Beta 18b-Glycyrrhetinic Acid Derivatives Induced Mitochondrial-Mediated Apoptosis through Reactive Oxygen Species-Mediated P53 Activation in Ntub1 Cells
Resource
BIOORGANIC & MEDICINAL CHEMISTRY v.19 n.14 pp.4274-4285
Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Journal Volume
v.19
Journal Issue
n.14
Pages
4274-4285
Date Issued
2011
Date
2011
Author(s)
LIN, KAI-WEI
HUANG, A-MEI
HOUR, TZYH-CHYUAN
YANG, SHYH-CHYUN
PU, YEONG-SHIAU
LIN, CHUN-NAN
Abstract
Twenty six 18 beta-glycyrrhetinic acid GA 1 derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells human bladder cancer cell lines. seco-Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC50 values of 2.34 +/- 0.28, 4.76 +/- 1.15, and 3.31 +/- 0.61 mu M, respectively. Exposure of NTUB1 to 25 for 24 h significantly increased the production of reactive oxygen species ROS. Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose-dependant manner after 24 h. Mitochondrial membrane potential MMP decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24 h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p 53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial-mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25.
Subjects
Synthesis
18 beta-Glycyrrhetinic acid derivatives
Cytotoxicity
p53
Antioxidant
SDGs