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Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells

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Summary

Prostate cancers are reliant on androgens for growth and survival. Clinicians and researchers are looking for potent treatments for the resistant forms of prostate cancer; however, a handful of small molecules used in the treatment of castration-resistant prostate cancer have not shown potent effects owing to the mutations in the AR (Androgen Receptor). We used SBF-1, a well-characterized antitumor agent with potent cytotoxic effects against different kinds of cancers and investigated its effect on human prostate cancer. SBF-1 substantially inhibited the proliferation, induced apoptosis, and caused cell cycle arrest in LNCaP and PC3/AR+ prostate cancer cell lines. SBF-1 inhibited the activation of the IGF-1-PNCA pathway, as demonstrated by decreased expression of IGF-1 (insulin-like growth factor 1), proliferating cell nuclear antigen (PCNA), and its downstream Bcl-2 protein. Using microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) assays, we observed a direct binding of SBF-1 to the AR. SBF-1 binds to the AR-DBD (DNA-binding domain) and blocks the transcription of its target gene. SBF-1 demonstrated a potent antitumor effect in vivo; it inhibited AR signaling and suppressed tumor growth in animals. Our study suggests that SBF-1 is an inhibitor of the AR and might be used in the treatment of prostate cancer.

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Acknowledgments

Nanjing Sky Technology Co. Ltd. supported this study.

Funding

Nanjing Sky Technology Co., Ltd. Supported this study.

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Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 200032, China

    Ahmed Elgehama, Wenjie Guo & Qiang Xu

  2. State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, 200032, China

    Lijun Sun & Biao Yu

  3. Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026, Anhui, China

    Lijun Sun

  4. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China

    Qiang Xu

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  1. Ahmed Elgehama
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  2. Lijun Sun
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  3. Biao Yu
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  4. Wenjie Guo
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  5. Qiang Xu
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Contributions

Conceptualization: [Ahmed Elgehama]; Methodology: [Ahmed Elgehama]; formal analysis and investigation: [Ahmed Elgehama]; Writing–original draft preparation: [Ahmed Elgehama]; Writing - review and editing: [Guo Wenjie, Qiang Xu]; Funding acquisition: [Ahmed Elgehama, Qiang Xu]; Resources: [Li Junsun, Biao Yu, Qiang Xu, Ahmed Elgehama]; Supervision: [Qiang Xu].

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Correspondence to Qiang Xu.

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Supplementary Information

Fig. S1

SBF-1 displayed potent cytotoxicity against PC3 cells. (A) 1 × 105 PC3 cells were seeded into 96-well microplates and incubated with various concentrations of SBF-1 for 24 h. Cell viability was determined by MTT assay. (B) Cell adhesive ability was tested toward fibronectin and laminin. (C) PC3 cells were treated with SBF-1 for 6 h at 200 nM final concentration in the presence or absence of DHT (10 nM). The protein levels of AR, pARS515, p-AKTS473, AKT1, IGF-1, FOXO1, p-FOXO1S256, PCNA, and Bcl-2 were determined in the whole lysate by western blot. GAPDH was used as a loading control. (D) PC3 cells were treated in the presence or absence of SBF-1 (200 nM) or DHT (10 nM) for 6 h, and the mRNA levels of IGF-1 and PCNA were determined. (E) PC3 cells were treated with SBF-1 for 6 h at 200 nM final concentration in the presence or absence of DHT (10 nM). The protein levels of AR, pARS515, IGF-1, and PCNA were determined in the whole lysate by western blot. GAPDH was used as a loading control. (F) Annexin V/PI staining determined the percentages of apoptotic cells. (G) The cell cycle was determined by PI staining. Values in A and B were shown as the mean ± SEM. Data in F and G were representative of three independent experiments. (PDF 100 kb)

Fig. S2

Computer analysis of SBF-1 docking to the AR. Autodock vina 4.2 revealed that SBF-1 interacts with AR protein in a location where AR binds to the ARE. (PDF 99 kb)

Fig. S3

SBF-1 blocked the AR-DNA interaction. (A) Schematic diagram of the DNA pull-down assay for IGF-1 and PCNA. (B) Biotinylated IGF-1 and PCNA sequences were pulled down, and the total cell extract was used to determine the binding of AR. Biotin was used as input control. Data were representative of three independent experiments. (PDF 98 kb)

Fig. S4

TCGA Analysis of the AR expression in human prostate cancer. (A) Differential expression of AR in tumor versus healthy tissues of patients from the TCGA database. (B) The high (red) and low (blue) risk groups of TCGA-PRAD patients were stratified based on AR’s expression pattern. Kaplan-Meier curves of AR overexpressed high-risk groups of patients and those low in the TCGA-PRAD cohort. (PDF 375 kb) (PDF 95 kb)

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Elgehama, A., Sun, L., Yu, B. et al. Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells. Invest New Drugs 39, 442–457 (2021). https://doi.org/10.1007/s10637-020-01050-w

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