Niclosamide and bicalutamide combination treatment overcomes enzalutamide- and bicalutamide-resistant prostate cancer

Chengfei Liu, Cameron M. Armstrong, Wei Lou, Alan P. Lombard, Vito Cucchiara, Xinwei Gu, Joy C. Yang, Nagalakshmi Nadiminty, Chong-Xian Pan, Christopher P Evans, Allen C Gao

Research output: Contribution to journalArticle

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Abstract

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.

Original languageEnglish (US)
Pages (from-to)1521-1530
Number of pages10
JournalMolecular Cancer Therapeutics
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2017

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Niclosamide
Androgen Receptors
Prostatic Neoplasms
MDV 3100
bicalutamide
Therapeutics
Androgen Antagonists

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Niclosamide and bicalutamide combination treatment overcomes enzalutamide- and bicalutamide-resistant prostate cancer. / Liu, Chengfei; Armstrong, Cameron M.; Lou, Wei; Lombard, Alan P.; Cucchiara, Vito; Gu, Xinwei; Yang, Joy C.; Nadiminty, Nagalakshmi; Pan, Chong-Xian; Evans, Christopher P; Gao, Allen C.

In: Molecular Cancer Therapeutics, Vol. 16, No. 8, 01.08.2017, p. 1521-1530.

Research output: Contribution to journalArticle

Liu, Chengfei ; Armstrong, Cameron M. ; Lou, Wei ; Lombard, Alan P. ; Cucchiara, Vito ; Gu, Xinwei ; Yang, Joy C. ; Nadiminty, Nagalakshmi ; Pan, Chong-Xian ; Evans, Christopher P ; Gao, Allen C. / Niclosamide and bicalutamide combination treatment overcomes enzalutamide- and bicalutamide-resistant prostate cancer. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 8. pp. 1521-1530.
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AU - Armstrong, Cameron M.

AU - Lou, Wei

AU - Lombard, Alan P.

AU - Cucchiara, Vito

AU - Gu, Xinwei

AU - Yang, Joy C.

AU - Nadiminty, Nagalakshmi

AU - Pan, Chong-Xian

AU - Evans, Christopher P

AU - Gao, Allen C

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AB - Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.

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