Li Xuesen, Song Liankun, Xu Shan, Tippin Matthew, Meng Shuan, Xie Jun, Uchio Edward, Zi Xiaolin
Department of Urology, University of California, Irvine, Orang, CA 92868, USA.
Chao Family Comprehensive Cancer Center, University of California, Orange, CA 92868, USA.
J Transl Genet Genom. 2021;5:163-172. doi: 10.20517/jtgg.2021.22. Epub 2021 May 28.
Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava.
TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis.
Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.
Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.
在此，我们旨在评估卡瓦根提取物（KRE）对小鼠前列腺转基因腺癌（TRAMP）小鼠的化学预防效果，并研究卡瓦主要成分卡瓦内酯的潜在分子靶点。
给TRAMP小鼠喂食添加KRE的饲料不同时间段，然后比较载体对照组和喂食KRE饲料组之间高级前列腺上皮内瘤变（HG-PIN）和腺癌的发生率以及肿瘤负荷。此外，通过市售抑制剂筛选试剂盒检测KRE和卡瓦内酯对单胺氧化酶A（MAO-A）和赖氨酸特异性去甲基化酶1（LSD1）酶活性的抑制作用。还使用蛋白质印迹分析在前列腺癌细胞和肿瘤组织中评估组蛋白H3赖氨酸9二甲基化。
从6周龄到12周龄给TRAMP小鼠喂食0.3%和0.6%的KRE，分别使HG-PIN的发生率降低了43.5%和59.7%，前列腺腺癌的发生率分别降低了53.5%和66.4%。此外，从6周龄到24周龄喂食0.6% KRE的TRAMP小鼠泌尿生殖系统重量（肿瘤负荷的替代指标）显著降低了54.5%，体重增加减少。此外，KRE和卡瓦内酯对LSD1和MAO-A酶活性有显著抑制作用。
我们的结果表明，通过饮食摄入卡瓦产品可以延缓前列腺癌的发生和发展，并且卡瓦内酯可能是开发一种有效的LSD1和MAO-A双重抑制剂的新结构模型。
