AUTHOR=Guerra Liberal Francisco D. C. , Moreira Hugo , Redmond Kelly M. , O’Sullivan Joe M. , Alshehri Ali H. D. , Wright Timothy C. , Dunne Victoria L. , Campfield Caoimhghin , Biggart Sandra , McMahon Stephen J. , Prise Kevin M. TITLE=Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.877302 DOI=10.3389/fonc.2022.877302 ISSN=2234-943X ABSTRACT=Introduction

Radium-223 (223Ra) 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 223Ra at the cellular level.

Methods

We evaluated the effects of 223Ra 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

223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe.

Conclusions

These results suggest that 223Ra 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.