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

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. © © 2012 IUBMB Life, 64(9): 783–794, 2012

Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway

“…In the present study, the levels of GSH generation had significant roles in the anticancer effects of alantolactone on HeLa cells. Khan et al (15,20) demonstrated that alantolactone was able to induce apoptosis of HepG2 cells and glioblastoma cells via GSH depletion.…”

“…It has been confirmed to exert antitumor, anti-inflammatory and antibacterial effects (12)(13)(14). Previous findings have shown that alantolactone was able to induce U87 glioma cell apoptosis by mitochondrial injury, via an increase in ROS production (15).…”

The Stance of Antioxidants in Brain Tumors

“…The elevated iron levels in these cells also makes them daintily exquisite to ROS generation based on chemotherapeutics (Yonezawa, et al, 1996). In a study, alantolactone which inhibits tumor growth and triggers apoptosis and GSH depletion in glioblastoma, is suggested as a potential lead compound for antiglioma therapy (Khan, et al, 2012). …”

Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

“…Determination of mitochondrial transmembrane potential (MMP) depolarization TBMS1-induced MMP depolarization in DU145 cells was assessed using rhodamine 123 (Rho123) as described previously [23] . The DU145 cells were treated with different concentrations of TBMS1 for 24 h. Following treatment, the cells were collected by centrifugation, washed with PBS twice and then stained with rhodamine 123 (10 μg/mL) at 37 °C for 30 min in dark.…”

“…The cells were collected, and the protein was extracted as described previously [23] . Protein concentrations of the supernatants were determined using a BCA Protein Assay Kit.…”