptotic cell death in murine vascular endothelial cell.
Cyclophosphamide (CPA) is one of the therapeutic agents for systemic inflammatory disorders. In murine dermal endothelial cells (F-2), 4-hydroxycyclophosphamide (4-HC), which is active metabolite of CPA, enhanced TNF-alpha-induced DNA fragmentation. In addition, 4-HC was shown to elevate TNF-alpha-induced caspase-3 activation. Caspase-8 activation was identified by the treatment of TNF-alpha, whereas 4-HC was no effect. In contrast, only when treated with 4-HC, caspase-9 activation and the increase in the intracellular expression of Bax were detected. These results suggest that CPA may sensitize endothelial cells to TNF-alpha-induced apoptosis through a mitochondria-dependent pathway and clinically may contribute to the limitation of inflammatory process.
Department of Dermatology, Wakayama Medical University, 811-1 Kimi-idera, Wakayama, Japan. tossan@wakayama-med.ac.jp
Toshio
T
Ohtani
Tomoyuki
T
Nakamura
Ken-Ichi
K
Toda
Fukumi
F
Furukawa
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D018501:Antirheumatic Agents; D061945:Caspase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D003546:Cysteine Endopeptidases