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V8, a newly synthetic flavonoid, induces apoptosis through ROS-mediated ER stress pathway in hepatocellular carcinoma.
- Source :
-
Archives of Toxicology . Jan2014, Vol. 88 Issue 1, p97-107. 11p. - Publication Year :
- 2014
-
Abstract
- Natural flavonoids from plants have been demonstrated to possess promising chemopreventive activities against various diseases. 7-{4-[Bis-(2-hydroxy-ethyl)-amino]-butoxy}-5-hydroxy-8-methoxy-2-phenyl-chromen-4-one (V8), a newly synthesized derivative of wogonin may have antioxidant, antiviral, anti-inflammatory and anti-tumor potentials as wogonin. Based on the recent findings of V8, the anti-tumor activities and fundamental mechanisms by which V8 inhibits growth of hepatocellular carcinoma were further investigated in this study. After the treatment of V8, a significant inhibition of HepG2 cell proliferation was observed in a dose-dependent manner with the IC value of 23 μM using MTT assay. The exposure to V8 also resulted in apoptosis induction and an accumulation of ROS and Ca. Meanwhile, a release of cytochrome c (Cyt-c), activation of BH-3 only proteins and Bax, decrease in mitochondrial membrane potential ΔΨ, as well as a suppression of Bcl-2, pro-caspase9 and pro-caspase3 expression were shown. Moreover, knocking down CHOP partly decreased the effect of V8-mediated apoptosis and activation of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP modulated ER stress triggered by V8. In vivo, V8 inhibited the transplanted mice H22 liver carcinomas in a dose-dependent manner. Compared with wogonin, V8 exhibited stronger anti-proliferative effects both in vitro and in vivo. The underlying mechanism of activating PERK-eIF2α-ATF4 pathway by which V8 induces apoptosis was verified once again in vivo. The apoptosis induction via the mitochondrial pathway by modulating the ROS-mediated ER signaling pathway might serve to provide support for further studies of V8 as a possible anticancer drug in the clinical treatment of cancer. [ABSTRACT FROM AUTHOR]
- Subjects :
- *LIVER cancer
*APOPTOSIS
*CANCER treatment
*FLAVONOIDS
*CELL proliferation
Subjects
Details
- Language :
- English
- ISSN :
- 03405761
- Volume :
- 88
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Archives of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 93436380
- Full Text :
- https://doi.org/10.1007/s00204-013-1085-6