Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, has recently been shown to have anti-glioma activity. I found that OP-A induces paraptosis-like cell death accompanied by the endoplasmic reticulum (ER) dilation, accumulation of poly-ubiquitinated proteins in glioma cells and CHOP-mediated ER stress plays a critical role in this process. Inhibition of protein synthesis using cycloheximide (CHX) almost completely blocked the vacuolation and glioma cell death, suggesting a requirement of new protein synthesis for this death accompanied by vacuolation. Interestingly, thiol-based antioxidants, including N-acetylcysteine (NAC) and reduced glutathione (GSH) and N-(2-mercaptopropionyl)-glycine (NMPG), but not other non-thiol antioxidants, including Ascorbic acid and Tiron and MnTBAP (Mn(III)tetrakis (4-benzoic acid) porphyrin) very effectively blocked OP-A-induced vacuolation and cell death. In addition, notable generation of reactive oxygen species (ROS) by OP-A was not detected, suggesting that the anti-cancer effects of OP-A may be mediated though its ability to covalently modify free sulfhydryl groups on proteins causing protein misfolding, rather than through ROS generation. Collectively, our results indicate that ER stress due to disruption of thiol proteostasis may be responsible for the potent anti-glioma activity of OP-A.
