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Abiraterone acetate exerts a cytotoxic effect in human prostate cancer cell lines

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Abstract

To study the capability of the CYP17A1 inhibitor abiraterone acetate (AER) to antagonize the androgen receptor (AR) activation in human prostate cancer (PCa) cell lines. T877A-AR-LNCaP, WT-AR-VCaP, AR-negative DU145, and PC3 PCa cell lines were used by MTT and cell count to study the ability of AER and enzalutamide (ENZ) to modify cell viability. The role of ARs in LNCaP was demonstrated through a gene-silencing experiment. The mechanism of AER cytotoxicity in LNCaP cells was studied, as well as the ability of AER to modulate AR gene expression. The in silico docking approach was applied to study the interaction of AER and ENZ with T877A-AR. Through high-performance liquid chromatography, the production of the AER main metabolite Δ4A was studied. AER bound AR in an almost identical manner to that of dihydrotestosterone (DHT). The higher binding energy for AER in T877A-AR could explain the major cytotoxic effect observed in LNCaP cells. The capability of LNCaP cells to synthesize Δ4A could mediate, at least in part, this effect. AER cytotoxicity in LNCaP cells was mainly due to the activation of apoptosis. Further, AER induced modification of AR target gene expression, suggesting a direct effect on AR activity. AER-induced cytotoxicity on PCa cell lines seemed to be mediated by binding with AR. The higher affinity of AER for T877A-AR may suggest a potential role of AER in the management of CRPC carrying this mutation; however, T877A-AR expressing CRPC patients developed AER resistance, probably due to the increase of progesterone.

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Abbreviations

ADT:

Androgen-deprivation therapy

AER:

Abiraterone acetate

AR:

Androgen receptor

CRPC:

Castration-resistant prostate cancer

Δ4A:

Δ4-abiraterone

DHT:

Dihydrotestosterone

ENZ:

Enzalutamide

LBD:

Ligand-binding domain

MTT:

3-(4,5-Dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide

PCa:

Prostate cancer

si-AR:

siRNA targeting a region of an isoform of the AR gene

si-ctrl:

Non-targeting negative control siRNA

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Authorship contributions

Participated in research design: S. Sigala, D. Galli, A. Berruti, M. Fragni. Conducted experiments: D. Galli, E. Rossini, M. Nardini, M. Zametta, M. Fragni, S. Vezzoli, F. Longhena, A. Bellucci. Contributed new reagents or analytic tools: n.a. Performed data analysis: D. Galli, M. Nardini, S. Vezzoli, M. Fragni. Wrote or contributed to the writing of the manuscript: all authors

Funding

The project was supported by donations of the “Memorial Michelangelo Barcella,” by the “Cremona Rugby Association” with a grant within the “Movember 2015” project and by University of Brescia local grants.

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Author notes

  1. Martina Fragni and Diego Galli contributed equally to this work.

Authors and Affiliations

  1. Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, V.le Europa 11, 25123, Brescia, Italy

    Martina Fragni, Diego Galli, Elisa Rossini, Matteo Zametta, Francesca Longhena, Arianna Bellucci, Maurizio Memo & Sandra Sigala

  2. Department of Biosciences, University of Milano, Milan, Italy

    Marco Nardini

  3. Forensic Medicine Institute, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy

    Sara Vezzoli

  4. Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia – A.S.S.T. degli Spedali Civili, Brescia, Italy

    Elisa Roca & Alfredo Berruti

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Fragni, M., Galli, D., Nardini, M. et al. Abiraterone acetate exerts a cytotoxic effect in human prostate cancer cell lines. Naunyn-Schmiedeberg's Arch Pharmacol 392, 729–742 (2019). https://doi.org/10.1007/s00210-019-01622-5

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