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

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 hydro...

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Autores principales: Abramenkovs, Andris, Hariri, Mehran, Spiegelberg, Diana, Nilsson, Sten, Stenerlöw, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489499/
https://www.ncbi.nlm.nih.gov/pubmed/36126563
http://dx.doi.org/10.1016/j.tranon.2022.101543
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author Abramenkovs, Andris
Hariri, Mehran
Spiegelberg, Diana
Nilsson, Sten
Stenerlöw, Bo
author_facet Abramenkovs, Andris
Hariri, Mehran
Spiegelberg, Diana
Nilsson, Sten
Stenerlöw, Bo
author_sort Abramenkovs, Andris
collection PubMed
description 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.
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spelling pubmed-94894992022-09-30 Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines Abramenkovs, Andris Hariri, Mehran Spiegelberg, Diana Nilsson, Sten Stenerlöw, Bo Transl Oncol Original Research 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. Neoplasia Press 2022-09-18 /pmc/articles/PMC9489499/ /pubmed/36126563 http://dx.doi.org/10.1016/j.tranon.2022.101543 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Research
Abramenkovs, Andris
Hariri, Mehran
Spiegelberg, Diana
Nilsson, Sten
Stenerlöw, Bo
Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title_full Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title_fullStr Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title_full_unstemmed Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title_short Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines
title_sort ra-223 induces clustered dna damage and inhibits cell survival in several prostate cancer cell lines
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489499/
https://www.ncbi.nlm.nih.gov/pubmed/36126563
http://dx.doi.org/10.1016/j.tranon.2022.101543
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