The synergistic effect of 1'-acetoxychavicol acetate and sodium butyrate on the death of human hepatocellular carcinoma cells.
It has been suggested that the combined effect of natural products may improve the effect of treatment against the proliferation of cancer cells. In this study, we evaluated the combination of 1'-acetoxychavicol acetate (ACA), obtained from Alpinia galangal, and sodium butyrate, a major short chain fatty acid, on the growth of HepG2 human hepatocellular carcinoma cells and found that treatment had a synergistic inhibitory effect. The number of HepG2 cells was synergistically decreased via apoptosis induction when cells were treated with both ACA and sodium butyrate. In ACA- and sodium butyrate-treated cells, intracellular reactive oxygen species (ROS) levels and NADPH oxidase activities were increased significantly. The decrease in cell number after combined treatment of ACA and sodium butyrate was diminished when cells were pretreated with catalase. These results suggest that an increase in intracellular ROS levels is involved in cancer cell death. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays an essential role in controlling processes related to tumor development. In ACA- and sodium butyrate-treated cells, AMPK phosphorylation was induced significantly, and this induction improved when cells were pretreated with catalase. These results suggest that the increase in intracellular ROS is involved in the increase of AMPK phosphorylation. In normal hepatocyte cells, treatment with ACA and sodium butyrate did not decrease cell numbers or increase ROS levels. In conclusion, combined treatment with ACA and sodium butyrate synergistically induced apoptotic cell death via an increase in intracellular ROS and phosphorylation of AMPK. Our findings may provide new insight into the development of novel combination therapies against hepatocellular carcinoma.
Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan.
Rie
R
Kato
Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan.
Isao
I
Matsui-Yuasa
Department of Applied and Bioapplied Chemistry, Graduate School of Engineering, Osaka City University, Osaka, Japan.
Hideki
H
Azuma
Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan. Electronic address: kojima@life.osaka-cu.ac.jp.
Akiko
A
Kojima-Yuasa
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001592:Benzyl Alcohols / Q000494:pharmacology*; D020148:Butyric Acid / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002374:Catalase / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D019073:HT29 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D001592:Benzyl Alcohols; D017382:Reactive Oxygen Species; D020148:Butyric Acid; D002374:Catalase; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases; C047948:1'-acetoxychavicol acetate
1′-Acetoxychavicol acetate (ACA); AMP-activated protein kinase (AMPK); HepG2 cell; Reactive oxygen species (ROS); Sodium butyrate (NaB); Synergistic effect