Carnosic acid induces apoptosis of hepatocellular carcinoma cells via ROS-mediated mitochondrial pathway

Carnosic acid (CA), an important bioactive phenolic diterpene mainly found in labiate plants, exerts various biological functions, including antioxidant, anti-inflammatory, antitumor, and neuroprotective activities. In the present study, we proved the deleterious effects of CA against hepatocellular...

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Bibliographic Details
Published in:Chemico-biological interactions Vol. 277; pp. 91 - 100
Main Authors: Zhang, Xinrui, Chen, Yiling, Cai, Guangsheng, Li, Xin, Wang, Di
Format: Journal Article
Language:English
Published: Ireland Elsevier B.V 01.11.2017
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Apoptosis - drug effects
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Carnosic acid (CA)
Diterpenes, Abietane - pharmacology
Diterpenes, Abietane - therapeutic use
Hep G2 Cells
Hepatocellular carcinoma
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Mice, Inbred BALB C
Mitochondria
Mitochondria - drug effects
Mitochondria - pathology
Reactive oxygen species (ROS)
Reactive Oxygen Species - metabolism
Bcl-2
DMSO
Hepatocellular carcinoma
PARP
Carnosic acid (CA)
MTT
RIPA
NF-κB
DMEM
BSA
Mitochondria
ANOVA
FBS
mTOR
Apaf-1
CA
PBS
Reactive oxygen species (ROS)
HCC
IL-2
H&E staining
PVDF
MMP
NAC
DCFH-DA
PMSF
ROS
PI
MPTP
GAPDH
Apoptosis
JC-1
ISSN:0009-2797, 1872-7786, 1872-7786
Online Access:Get full text
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Summary:Carnosic acid (CA), an important bioactive phenolic diterpene mainly found in labiate plants, exerts various biological functions, including antioxidant, anti-inflammatory, antitumor, and neuroprotective activities. In the present study, we proved the deleterious effects of CA against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. In vitro, CA significantly decreased cell viability, inhibited cell proliferation and migration, enhanced apoptosis, and increased caspase-3, -8, and -9 activities in HepG2 and SMMC-7721 cells. Specifically, CA led to a decreased mitochondrial membrane potential (MMP) and increases in intracellular reactive oxygen species (ROS) levels and apoptosis-related protein expression. Pre-incubation of HCC cells with N-Acetyl-l-cysteine (NAC), a ROS inhibitor, strongly suppressed CA-induced apoptotic phenomena, including reduced cell viability, excessive ROS levels, MMP decreases, and abnormal protein expression, suggesting an association of CA-induced apoptosis with oxidative stress-mediated mitochondrial pathways. In HepG2-and SMMC-7721-xenograft tumor mouse models, treatment with CA inhibited tumor growth and modulated apoptosis-related protein expression, confirming the anti-HCC effects of this chemical. Moreover, the CA-mediated anti-HCC effects associated with oxidative stress provide experimental evidence to support the potential use of CA as a drug therapy for HCC. •Carnosic acid (CA) induces apoptosis in hepatocellular carcinoma cells.•CA inhibited the growth of HepG2-and SMMC-7721-xenografted tumor in mice.•CA-induced HCC cell apoptosis via oxidative stress-mediated mitochondrial pathway.•CA regulates the phosphorylation of NF-κB and mTOR involved in its pro-apoptosis.
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ISSN:0009-2797
1872-7786
1872-7786
DOI:10.1016/j.cbi.2017.09.005