Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1.
Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1.
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DOI：
10.20517/jtgg.2021.22
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zi X
中科院分区：
文献类型：
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作者：
Li X;Song L;Xu S;Tippin M;Meng S;Xie J;Uchio E;Zi X
在这里，我们的目的是评估卡瓦根提取物（KRE）在转基因小鼠前列腺腺癌（TRAMP）小鼠的化学预防效果，并研究卡瓦的主要成分卡瓦内酯的潜在分子靶点。向TRAMP小鼠施用KRE配制的食物持续不同的时间段，然后在媒介物对照组和KRE食物饲喂组之间比较高级前列腺上皮内瘤变（HG-PIN）和腺癌的发生率和肿瘤负荷。此外，KRE和卡法根内酯对单胺氧化酶A（MAO-A）和赖氨酸特异性脱甲基酶1（LSD 1）酶活性的抑制作用通过市售的抑制剂筛选试剂盒进行检查。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，饮食喂养0.3%和0.6%的KRE对HG-PIN的抑制率分别为43.5%和59.7%，对前列腺癌的抑制率分别为53.5%和66.4%。此外，从6周龄至24周龄的0.6%KRE喂养的TRAMP小鼠表现出泌尿生殖器重量（肿瘤负荷的替代物）显著降低54.5%和体重增加减少。此外，KRE和卡法根内酯显示出对LSD 1和MAO-A酶活性的显著抑制。我们的研究结果表明，通过饮食消费卡瓦产品可以延缓前列腺癌的发展和进展，卡瓦内酯可能是开发LSD 1和MAO-A的有效双重抑制剂的新结构模型。
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.