Anemone rivularis inhibits pyruvate dehydrogenase kinase activity and tumor growth

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Title
Anemone rivularis inhibits pyruvate dehydrogenase kinase activity and tumor growth
Author(s)
T W Chung; J H Lee; H J Choi; M J Park; E Y Kim; J H Han; S B Jang; S O Lee; Sang Woo Lee; J Hang; L W Yi; K T Ha
Bibliographic Citation
Journal of Ethnopharmacology, vol. 203, pp. 47-54
Publication Year
2017
Abstract
Ethnopharmacological relevance Anemone rivularis Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of A. rivularis. Aim of study The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of A. rivularis on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis. Materials and methods The ethanol extract of whole plant of A. rivularis (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to in vitro and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. In vivo anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice. Results ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD-1, and LLC. ARE suppressed PDHK activity in in vitro kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the in vitro tumor growth through mitochondria-mediated apoptosis. The growth rates of allograft LLC cells were also reduced by ARE treatment. Conclusions Here, we firstly report that ARE inhibits PDHK activity and growth of tumor in both in vitro and in vivo experiments. Therefore, we suggest ARE as a potential candidate for developing anti-cancer drugs
Keyword
Anemone rivularisApoptosisMitochondriaPyruvate dehydrogenase kinaseWarburg's effect
ISSN
0378-8741
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.jep.2017.03.034
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > International Biological Material Research Center > 1. Journal Articles
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