Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe
Francisco Liberal, Hugo Moreira, Kelly M. Redmond, Joe M. O’Sullivan, Ali Alshehri, Timothy Wright, Victoria L. Dunne, Caoimhghin Campfield, Sandra Biggart, Stephen J. McMahon, Kevin M. Prise
Abstract
Introduction Radium-223 ( 223 Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223 Ra at the cellular level. Methods We evaluated the effects of 223 Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics. Results 223 Ra exposures had very high, cell-type-dependent RBE 50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE 50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223 Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223 Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223 Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe. Conclusions These results suggest that 223 Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization.