一种新型黄酮类衍生物对雄激素敏感至卡巴他赛耐药的前列腺癌细胞具有抗肿瘤作用。

A new flavonoid derivative exerts antitumor effects against androgen-sensitive to cabazitaxel-resistant prostate cancer cells.

机构信息

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

Department of Histology and Cell Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

出版信息

Prostate. 2021 Apr;81(5):295-306. doi: 10.1002/pros.24106. Epub 2021 Jan 25.

DOI:10.1002/pros.24106

PMID:33493355

Abstract

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.

摘要

背景

我们之前的报告表明，黄酮类化合物 2'-羟基黄烷酮（2'-HF）对雄激素受体（AR）活性具有抑制作用，可抑制雄激素敏感的前列腺癌（PCa）细胞 LNCaP，并对雄激素不敏感的 PCa 细胞 PC-3 和 DU145 表现出抗肿瘤作用。在本研究中，我们制备了 2'-HF 的衍生物 16MS7F1924，并证实了该衍生物对 PCa 细胞的作用。

方法

采用 LNCaP、PC-3、DU145 以及 docetaxel 耐药和 cabazitaxel 耐药的 PC-3-TxR/CxR 和 DU145-TxR/CxR 细胞系，研究 16MS7F1924 对 PCa 细胞的增殖抑制作用。通过逆转录聚合酶链反应和 Western blot 分析，在 LNCaP 中证实全细胞和核内的前列腺特异性抗原（PSA）和 AR 表达水平。通过 PSA 启动子驱动的报告基因，使用荧光素酶测定法检测 LNCaP 细胞中的 AR 活性。为了分析增殖抑制作用，采用流式细胞术、免疫细胞化学和 TUNEL 分析以及 Western blot 分析等细胞为基础的测定法。此外，将人 PCa 细胞的 PC-3、DU145 和每种化学耐药株皮下接种。在体内评估 16MS7F1924 的抗肿瘤作用。

结果

16MS7F1924 呈剂量依赖性抑制所有 PCa 细胞的肿瘤生长。16MS7F1924 呈剂量依赖性降低 PSA 信使 RNA（mRNA）和蛋白的表达，并抑制 AR 活性，而 AR 蛋白和 mRNA 的表达则被 16MS7F1924 下调。16MS7F1924 诱导有丝分裂灾难和细胞凋亡。凋亡细胞呈剂量依赖性增加，凋亡是通过 Akt 途径介导的。16MS7F1924 腹腔内和口服给药可安全且显著抑制体内肿瘤生长。