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 [C 5 H 10 O 2 ]), 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.

Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement used to treat sleeping disorders and insomnia. The herb’s ability to ameliorate sleep dysfunction may signify an unexplored anti-tumorigenic effect due to the connection between circadian factors and tumorigenesis. Of particular interest are the structural similarities shared between valeric acid, valerian's active chemical ingredient, and certain histone deacteylase (HDAC) inhibitors, which imply that valerian may play a role in epigenetic gene regulation. In this study, we tested the hypothesis that the circadian-related herb valerian can inhibit breast cancer cell growth and explored epigenetic changes associated with valeric acid treatment. Our results showed that aqueous valerian extract reduced growth of breast cancer cells. In addition, treatment of valeric acid was associated with decreased breast cancer cell proliferation, migration, colony formation and 3D formation in vitro in a dose- and time-dependent manner, as well as reduced HDAC activity and a global DNA hypomethylation. Overall, these findings demonstrate that valeric acid can decrease the breast cancer cell proliferation possibly by mediating epigenetic modifications such as the inhibition of histone deacetylases and alterations of DNA methylation. This study highlights a potential utility of valeric acid as a novel HDAC inhibitor and a therapeutic agent in the treatment of breast cancer.