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Naturally occurring asteriscunolide A induces apoptosis and activation of mitogen-activated protein kinase pathway in human tumor cell lines.

Abstract
Sesquiterpene lactones have attracted much attention because they display a wide range of biological activities, including antitumor properties. Here, we show the effects of the naturally occurring sesquiterpene lactone asteriscunolide A (AS) on viability of human melanoma, leukemia and cells that overexpress antiapoptotic proteins, namely Bcl-2 and Bcl-x(L). All cell lines were sensitive to this compound, with IC(50) values of approximately 5 microM. The cytotoxic effects of AS were accompanied by a G(2)-M phase arrest of the cell cycle and a concentration- and time-dependent appearance of apoptosis as determined by DNA fragmentation, translocation of phosphatidylserine to the cell surface and sub-G(1) ratio. Apoptosis was associated with caspase-3 activity and poly(ADP-ribose) polymerase cleavage and was prevented by the nonspecific caspase inhibitor z-VAD-fmk, indicating that caspases are essential components in this pathway. The apoptotic effect of AS was also associated with (i) the release of cytochrome c from mitochondria which was accompanied by dissipation of the mitochondrial membrane potential (Delta Psi(m)) and (ii) the activation of the mitogen-activated protein kinases (MAPKs) pathway. AS-induced cell death was potentiated by inhibition of extracellular signal-regulated kinases (ERK) 1/2 signaling with U0126 and PD98059. Intracellular reactive oxygen species (ROS) seem to play a pivotal role in this process since high levels of ROS were produced early (1 h) and apoptosis was completely blocked by the free radical scavenger N-acetyl-L-cysteine (NAC). The present study demonstrates that AS-induced cell death is mediated by an intrinsic-dependent apoptotic event involving mitochondria and MAPKs, and through a mechanism dependent on ROS generation.
AuthorsGledy Negrín, José L Eiroa, Manuel Morales, Jorge Triana, José Quintana, Francisco Estévez
JournalMolecular carcinogenesis (Mol Carcinog) Vol. 49 Issue 5 Pg. 488-99 (May 2010) ISSN: 1098-2744 [Electronic] United States
PMID20232365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright(c) 2010 Wiley-Liss, Inc.
Chemical References
  • Lactones
  • Reactive Oxygen Species
  • Sesquiterpenes
  • asteriscunolide A
Topics
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Enzyme Activation
  • Humans
  • Lactones (pharmacology)
  • MAP Kinase Signaling System (drug effects)
  • Microscopy, Electron, Transmission
  • Reactive Oxygen Species (metabolism)
  • Sesquiterpenes (pharmacology)

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