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- Abramenkovs, AndrisUppsala universitet,Medicinsk strålningsvetenskap,Bo Stenerlöw (author)
The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
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- LIBRIS-ID:oai:DiVA.org:uu-378720
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-378720URI
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- Language:English
- Summary in:English
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- The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.
Subject headings and genre
- MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Radiologi och bildbehandling hsv//swe
- MEDICAL AND HEALTH SCIENCES Clinical Medicine Radiology, Nuclear Medicine and Medical Imaging hsv//eng
- Prostate cancer
- ARv7
- DNA damage
- Ra-223
- high-LET
- Medical Cell Biology
- Medicinsk cellbiologi
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- Spiegelberg, Diana,1982-Uppsala universitet,Medicinsk strålningsvetenskap,Öron-, näs- och halssjukdomar,Göran Laurell(Swepub:uu)diasp673 (author)
- Nilsson, StenDepartment of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden,Sten Nilsson (author)
- Stenerlöw, BoUppsala universitet,Medicinsk strålningsvetenskap,Bo Stenerlöw(Swepub:uu)bostener (author)
- Uppsala universitetMedicinsk strålningsvetenskap (creator_code:org_t)
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