Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines

Abstract

The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in prostate cancer. The alpha-particle emitter Ra-223, targets regions undergoing active bone remodeling and strongly binds to bone hydroxyapatite (HAp). However, the toxicity mechanism and properties of Ra-223 binding to hydroxyapatite are not fully understood. By exposing 2D and 3D (spheroid) prostate cancer cell models to free and HAp-bound Ra-223 we here studied cell toxicity, apoptosis and formation and repair of DNA double-strand breaks (DSBs). The rapid binding with a high affinity of Ra-223 to bone-like HAp structures was evident (KD= 19.2 × 10−18 M) and almost no dissociation was detected within 24 h. Importantly, there was no significant uptake of Ra-223 in cells. The Ra-223 alpha-particle decay produced track-like distributions of the DNA damage response proteins 53BP1 and ɣH2AX induced high amounts of clustered DSBs in prostate cancer cells and activated DSB repair through non-homologous end-joining (NHEJ). Ra-223 inhibited growth of prostate cancer cells, independent of cell type, and induced high levels of apoptosis. In summary, we suggest the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by α-particles.