Valeric Acid Suppresses Liver Cancer Development by Acting as a Novel HDAC Inhibitor.
Valeric Acid Suppresses Liver Cancer Development by Acting as a Novel HDAC Inhibitor.
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DOI：
10.1016/j.omto.2020.08.017
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发表时间：
2020-12-16
期刊：
影响因子：
--
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Han R;Nusbaum O;Chen X;Zhu Y
由于肝癌的侵袭性和缺乏有效的治疗方法，肝癌是美国增长最快的癌症死亡原因。目前的临床前研究考察了缬草根提取物的主要化合物之一戊酸（pentanoic acid [C5H10O2]）在肝癌治疗中的治疗作用。通过一系列体外实验和原位异种移植小鼠模型检测了戊酸的抗癌作用。预测了戊酸的分子靶点，并进行了功能鉴定。戊酸具有广谱的抗癌活性，在肝癌细胞增殖、菌落形成、伤口愈合、细胞侵袭和三维球体形成试验中具有特别高的细胞毒性。小鼠模型进一步表明，系统给药脂基纳米颗粒包埋的戊酸可显著降低肿瘤负荷，提高生存率。通过结构靶点预测工具和HDAC活性测定，揭示了戊酸对组蛋白去乙酰化酶（HDAC）的抑制作用。进一步的转录谱分析和网络分析表明，戊酸影响几种可能诱导细胞凋亡的癌症相关途径。总之，我们首次证明了戊酸作为一种潜在的新型HDAC抑制剂抑制肝癌的发展，值得进一步研究其治疗意义。本研究证明了缬草根提取物的活性化合物作为一种新型化疗药物治疗肝细胞癌的可行性。我们表明，在一系列体外实验和原位异种移植小鼠模型中，戊酸可能通过作为一种新型组蛋白去乙酰化酶抑制剂来抑制肝癌的发展。
Liver cancer is the fastest growing cause of cancer deaths in the United States due to its aggressiveness and lack of effective therapies. The current preclinical study examines valeric acid (pentanoic acid [C5H10O2]), one of the main compounds of valerian root extract, for its therapeutic use in liver cancer treatment. Anticancer efficacy of valeric acid was tested in a series of in vitro assays and orthotopic xenograft mouse models. The molecular target of valeric acid was also predicted, followed by functional confirmation. Valeric acid has a broad spectrum of anticancer activity with specifically high cytotoxicity for liver cancer in cell proliferation, colony formation, wound healing, cell invasion, and 3D spheroid formation assays. Mouse models further demonstrate that systematic administration of lipid-based nanoparticle-encapsulated valeric acid significantly reduces the tumor burden and improves survival rate. Histone deacetylase (HDAC)-inhibiting functions of valeric acid are also revealed by a structural target prediction tool and HDAC activity assay. Further transcriptional profiling and network analyses illustrate that valeric acid affects several cancer-related pathways that may induce apoptosis. In summary, we demonstrate for the first time that valeric acid suppresses liver cancer development by acting as a potential novel HDAC inhibitor, which warrants further investigation on its therapeutic implications. This study demonstrates the viability of an active compound from valerian root extract as a novel chemotherapeutic for the treatment of hepatocellular carcinoma. We show that valeric acid suppresses liver cancer development in a series of in vitro assays and in orthotopic xenograft mouse models, possibly by acting as a novel histone deacetylase inhibitor.
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影响因子：
3.8
作者：
Müller BM;Jana L;Kasajima A;Lehmann A;Prinzler J;Budczies J;Winzer KJ;Dietel M;Weichert W;Denkert C
通讯作者：
Denkert C
影响因子：
3.7
作者：
Kakehashi A;Kato A;Ishii N;Wei M;Morimura K;Fukushima S;Wanibuchi H
通讯作者：
Wanibuchi H
组蛋白脱乙酰酶 3 通过信号转导器和转录 3 信号通路激活剂促进肝脏再生和肝癌细胞增殖。
影响因子：
9
作者：
Lu XF;Cao XY;Zhu YJ;Wu ZR;Zhuang X;Shao MY;Xu Q;Zhou YJ;Ji HJ;Lu QR;Shi YJ;Zeng Y;Bu H
通讯作者：
Bu H
影响因子：
2.7
作者：
Lin, Sheng;Fu, Peng;Zhang, Wei-Dong
通讯作者：
Zhang, Wei-Dong
影响因子：
14.5
作者：
Amin ARMR;Karpowicz PA;Carey TE;Arbiser J;Nahta R;Chen ZG;Dong JT;Kucuk O;Khan GN;Huang GS;Mi S;Lee HY;Reichrath J;Honoki K;Georgakilas AG;Amedei A;Amin A;Helferich B;Boosani CS;Ciriolo MR;Chen S;Mohammed SI;Azmi AS;Keith WN;Bhakta D;Halicka D;Niccolai E;Fujii H;Aquilano K;Ashraf SS;Nowsheen S;Yang X;Bilsland A;Shin DM
通讯作者：
Shin DM