Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe
IntroductionRadium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level.MethodsWe eva...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.877302/full |
| _version_ | 1818002038462611456 |
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| author | Francisco D. C. Guerra Liberal Hugo Moreira Kelly M. Redmond Joe M. O’Sullivan Joe M. O’Sullivan Ali H. D. Alshehri Ali H. D. Alshehri Timothy C. Wright Victoria L. Dunne Caoimhghin Campfield Sandra Biggart Stephen J. McMahon Kevin M. Prise |
| author_facet | Francisco D. C. Guerra Liberal Hugo Moreira Kelly M. Redmond Joe M. O’Sullivan Joe M. O’Sullivan Ali H. D. Alshehri Ali H. D. Alshehri Timothy C. Wright Victoria L. Dunne Caoimhghin Campfield Sandra Biggart Stephen J. McMahon Kevin M. Prise |
| author_sort | Francisco D. C. Guerra Liberal |
| collection | DOAJ |
| description | IntroductionRadium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level.MethodsWe evaluated the effects of 223Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics.Results223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe.ConclusionsThese results suggest that 223Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization. |
| first_indexed | 2024-04-14T03:41:41Z |
| format | Article |
| id | doaj.art-c036d2a956814f3e95393de65eb7ca6f |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T03:41:41Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c036d2a956814f3e95393de65eb7ca6f2022-12-22T02:14:31ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.877302877302Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastropheFrancisco D. C. Guerra Liberal0Hugo Moreira1Kelly M. Redmond2Joe M. O’Sullivan3Joe M. O’Sullivan4Ali H. D. Alshehri5Ali H. D. Alshehri6Timothy C. Wright7Victoria L. Dunne8Caoimhghin Campfield9Sandra Biggart10Stephen J. McMahon11Kevin M. Prise12The Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomNorthern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomDepartment of Radiological Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi ArabiaThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomNorthern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, United KingdomNorthern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomThe Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United KingdomIntroductionRadium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level.MethodsWe evaluated the effects of 223Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics.Results223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe.ConclusionsThese results suggest that 223Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization.https://www.frontiersin.org/articles/10.3389/fonc.2022.877302/fullalpha particlesradium-223mitotic catastropheradiation effectsbone metastases |
| spellingShingle | Francisco D. C. Guerra Liberal Hugo Moreira Kelly M. Redmond Joe M. O’Sullivan Joe M. O’Sullivan Ali H. D. Alshehri Ali H. D. Alshehri Timothy C. Wright Victoria L. Dunne Caoimhghin Campfield Sandra Biggart Stephen J. McMahon Kevin M. Prise Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe Frontiers in Oncology alpha particles radium-223 mitotic catastrophe radiation effects bone metastases |
| title | Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe |
| title_full | Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe |
| title_fullStr | Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe |
| title_full_unstemmed | Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe |
| title_short | Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe |
| title_sort | differential responses to 223ra and alpha particles exposure in prostate cancer driven by mitotic catastrophe |
| topic | alpha particles radium-223 mitotic catastrophe radiation effects bone metastases |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.877302/full |
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