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Updated: Nov 20, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
A new flavonoid derivative exerts antitumor effects against androgen-sensitive to cabazitaxel-resistant prostate
Renato Naito1, Hiroshi Kano1, Takashi Shimada1
1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
Background:
Our previous report has shown that the flavonoid 2'-hydroxyflavanone (2'-HF) showed inhibition of androgen receptor (AR) activity against androgen-sensitive prostate cancer (PCa) cells, LNCaP, and exhibited antitumor effects against androgen-insensitive PCa cells, PC-3, and DU145. In the present study, we prepared a derivative of 2'-HF, 16MS7F1924, and confirmed the effects of this derivative on PCa cells.
Methods:
The antiproliferation effects of 16MS7F1924 were investigated in PCa cells using LNCaP, PC-3, DU145 and docetaxel-resistant and cabazitaxel-resistant cell lines of PC-3-TxR/CxR and DU145-TxR/CxR. Prostate-specific antigen (PSA) and AR expression level in whole cells and the nucleus were confirmed in LNCaP by reverse transcriptase polymerase chain reaction and Western blot analysis. AR activity in LNCaP cells was confirmed by luciferase assay using PSA promoter-driven reporter. To analyze the antiproliferative effects, cell-based assays using flow cytometry, immunocytochemistry, and TUNEL assay as well as Western blot analysis were employed. Furthermore, PC-3, DU145 and each chemoresistant strain of human PCa cells were subcutaneously xenografted. The antitumor effects of 16MS7F1924 were evaluated in vivo.
Results:
16MS7F1924 showed antitumor effect on all PCa cells in a dose-dependent manner. 16MS7F1924 reduced the expression of PSA messenger RNA (mRNA) and protein and inhibited AR activity in a dose-dependent manner, while expression of AR protein and mRNA was reduced by 16MS7F1924. 16MS7F1924 induced mitotic catastrophe and apoptosis. Apoptotic cells were increased in a dose-dependent manner, and the apoptosis was mediated through the Akt pathway. Tumor growth was safely and significantly inhibited by both intraperitoneal and oral administration of 16MS7F1924 in vivo.
Conclusion:
16MS7F1924 had sufficient antitumor activity against androgen-sensitive and cabazitaxel-resistant PCa cells and may be useful as a novel therapeutic agent overcoming hormone- and chemoresistant PCas.
Insights
A novel flavonoid derivative, 16MS7F1924, demonstrates significant antitumor effects against prostate cancer (PCa) cells, including hormone- and chemoresistant types. This compound effectively inhibits androgen receptor (AR) activity and induces apoptosis, showing promise as a new therapeutic agent for advanced PCa.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Previous research identified 2'-hydroxyflavanone (2'-HF) as an inhibitor of androgen receptor (AR) activity in prostate cancer (PCa) cells.
- 2'-HF also demonstrated antitumor effects against both androgen-sensitive and insensitive PCa cell lines.
- This study investigates a novel 2'-HF derivative, 16MS7F1924, for its therapeutic potential in PCa.
Purpose of the Study:
- To evaluate the antiproliferative and antitumor effects of the 2'-HF derivative, 16MS7F1924, on various PCa cell lines.
- To assess the compound's efficacy against docetaxel- and cabazitaxel-resistant PCa cells.
- To investigate the mechanisms underlying 16MS7F1924's effects on AR signaling and cell death pathways.
Main Methods:
- Antiproliferation assays were performed on LNCaP, PC-3, DU145, and their chemoresistant variants (PC-3-TxR/CxR, DU145-TxR/CxR).
- Androgen receptor (AR) activity and expression (mRNA and protein) were analyzed using luciferase assays, RT-PCR, and Western blot.
- Apoptosis and cell cycle effects were assessed via flow cytometry and TUNEL assays; in vivo antitumor activity was evaluated in xenograft models.
Main Results:
- 16MS7F1924 exhibited dose-dependent antitumor effects across all tested PCa cell lines.
- The compound significantly reduced prostate-specific antigen (PSA) and AR expression (mRNA and protein) and inhibited AR activity.
- 16MS7F1924 induced mitotic catastrophe and apoptosis, mediated through the Akt pathway, and demonstrated significant tumor growth inhibition in vivo.
Conclusions:
- 16MS7F1924 possesses potent antitumor activity against both androgen-sensitive and cabazitaxel-resistant PCa cells.
- The compound effectively targets AR signaling and induces apoptosis, suggesting a broad therapeutic potential.
- 16MS7F1924 represents a promising novel therapeutic agent for overcoming hormone- and chemoresistance in prostate cancer.
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