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

Abramenkovs, AndrisUppsala universitet,Institutionen för immunologi, genetik och patologi,Rudbecklaboratoriet (författare)

The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended sur-vival 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 x 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 gamma H2AX 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 alpha-particles.

Hariri, MehranUppsala universitet,Institutionen för immunologi, genetik och patologi,Rudbecklaboratoriet(Swepub:uu)mehha904 (författare)
Spiegelberg, Diana,1982-Uppsala universitet,Plastikkirurgi,Cancerprecisionsmedicin,Öron-, näs- och halssjukdomar,Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-75185, Sweden,Rudbecklaboratoriet(Swepub:uu)diasp673 (författare)
Nilsson, StenKarolinska Institutet (författare)
Stenerlöw, BoUppsala universitet,Cancerprecisionsmedicin,Rudbecklaboratoriet(Swepub:uu)bostener (författare)
Uppsala universitetInstitutionen för immunologi, genetik och patologi (creator_code:org_t)

Av författaren/redakt...: Abramenkovs, And ...; Hariri, Mehran; Spiegelberg, Dia ...; Nilsson, Sten; Stenerlöw, Bo

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Cancer och onkol ...

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