https://orcid.org/0000-0001-5690-3020
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Abstract
Background
Metastatic castration-resistant prostate cancer (mCRPC) is associated with a very unfavorable prognosis. At this advanced stage of the disease, there are several therapeutic strategies approved in recent times, being one of them Radium-223 dichloride (Radium-223). However, its mechanisms of action and the process that conducts to cell death are not fully understood. Given this, our main goal is to characterize the radiobiological effects induced by Radium-223 and to evaluate its kinetics on metastatic Prostate Cancer (mPCa) cells.
Materials and Methods
In vitro studies were conducted using two mPCa cell lines, the LNCaP and PC3, the first being derived from lymph node metastasis and the second from bone metastasis. Kinetic studies were conducted to access the capacity of these cell lines to uptake, retain and internalize the Radium-223. For the assessment of radiobiological effects, cells were first exposed to different doses of Radium-223 and the clonogenic assay was done to evaluate cell survival and to determine lethal doses (LD50). Then, the effects were also evaluated in terms of proliferation, oxidative stress, morphological changes and cell damage.
Results
Radium-223 is uptaken by mPCa cells and reaches the nucleus, where it is retained over time. Irradiation decreases cell survival and proliferation, with LNCaP cells (LD50 = 1.73mGy) being more radiosensitive than PC3 cells (LD50 = 4.20mGy). Irradiated cells showed morphological changes usually associated with apoptosis and a dose-dependent increase in DNA damage. Moreover, activation of cell cycle checkpoints occurs through ATM/CHK2 pathway, which is involved in cell cycle arrest and cell death.
Conclusions
The cytotoxic and anti-proliferative effects on both cell lines showed that Radium-223 can decrease the aggressiveness of tumor cells by decreasing the cell survival and proliferation and, also, by increasing the DNA damage. The similar results observed in both cell lines indicated that Radium-223 may have the potential to be used as a therapeutic option also for mCRPC patients with lymph node metastasis. The activation of DNA Damage Response pathways allows the possibility to understand the importance of these checkpoints as targets for new combined therapies.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Inês A. Marques
Inês A. Marques, MSc, PhD Student in Pharmaceutical Sciences, hosted at Biophysics Institute, Coimbra Institute for Clinical and Biomedical Research – Group of Environment Genetics and Oncobiology (iCBR-CIMAGO).
Ana M. Abrantes
Ana M. Abrantes, PhD in Health Sciences, is an Assistant Professor at the Faculty of Medicine of the University of Coimbra and a Researcher at Biophysics Institute of iCBR-CIMAGO.
Ana S. Pires
Ana S. Pires, PhD in Biomedical Engineering, is an Assistant Professor at Faculty of Medicine of University of Coimbra (FMUC) and a Researcher at Biophysics Institute, iCBR-CIMAGO.
Ana R. Neves
Ana R. Neves, MSc in Biomedical Engineering, is now a data science researcher in the Mathematics and Computer Science Department at the Eindhoven University of Technology. Prior to this position, she was a Researcher at Biophysics Institute, iCBR-CIMAGO.
Francisco J. Caramelo
Francisco J. Caramelo, PhD, is an Assistant Professor at the Faculty of Medicine of the University of Coimbra and a Researcher at Laboratory of Biostatistics and Medical Informatics, iCBR.
Tiago Rodrigues
Tiago Rodrigues, PhD in Health Sciences, is a Researcher at Institute of Physiology of iCBR.
Paulo Matafome
Paulo Matafome, PhD in Biomedical Sciences, is an Invited Auxiliary Professor at ESTeSC, Polytechnic Institute of Coimbra and a Researcher at the FMUC.
Edgar Tavares-da-Silva
Edgar Tavares-da-Silva, M.D., Urologist at the Kidney Transplantation and Organ Harvesting Team at the Centro Hospitalar e Universitário de Coimbra (CHUC) and a PhD Student at the FMUC.Ana C. Gonçalves, PhD in Health Sciences, is an Assistant Professor at FMUC and a Researcher at Laboratory of Oncobiology and Hematology and University Clinic of Hematology, iCBR-CIMAGO.
Cristiana C. Pereira
Cristiana C. Pereira, PhD in Metabolism, is an Assistant Researcher (career) at the National Institute of Health Doctor Ricardo Jorge IP and at the University of Porto Institute of Public Health.
João P. Teixeira
João P. Teixeira, PhD in Biomedical Sciences, is a Researcher and the Head of Research Unit, Environmental Health Department in the National Institute of Health (Portugal) and coordinator of Environmental and Laboratory Epidemiology (ELE) from the EPIUnit.
Raquel Seiça
Raquel Seiça, M.D., PhD and Aggregation in Medicine, is a Full-Professor of Medicine, Head of the Institute of Physiology at iCBR, FMUC and collaborator Investigator in the Center for Classical and Humanistic Studies, Faculty of Arts and Humanities, University of Coimbra.
Grancinda Costa
Maria. F. Botelho, M.D., PhD in Medicine, is a Full-Professor of Medicine at FMUC, Leader of the Research Line Modeling in Oncolobiology and Director of Biophysics Institute of iCBR-CIMAGO.
Arnaldo Figueiredo
Arnaldo Figueiredo, M.D., PhD in Medicine, is the director of the Department of Urology and Renal Transplantation of the Centro Hospitalar e Universitário de Coimbra (CHUC) and Professor of Urology at FMUC.