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Article

Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair

1
Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
2
Department of Tumor Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
3
Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
4
Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
5
Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
6
Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
7
Department of Urology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2467; https://doi.org/10.3390/cancers12092467
Received: 10 August 2020 / Revised: 27 August 2020 / Accepted: 27 August 2020 / Published: 31 August 2020
(This article belongs to the Section Molecular Cancer Biology)
The combination of RT and the first generation AR blockers to improve the outcome in prostate cancer remain a matter of controversial debate in clinical trials. In the current study we aim to investigate the effect of three FDA approved second-generation antiandrogens (abiraterone acetate, apalutamide and enzalutamide), as more potent inhibitors of the AR signaling, on the cytotoxicity of RT in pre-clinical models. In vitro and ex vivo analyses revealed a strong radiosensitising effect for the second-generation antiandrogens, regardless of the castration state. The first-generation AR-blocker bicalutamide failed to show any radiosensitising effect. The radiosensitising effect of the second-generation antiandrogens was attributed to the inhibition of DSB repair. Together, we provide a proof-of-principle pre-clinical evidence to rationalize the clinical use of the second-generation antiandrogens to enhance the effect of IR as a potential strategy to improve the outcomes of PCa patients with localized disease who undergo ablative RT.
(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 γH2AX/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 γH2AX 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. View Full-Text
Keywords: abiraterone acetate; apalutamide; enzalutamide; DNA double strand break repair; prostate cancer; radiosensitization abiraterone acetate; apalutamide; enzalutamide; DNA double strand break repair; prostate cancer; radiosensitization
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Figure 1

MDPI and ACS Style

Elsesy, M.E.; Oh-Hohenhorst, S.J.; Löser, A.; Oing, C.; Mutiara, S.; Köcher, S.; Meien, S.; Zielinski, A.; Burdak-Rothkamm, S.; Tilki, D.; Huland, H.; Schwarz, R.; Petersen, C.; Bokemeyer, C.; Rothkamm, K.; Mansour, W.Y. Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair. Cancers 2020, 12, 2467. https://doi.org/10.3390/cancers12092467

AMA Style

Elsesy ME, Oh-Hohenhorst SJ, Löser A, Oing C, Mutiara S, Köcher S, Meien S, Zielinski A, Burdak-Rothkamm S, Tilki D, Huland H, Schwarz R, Petersen C, Bokemeyer C, Rothkamm K, Mansour WY. Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair. Cancers. 2020; 12(9):2467. https://doi.org/10.3390/cancers12092467

Chicago/Turabian Style

Elsesy, Mohamed E., Su J. Oh-Hohenhorst, Anastassia Löser, Christoph Oing, Sally Mutiara, Sabrina Köcher, Stefanie Meien, Alexandra Zielinski, Susanne Burdak-Rothkamm, Derya Tilki, Hartwig Huland, Rudolf Schwarz, Cordula Petersen, Carsten Bokemeyer, Kai Rothkamm, and Wael Y. Mansour. 2020. "Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair" Cancers 12, no. 9: 2467. https://doi.org/10.3390/cancers12092467

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