Apoptotic Effect of Wortmannolone on Cancer Cells through Potent ROS Induction

Nuclear factor κappa-B inhibitors isolated from natural sources that induce apoptosis are promising new agents with anticancer properties. Wortmannin and wortmannolone were isolated from endophytic fungus (Penicillum polonicum) and showed NF-κB inhibitory effects with inhibitory concentration (IC₅₀) of 0.47 μM and 2.06 μM for wortmannin and wortmannolone, respectively. The activity was compared with rocaglamide (IC₅₀=0.075 μM). The mechanism through which wortmannin and wortmannolone exhibited an attenuating effect on the NF-κB pathway was further evaluated in this study. Wortmannolone showed significant reactive oxygen species (ROS) inducing effects in HeLa cervical cells. The ROS inducing effect was concentration dependent, and the ROS generating activity was comparable with daunomycin, a potent chemotherapeutic agent. The findings suggested that the elevated formation of ROS was partially involved in the induction of apoptosis in treated cells. Potent cytotoxic and apoptotic effects were also displayed in MDA-MB-231 hormone independent breast cancer cells when treated with wortmannolone (IC₅₀=3.79 nM). Thus, wortmannolone, a furanosteroid from an endophytic fungus, is a promising agent for further drug development.