Parthenolide induces apoptosis in glioblastomas without affecting NF-kappaB.

Department of Biological Sciences, Western Michigan University, Kalamazoo 49008, USA.
Journal of Pharmacological Sciences (Impact Factor: 2.11). 03/2008; 106(2):318-20. DOI: 10.1254/jphs.SC0060164
Source: PubMed

ABSTRACT Parthenolide is a sesquiterpene lactone that has been isolated from Tanacetum parthenium (feverfew). Parthenolide has several biological activities including the induction of apoptosis and inhibition of NF-kappaB. Because of its activities against several tumor types and because it is relatively well tolerated, in clinical trial, parthenolide is an attractive compound for the treatment of brain tumors. However, there have been no reports concerning its ability to induce apoptosis in any brain tumor cell lines. In this report we demonstrate that treatment of glioblastoma cells with parthenolide resulted in rapid apoptosis through caspase 3/7 without a suppression of NF-kappaB activity.

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    ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time- and dose-dependent manner. The alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl-2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP-ribose) polymerase. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine, whereas other antioxidant (polyethylene glycol (PEG)-catalase and PEG-superoxide-dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF-κB into nucleus; however, NF-κB inhibitor, SN50 failed to potentiate alantolactone-induced apoptosis indicating that alantolactone induces NF-κB-independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy.
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