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

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Author

  • Marcin Okroj
  • Wojciech Kamysz
  • Ewa M Slominska
  • Andrzej Mysliwski
  • Jacek Bigda

Summary, in English

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.

Publishing year

2005

Language

English

Pages

817-823

Publication/Series

Anti-Cancer Drugs

Volume

16

Issue

8

Document type

Journal article

Publisher

Rapid Communications

Topic

  • Other Basic Medicine

Status

Published

Research group

  • Protein Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 0959-4973