Antiandrogens inhibit ABCB1 efflux and ATPase activity and reverse docetaxel resistance in advanced prostate cancer

Yezi Zhu, Chengfei Liu, Cameron Armstrong, Wei Lou, Amandeep Sandher, Allen C Gao

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Purpose: Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2BTaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel. Experimental Design: ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo. Results: We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel- resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel- resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status. Conclusions: We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/ enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer.

Original languageEnglish (US)
Pages (from-to)4133-4142
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2015

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docetaxel
Androgen Antagonists
Adenosine Triphosphatases
Prostatic Neoplasms
Androgen Receptors
bicalutamide
MDV 3100
Rhodamines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antiandrogens inhibit ABCB1 efflux and ATPase activity and reverse docetaxel resistance in advanced prostate cancer. / Zhu, Yezi; Liu, Chengfei; Armstrong, Cameron; Lou, Wei; Sandher, Amandeep; Gao, Allen C.

In: Clinical Cancer Research, Vol. 21, No. 18, 15.09.2015, p. 4133-4142.

Research output: Contribution to journalArticle

Zhu, Yezi ; Liu, Chengfei ; Armstrong, Cameron ; Lou, Wei ; Sandher, Amandeep ; Gao, Allen C. / Antiandrogens inhibit ABCB1 efflux and ATPase activity and reverse docetaxel resistance in advanced prostate cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 18. pp. 4133-4142.
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abstract = "Purpose: Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2BTaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel. Experimental Design: ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo. Results: We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40{\%}, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60{\%}. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel- resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel- resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status. Conclusions: We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/ enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer.",
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AU - Zhu, Yezi

AU - Liu, Chengfei

AU - Armstrong, Cameron

AU - Lou, Wei

AU - Sandher, Amandeep

AU - Gao, Allen C

PY - 2015/9/15

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N2 - Purpose: Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2BTaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel. Experimental Design: ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo. Results: We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel- resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel- resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status. Conclusions: We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/ enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer.

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