Page 68 - ebook
P. 68
[A. Biochemistry/Molecular Biology] A-34
Andrographolide, a Novel Pyruvate Dehydrogenase Kinase
Inhibitor, Induces Apoptosis of Human Lung Cancer Cells
Yoonju Do¹,², EunSun Yang², Jung-Suk Jin², Kibong Kim³, Ki-Tae Ha¹,²*
¹Department of Korean Medical Science, School of Korean Medicine, Pusan national university, Yangsan 50612,
Korea, ²Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan 50612, Korea,
³Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan 50612, Korea,
⁴Department of Pediatrics, Pusan National University Korean Hospital, Yangsan 50612, Korea, ⁵Department of
Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea
Most cancer cells produce their energy through a high level of glycolysis followed by lactic acid fermentation even
in the presence of abundant oxygen. The pyruvate dehydrogenase kinase (PDK) 1 is commonly overexpressed in
tumors and recognized as a therapeutic target in cancer. Here, we report Andrographolide (AG), a diterpenoid
lactone isolated from Andrographis paniculate, as a novel PDK inhibitor through screening from the natural product
library. AG has been reported to have anti-inflammatory, anti-viral, immune-stimulant properties and induced
apoptosis in cancer cells. However, the precise mechanism of AG induces apoptosis has not yet been clearly
elucidated. As a result of checking the cell viability by MTT assay with various cells with drugs, only AG showed
cytotoxicity correlated with PDK1 expression among the 17 types of PDK1 inhibitors searched. AG decreases the
PDK1 activity in both in vitro enzymatic kinase assay and intracellular phosphorylation of PDHA1 in H292 cells with
high PDK1 expression than in A549 cells. The production of lactic acid was inhibited only in H292 cells. And,
mitochondrial damages and mitochondrial ROS were increased. Apoptosis signals increased. Collectively, AG
suppressed the viability of lung cancer cells through inhibiting PDK1 activity and subsequently inducing
mitochondrial ROS-dependent apoptotic cell death.
