Antiandrogens such as bicalutamide and enzalutamide can resensitize docetaxel-resistant prostate cancer cells to docetaxel treatment, by inhibiting efflux of the ATP-binding cassette (ABC) transporter ABCB1, according to a study published in Clinical Cancer Research.
ABC transporters carry substances, including docetaxel, out of cells, reducing their intracellular concentration and, therefore, their efficacy. ABCB1 overexpression has been shown to confer resistance to chemotherapy and is directly correlated with tumour stage and grade in prostate cancer. Previous studies showed that ABCB1 is overexpressed in docetaxel-resistant TaxR cells, compared with docetaxel-sensitive C4-2B cells.
Zhu et al. used in vitro measures of prostate cell growth and in vivo tumour growth assessment to determine the effect of enzalutamide and bicalutamide on docetaxel sensitivity, and a rhodamine efflux assay to investigate ABCB1 efflux activity. They observed that both bicalutamide and enzalutamide inhibited ABCB1 efflux activity by 40% and 60%, respectively. Treatment of TaxR cells with a combination of docetaxel and bicalutamide reduced cell growth to ∼40–50%—an effect not seen with bicalutamide alone—and reduced clone number by a similar extent, suggesting that bicalutamide restores docetaxel activity in these cells. Similar results were seen with enzalutamide treatment.
The team also investigated whether this effect occurred in vivo. Mice carrying TaxR tumours were treated with either vehicle, docetaxel or bicalutamide alone, or combination therapy. Neither monotherapy was effective, but combination treatment did reduce tumour growth. Bicalutamide also had similar effects in vitro and in vivo in androgen receptor (AR)-negative DU145 cells, suggesting that the effect on ABCB1 is independent of the AR.
Docetaxel resistance is a huge problem in advanced prostate cancer, and ABCB1 overactivity one mechanism by which it might occur. These data could lead to the development of combination therapies with antiandrogens and docetaxel that could be effective regardless of AR status.
References
Zhu, Y. et al. Anti-androgens inhibit ABCB1 efflux and ATPase activity and reverse docetaxel resistance in advanced prostate cancer. Clin. Cancer Res. 10.1158/1078-0432.CCR-15-0269
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Fenner, A. Antiandrogens reverse docetaxel resistance via ABCB1 inhibition. Nat Rev Urol 12, 361 (2015). https://doi.org/10.1038/nrurol.2015.135
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DOI: https://doi.org/10.1038/nrurol.2015.135