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

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Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair. / Elsesy, Mohamed E; Oh-Hohenhorst, Su Jung; Löser, Anastassia; Oing, Christoph; Mutiara, Sally; Köcher, Sabrina; Meien, Stefanie; Zielinski, Alexandra; Burdak-Rothkamm, Susanne; Tilki, Derya; Huland, Hartwig; Schwarz, Rudolf; Petersen, Cordula; Bokemeyer, Carsten; Rothkamm, Kai; Mansour, Wael Y.

in: CANCERS, Jahrgang 12, Nr. 9, 31.08.2020.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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 2020, 'Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair', CANCERS, Jg. 12, Nr. 9. https://doi.org/10.3390/cancers12092467

APA

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. (2020). Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair. CANCERS, 12(9). https://doi.org/10.3390/cancers12092467

Vancouver

Elsesy ME, Oh-Hohenhorst SJ, Löser A, Oing C, Mutiara S, Köcher S et al. Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair. CANCERS. 2020 Aug 31;12(9). https://doi.org/10.3390/cancers12092467

Bibtex

@article{70ba3e79274a4e3689f098caa2ab3ee1,
title = "Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair",
abstract = "(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.",
author = "Elsesy, {Mohamed E} and Oh-Hohenhorst, {Su Jung} and Anastassia L{\"o}ser and Christoph Oing and Sally Mutiara and Sabrina K{\"o}cher and Stefanie Meien and Alexandra Zielinski and Susanne Burdak-Rothkamm and Derya Tilki and Hartwig Huland and Rudolf Schwarz and Cordula Petersen and Carsten Bokemeyer and Kai Rothkamm and Mansour, {Wael Y}",
year = "2020",
month = aug,
day = "31",
doi = "10.3390/cancers12092467",
language = "English",
volume = "12",
journal = "CANCERS",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "9",

}

RIS

TY - JOUR

T1 - Second-Generation Antiandrogen Therapy Radiosensitizes Prostate Cancer Regardless of Castration State through Inhibition of DNA Double Strand Break Repair

AU - Elsesy, Mohamed E

AU - Oh-Hohenhorst, Su Jung

AU - Löser, Anastassia

AU - Oing, Christoph

AU - Mutiara, Sally

AU - Köcher, Sabrina

AU - Meien, Stefanie

AU - Zielinski, Alexandra

AU - Burdak-Rothkamm, Susanne

AU - Tilki, Derya

AU - Huland, Hartwig

AU - Schwarz, Rudolf

AU - Petersen, Cordula

AU - Bokemeyer, Carsten

AU - Rothkamm, Kai

AU - Mansour, Wael Y

PY - 2020/8/31

Y1 - 2020/8/31

N2 - (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.

AB - (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.

U2 - 10.3390/cancers12092467

DO - 10.3390/cancers12092467

M3 - SCORING: Journal article

C2 - 32878283

VL - 12

JO - CANCERS

JF - CANCERS

SN - 2072-6694

IS - 9

ER -