Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

Central Research Laboratory, Jilin University Bethune Second Hospital, Changchun, People's Republic of China.
International Union of Biochemistry and Molecular Biology Life (Impact Factor: 3.14). 09/2012; 64(9):783-94. DOI: 10.1002/iub.1068
Source: PubMed


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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Available from: Dr-Muhammad Khan, Oct 30, 2014
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    • "In addition, our findings also demonstrated the sensitivity of tumor cells to alantolactone that appears as a result of GSH depletion and ROS production [49]. Further studies reveal that apoptosis induction more or less depends on many factors like increase in ROS, oxidation of cardiolipin, reduced mitochondrial membrane potential, and release of cytochrome c [49]. Khan et al. [52] have explained the involvement of ROS in isoalantolactonemediated apoptosis. "
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    • "Alantolactone, a sesquiterpene lactone compound, was found to effectively inhibit growth and triggering apoptosis in glioblastoma cells in a time-and dose-dependent manner. The alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, and reactive oxygen species (ROS) generation (Khan et al., 2012). In order to assess the neuroprotective properties of plant extracts, prepared, from herbal drugs commonly used in traditional Mediterranean medicine, our attention has been paid to bay leaves. "
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