A novel mechanism of action of the fumagillin analog, TNP-470, in the B16F10 murine melanoma cell line.

Abstract

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.

• Authors: Marcin Okrój, Wojciech Kamysz, Ewa M Slominska, Andrzej Mysliwski, Jacek Bigda
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 16 Issue 8 Pg. 817-23 (Sep 2005) ISSN: 0959-4973 [Print] England
• PMID: 16096429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cyclohexanes
• Reactive Oxygen Species
• Sesquiterpenes
• Acetylcysteine
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Cells, Cultured (cytology, drug effects, metabolism)
• Cyclohexanes
• Endothelial Cells (cytology, drug effects, metabolism)
• HeLa Cells (cytology, drug effects, metabolism)
• Humans
• In Vitro Techniques
• Kidney (cytology, drug effects, metabolism)
• Melanoma, Experimental (drug therapy, metabolism)
• Mice
• O-(Chloroacetylcarbamoyl)fumagillol
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (pharmacology)