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Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models

British Journal of Cancer volume 129, pages 884–894 (2023)Cite this article

Subjects

Abstract

Background

It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers.

Methods

A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa.

Results

Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts.

Conclusion

Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.

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Fig. 1: Nicardipine selectively and potently inhibits chemoresistant PCa cells.
Fig. 2: Nicardipine is a putative EED inhibitor.
Fig. 3: Nicardipine targets noncanonical EZH2 survival signalling in chemoresistant PCa cells.
Fig. 4: RNA-seq analysis of potential target genes of nicardipine in C4-2B-TaxR cells.
Fig. 5: Nicardipine monotherapy inhibits the skeletal growth of chemoresistant PCa in male athymic nude mice.
Fig. 6: Nicardipine synergistically enhances the in vivo efficacy of docetaxel against the skeletal growth of C4-2 tumours in male athymic nude mice.

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Data availability

All raw data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr Rhea-Beth Markowitz at Georgia Cancer Center, Augusta University, for editorial assistance.

Funding

This work was supported by the National Cancer Institute grants R01CA256058 and R42CA217491, National Institute on Minority Health and Health Disparities Research Center in Minority Institution grant U54MD007590, Department of Education Title III Program at Clark Atlanta University, Georgia Research Alliance VentureLab grant, and Emory University Biological Discovery through Chemical Innovation Initiative Seed Grant (DW).

Author information

Authors and Affiliations

  1. Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA

    Xin Li, Nathan J. Bowen, Alira Danaher, Nicholas Cook, Dehong Li & Daqing Wu

  2. Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Xin Li, Yanhua Chen, Lijuan Bai, Rui Zhao & Daqing Wu

  3. Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Yanhua Chen

  4. Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Lijuan Bai

  5. Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

    Rui Zhao

  6. School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, GA, USA

    Yifei Wu & Zhong-Ru Xie

  7. Emory College of Arts and Sciences, Atlanta, GA, USA

    Jason M. Wu

  8. Department of Pharmacology and Chemical Biology, and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA

    Min Qui, Yuhong Du & Haian Fu

  9. Departments of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Adeboye O. Osunkoya

  10. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA

    Adeboye O. Osunkoya, Omer Kucuk & Daqing Wu

  11. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Omer Kucuk

  12. MetCure Therapeutics LLC, Atlanta, GA, USA

    Daqing Wu

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  1. Xin Li
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  2. Yanhua Chen
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Contributions

Conceptualisation: YD, HF, OK, DW. Methodology and investigation: XL, YC, YY, LB, RZ, YW, Z-RX, JMW, NJB, AD, NC, DL, MQ, YD. Data curation: XL, Z-RX, NJB, YD, DW. Formal analysis: XL, Z-RX, YD, DW. Funding acquisition: DW. Manuscript preparation: XL, YW, Z-RX, NJB, YD, HF, AOO, OK, DW.

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Correspondence to Daqing Wu.

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The Institutional Animal Care and Use Committee (IACUC) at Augusta University approved all animal protocols used in this study. All animal procedures were subjected to National Institutes of Health guidelines.

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Li, X., Chen, Y., Bai, L. et al. Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models. Br J Cancer 129, 884–894 (2023). https://doi.org/10.1038/s41416-023-02359-y

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