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

Andris Abramenkovs; Mehran Hariri; Diana Spiegelberg; Sten Nilsson; Bo Stenerlöw

doi:10.1016/j.tranon.2022.101543

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

Transl Oncol. 2022 Dec:26:101543. doi: 10.1016/j.tranon.2022.101543. Epub 2022 Sep 18.

Authors

Andris Abramenkovs¹, Mehran Hariri², Diana Spiegelberg³, Sten Nilsson⁴, Bo Stenerlöw⁵

Affiliations

¹ Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden.
² Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden. Electronic address: mehran.hariri@igp.uu.se.
³ Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
⁵ Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden. Electronic address: bo.stenerlow@igp.uu.se.

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.

Keywords: DNA damage; HAp; Prostate cancer; Ra-223; α-particle.