Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State Through Inhibition of DNA Double Strand Break Repair
| Autor: | Anastassia Löser, Christoph Oing, Carsten Bokemeyer, Hartwig Huland, Wael Y. Mansour, Su Jung Oh-Hohenhorst, Stefanie Meien, Cordula Petersen, Susanne Burdak-Rothkamm, Derya Tilki, Sally Mutiara, Sabrina Köcher, Kai Rothkamm, Alexandra Zielinski, Mohamed E Elsesy, Rudolf Schwarz |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Bicalutamide Antiandrogens medicine.drug_class Antiandrogen urologic and male genital diseases lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound Prostate cancer 0302 clinical medicine LNCaP medicine Enzalutamide apalutamide enzalutamide business.industry Apalutamide Abiraterone acetate medicine.disease prostate cancer lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Oncology chemistry abiraterone acetate DNA double strand break repair 030220 oncology & carcinogenesis Cancer research radiosensitization business medicine.drug |
| Zdroj: | Cancers, Vol 12, Iss 2467, p 2467 (2020) CANCERS Cancers Volume 12 Issue 9 |
| ISSN: | 2072-6694 |
| Popis: | (1) Background: The combination of the first-generation antiandrogens and radiotherapy (RT) has been studied extensively in the clinical setting of prostate cancer (PCa). Here, we evaluated the potential radiosensitizing effect of the second-generation antiandrogens abiraterone acetate, apalutamide and enzalutamide. (2) Methods: Cell proliferation and agarose-colony forming assay were used to measure the effect on survival. Double strand break repair efficiency was monitored using immunofluorescence staining of &gamma H2AX/53BP1. (3) Results: We report retrospectively a minor benefit for PCa patients received first-generation androgen blockers and RT compared to patients treated with RT alone. Combining either of the second-generation antiandrogens and 2Gy suppressed cell growth and increased doubling time significantly more than 2Gy alone, in both hormone-responsive LNCaP and castration-resistant C4-2B cells. These findings were recapitulated in resistant sub-clones to (i) hormone ablation (LNCaP-abl), (ii) abiraterone acetate (LNCaP-abi), (iii) apalutamide (LNCaP-ARN509), (iv) enzalutamide (C4-2B-ENZA), and in castration-resistant 22-RV1 cells. This radiosensitization effect was not observable using the first-generation antiandrogen bicalutamide. Inhibition of DNA DSB repair was found to contribute to the radiosensitization effect of second-generation antiandrogens, as demonstrated by a significant increase in residual &gamma H2AX and 53BP1 foci numbers at 24h post-IR. DSB repair inhibition was further demonstrated in 22 patient-derived tumor slice cultures treated with abiraterone acetate before ex-vivo irradiation with 2Gy. (4) Conclusion: Together, these data show that second-generation antiandrogens can enhance radiosensitivity in PCa through DSB repair inhibition, regardless of their hormonal status. Translated into clinical practice, our results may help to find additional strategies to improve the effectiveness of RT in localized PCa, paving the way for a clinical trial. |
| Databáze: | OpenAIRE |
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