Combination of withaferin A and X-ray irradiation enhances apoptosis in U937 cells.

Combined treatment with radiation has improved the outcome in various cancers and many radiosensitizers are used to enhance the therapeutic efficiency of radiotherapy. Withaferin A (Wit A), a natural compound derived from the medicinal plant Withania somnifera, has been reported for its anti-inflammatory and anti-tumor effects. In this study, we show that Wit A enhances the ionizing radiation (IR)-induced apoptosis in human lymphoma U937 cells. Wit A-enhanced IR-induced apoptosis is associated with the PARP cleavage, caspase-3 activation, as well as specifically down-regulation of anti-apoptotic protein Bcl-2, suggesting that Wit A may be useful as a potential radiosensitizer. In addition, pretreatment of U937 cells with SP600125 (JNK inhibitor) or SB203589 (p38 MAPK inhibitor) dose-dependently inhibited the proteolytic cleavage of PARP. We provide the evidence here that generation of reactive oxygen species (ROS), Bcl-2 down-regulation and activation of MAPKs pathway are critically involved in the apoptosis induced by Wit A and radiation.