Differential responses to (223)Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe

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.