Abstract
64CuCl2 has recently been proposed as a promising agent for prostate cancer (PCa) theranostics, based on preclinical studies in cellular and animal models, and on the increasing number of human studies documenting its use for PCa diagnosis. Nevertheless, the use of 64CuCl2 raises important radiobiological questions that have yet to be addressed. In this work, using a panel of PCa cell lines in comparison with a non-tumoral prostate cell line, we combined cytogenetic approaches with radiocytotoxicity assays to obtain significant insights into the cellular consequences of exposure to 64CuCl2. PCa cells were found to exhibit increased 64CuCl2 uptake, which could not be attributed to increased expression of the main copper cellular importer, hCtr1, as had been previously suggested. Early DNA damage and genomic instability were also higher in PCa cells, with the tumoral cell lines exhibiting deficient DNA-damage repair upon exposure to 64CuCl2. This was corroborated by the observation that 64CuCl2 was more cytotoxic in PCa cells than in non-tumoral cells. Overall, we showed for the first time that PCa cells had a higher sensitivity to 64CuCl2 than healthy cells, supporting the idea that this compound deserved to be further evaluated as a theranostic agent in PCa.
Highlights
Prostate cancer (PCa) is the cancer type with the highest incidence in the male population of the United States and in the Northern and Western countries of the European Union, being the second highest cancer-related cause of death among men in those countries [1,2]
99m Tc-methylene diphosphonate bone scintigraphy is the standard method used to detect bone metastases, while 18 F-choline and 11 C-choline positron emission tomography (PET) offer high sensitivity and specificity to detect lymph node involvement and distant metastases, as well as disease recurrence, being well established tracers for those purposes [4,5]. 68 Ga-prostate-specific membrane antigen targeted radiopharmaceuticals, which are designed to recognize a membrane glycoprotein that is highly expressed in human prostate cancer (PCa) cells, have emerged as having tremendous potential for the detection and re-staging of PCa after biochemical recurrence, offering superior contrast and sensitivity than 18 F-choline [4]
To explore if 64 CuCl2 would be able to enter into PCa cells as previously suggested by animal studies using human PCa xenografts [18], cellular uptake was assessed on a panel of PCa cell lines derived from bone (22RV1, PC3, and VCaP), brain (DU145) or lymph node (LNCaP) metastasis, using an immortalized, non-tumoral prostate cell line as a control (RWPE-1)
Summary
Prostate cancer (PCa) is the cancer type with the highest incidence in the male population of the United States and in the Northern and Western countries of the European Union, being the second highest cancer-related cause of death among men in those countries [1,2]. Despite being one of the most commonly used positron emission tomography (PET) tracers in oncology, 18 F-Fludeoxyglucose has limited sensitivity for the detection of primary. Current therapeutic alternatives to treat castration-resistant PCa include the use of chemotherapy, novel hormone therapies targeting androgen signaling, and the use of the radionuclide radium-223 for bone pain palliation [3]. These strategies focus only on the increase of the patients’ lifespan and improvement of the patients’ quality of life, as the disease remains fatal [3]. There is still a medical need for more efficient diagnostic methods and novel therapy alternatives that can overcome these limitations, in particular novel radiopharmaceuticals with the potential to be used simultaneously for imaging diagnosis and targeted therapy, that is, with theranostics potential [7]
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