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Translational Therapeutics

Apalutamide radio-sensitisation of prostate cancer

British Journal of Cancer volume 125, pages 1377–1387 (2021)Cite this article

Subjects

Abstract

Introduction

The combination of radiotherapy with bicalutamide is the standard treatment of prostate cancer patients with high-risk or locally advanced disease. Whether new-generation anti-androgens, like apalutamide, can improve the radio-curability of these patients is an emerging challenge.

Materials and methods

We comparatively examined the radio-sensitising activity of apalutamide and bicalutamide in hormone-sensitive (22Rv1) and hormone-resistant (PC3, DU145) prostate cancer cell lines. Experiments with xenografts were performed for the 22Rv1 cell line.

Results

Radiation dose–response viability and clonogenic assays showed that apalutamide had a stronger radio-sensitising activity for all three cell lines. Confocal imaging for γΗ2Αx showed similar DNA double-strand break repair kinetics for apalutamide and bicalutamide. No difference was noted in the apoptotic pathway. A striking cell death pattern involving nuclear karyorrhexis and cell pyknosis in the G1/S phase was exclusively noted when radiation was combined with apalutamide. In vivo experiments in SCID and R2G2 mice showed significantly higher efficacy of radiotherapy (2 and 4 Gy) when combined with apalutamide, resulting in extensive xenograft necrosis.

Conclusions

In vitro and in vivo experiments support the superiority of apalutamide over bicalutamide in combination with radiotherapy in prostate cancer. Clinical studies are encouraged to show whether replacement of bicalutamide with apalutamide may improve the curability rates.

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Fig. 1: Apalutamide radio-sensitises PCa cells in vitro.
Fig. 2: γH2Ax kinetics in prostate cancer cells  post radiation with or without anti-androgens.
Fig. 3: γH2Ax abnormal localisation and nuclear catastrophe following apalutamide exposure and cell irradiation.
Fig. 4: Combination of apalutamide with radiation does not induce an early apoptotic response.
Fig. 5: Treatment with radiation and apalutamide causes G1/S cell cycle arrest.
Fig. 6: Apalutamide radio-sensitises PCa cells in vivo.

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Data availability

All data reported in the study are available in our departments.

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Funding

The study has been supported by a research grant (ARN-I-15-GRC-001-V02) from Janssen Pharmaceutica NV (Principal Investigator MI Koukourakis).

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Author notes

  1. These authors contributed equally: Christos Kakouratos, Dimitra Kalamida.

Authors and Affiliations

  1. Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece

    Christos Kakouratos, Dimitra Kalamida, Ioannis Lamprou, Erasmia Xanthopoulou, Christos Nanos & Michael I. Koukourakis

  2. Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece

    Alexandra Giatromanolaki

Authors
  1. Christos Kakouratos
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  2. Dimitra Kalamida
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Contributions

CK: in vitro experiments, animal experiments, analysis and interpretation of data, writing of the paper, approval for submission. DK: confocal imaging experiments, analysis and interpretation of data, writing of the paper, approval for submission. IL: animal experiments, analysis and interpretation of data, writing of the paper, approval for submission. EX: in vitro experiments, western blot analysis, writing of the paper, approval for submission. CN: animal irradiation, writing of the paper, approval for submission. AG: conception and design, analysis and interpretation of data, writing of the paper. MIK: conception and design, analysis and interpretation of data, writing of the paper, study supervision.

Corresponding author

Correspondence to Michael I. Koukourakis.

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Ethics approval and consent to participate

The study has been approved by the local Animal Experimentation Research Committee and the Ethics Committee of the Democritus University of Thrace (AP19/28-7-17). The Veterinary Direction also approved all experimental procedures for Animal Research in the Department of Experimental Surgery at the Democritus University of Thrace.

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There are no individual person’s data included in the paper.

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The authors declare no competing interests.

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Kakouratos, C., Kalamida, D., Lamprou, I. et al. Apalutamide radio-sensitisation of prostate cancer. Br J Cancer 125, 1377–1387 (2021). https://doi.org/10.1038/s41416-021-01528-1

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