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

Okroj, Marcin LU ; Kamysz, Wojciech; Slominska, Ewa M; Mysliwski, Andrzej and Bigda, Jacek (2005) In Anti-Cancer Drugs 16(8). p.817-823
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Anti-Cancer Drugs
volume
16
issue
8
pages
817 - 823
publisher
Rapid Communications
external identifiers
  • pmid:16096429
  • scopus:24044502878
ISSN
0959-4973
language
English
LU publication?
yes
id
f6ae6aaf-dadd-42d2-adb6-064c54d69557 (old id 1132307)
date added to LUP
2008-06-30 11:25:02
date last changed
2017-01-01 05:05:54
@article{f6ae6aaf-dadd-42d2-adb6-064c54d69557,
  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.},
  author       = {Okroj, Marcin and Kamysz, Wojciech and Slominska, Ewa M and Mysliwski, Andrzej and Bigda, Jacek},
  issn         = {0959-4973},
  language     = {eng},
  number       = {8},
  pages        = {817--823},
  publisher    = {Rapid Communications},
  series       = {Anti-Cancer Drugs},
  title        = {A novel mechanism of action of the fumagillin analog, TNP-470, in the B16F10 murine melanoma cell line},
  volume       = {16},
  year         = {2005},
}