PMID- 24036456
OWN - NLM
STAT- MEDLINE
DCOM- 20140827
LR  - 20201209
IS  - 1878-5875 (Electronic)
IS  - 1357-2725 (Linking)
VI  - 45
IP  - 11
DP  - 2013 Nov
TI  - ONTD induces apoptosis of human hepatoma Bel-7402 cells via a MAPK-dependent 
      mitochondrial pathway and the depletion of intracellular glutathione.
PG  - 2632-42
LID - S1357-2725(13)00291-4 [pii]
LID - 10.1016/j.biocel.2013.08.021 [doi]
AB  - 3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile (ONTD) is a novel 
      synthetic derivative of glycyrrhetinic acid (GA), which has the ability to 
      inhibit the proliferation of human hepatocellular carcinoma (HCC) cells. However, 
      the mechanisms by which ONTD exerts its inhibitory effects remain elusive. The 
      present study was conducted to investigate the cytotoxicity of ONTD in Bel-7402 
      cells and its molecular mechanisms. We found that ONTD depleted intracellular 
      GSH, increased the level of ROS, and consequently induced mitochondrial 
      permeability transition (MPT) leading to the release of apoptosis-inducing factor 
      (AIF) and cytochrome c (Cyt c) to the cytosol. Mitochondrial alteration and 
      subsequent apoptotic cell death in ONTD-treated Bel-7402 cells could be blocked 
      by addition of exogenous antioxidants N-acetylcystein (NAC), GSH and the MTP 
      inhibitor cyclosporin A (CsA). In addition, ONTD activated the phosphorylation of 
      c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) 
      but not extracellular signal-regulated protein kinases (ERK 1/2). When the cells 
      were exposed to SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), the 
      deregulation of the expression of apoptotic proteins was attenuated. Furthermore, 
      40 mg/kg ONTD significantly reduced tumor weight (-70.62%, p<0.01) in the H22 
      tumor-bearing mouse model in vivo. Taken together, these findings provide the 
      first experimental evidence supporting that ONTD could induce apoptosis of 
      Bel-7402 cells via MAPK-mediated mitochondrial pathway and ONTD has the potential 
      to be developed as a therapeutic agent for the treatment of HCC.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Tan, Jiani
AU  - Tan J
AD  - State Key Laboratory of Natural Medicines, China Pharmaceutical University, 
      Nanjing 210009, PR China; Department of Pharmacology, China Pharmaceutical 
      University, Nanjing 210009, PR China.
FAU - Lai, Zhonghui
AU  - Lai Z
FAU - Liu, Ling
AU  - Liu L
FAU - Long, Wenyan
AU  - Long W
FAU - Chen, Tong
AU  - Chen T
FAU - Zha, Jun
AU  - Zha J
FAU - Wang, Linna
AU  - Wang L
FAU - Chen, Meiyu
AU  - Chen M
FAU - Ji, Hui
AU  - Ji H
FAU - Lai, Yisheng
AU  - Lai Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130911
PL  - Netherlands
TA  - Int J Biochem Cell Biol
JT  - The international journal of biochemistry & cell biology
JID - 9508482
RN  - 0 (3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile)
RN  - 0 (Antioxidants)
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Permeability Transition Pore)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Triterpenes)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Apoptosis/*drug effects
MH  - Body Weight/drug effects
MH  - Carcinoma, Hepatocellular/*enzymology/pathology
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Shape/drug effects
MH  - Cell Survival/drug effects
MH  - Glutathione/*metabolism
MH  - Humans
MH  - Intracellular Space/drug effects/metabolism
MH  - Liver Neoplasms/*enzymology/pathology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mitochondria/drug effects/*metabolism
MH  - Mitochondrial Membrane Transport Proteins/metabolism
MH  - Mitochondrial Permeability Transition Pore
MH  - Reactive Oxygen Species/metabolism
MH  - Triterpenes/chemistry/*pharmacology
OTO - NOTNLM
OT  - Apoptosis
OT  - GSH
OT  - Hepatocellular carcinoma
OT  - MAPKs
OT  - Mitochondria
EDAT- 2013/09/17 06:00
MHDA- 2014/08/29 06:00
CRDT- 2013/09/17 06:00
PHST- 2013/06/13 00:00 [received]
PHST- 2013/08/29 00:00 [revised]
PHST- 2013/08/31 00:00 [accepted]
PHST- 2013/09/17 06:00 [entrez]
PHST- 2013/09/17 06:00 [pubmed]
PHST- 2014/08/29 06:00 [medline]
AID - S1357-2725(13)00291-4 [pii]
AID - 10.1016/j.biocel.2013.08.021 [doi]
PST - ppublish
SO  - Int J Biochem Cell Biol. 2013 Nov;45(11):2632-42. doi: 
      10.1016/j.biocel.2013.08.021. Epub 2013 Sep 11.