A novel mechanism of action of the fumagillin analog, TNP-470, in the B16F10 murine melanoma cell line.
TNP-470, a semisynthetic derivative of fumagillin, is an acknowledged angiogenesis inhibitor, presently undergoing clinical trials. It exerts an anti-proliferative effect directed against endothelial cells. This effect is known to be based on cell cycle inhibition effected by the p53/p21 pathway. We observed short-term toxicity of TNP-470 in the B16F10 murine melanoma cell line in vitro and investigated the mechanism of action. Cell death occurred as soon as 2 h after the addition of TNP-470, without typical apoptotic features. The toxic effect could be modulated and it depended on the type of culture medium or supplementation with anti-oxidants. Addition of N-acetylcysteine protected B16F10 cells from TNP-470-induced death and inhibited an increase in the generation of reactive oxygen species (ROS), which are detected by the 2',7'-dichlorodihydrofluorescein diacetate probe. We conclude that TNP-470 can induce intracellular generation of ROS, which act toxically inside B16F10 cells. One may suggest that this novel activity of TNP-470 might be beneficial in some cases, but it could also be responsible for some undesirable side-effects. The possibility of its modulation gives a prospect for controlling the action of this potential drug and probably its derivatives.
Okrój
Marcin
M
Department of Cell Biology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdansk, Poland.
Kamysz
Wojciech
W
Slominska
Ewa M
EM
Mysliwski
Andrzej
A
Bigda
Jacek
J
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D000111:Acetylcysteine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol