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A new flavonoid derivative exerts antitumor effects against androgen‐sensitive to cabazitaxel‐resistant prostate cancer cells
Author(s) -
Naito Renato,
Kano Hiroshi,
Shimada Takashi,
Makino Tomoyuki,
Kadomoto Suguru,
Iwamoto Hiroaki,
Yaegashi Hiroshi,
Izumi Kouji,
Kadono Yoshifumi,
Nakata Hiroki,
Saito Yohei,
Goto Masuo,
NakagawaGoto Kyoko,
Mizokami Atsushi
Publication year - 2021
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.24106
Subject(s) - du145 , lncap , androgen receptor , prostate cancer , apoptosis , microbiology and biotechnology , flow cytometry , cancer research , biology , chemistry , cancer , biochemistry , genetics
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.