TY - JOUR
T1 - Bisdemethoxycurcumin induces apoptosis in Activated Hepatic Stellate Cells via cannabinoid receptor 2
AU - Lee, Phil Jun
AU - Woo, Seung Je
AU - Jee, Jun Goo
AU - Sung, Sang Hyun
AU - Kim, Hong Pyo
N1 - Publisher Copyright:
©2015 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl 2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.
AB - Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl 2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.
KW - Adenosine triphosphate (ATP)
KW - Bisdemethoxycurcumin (BDMC)
KW - Cannabinoid receptor (CBR) 2
KW - Curcumin
KW - Death-inducing signaling complex (DISC)
KW - Hepatic stellate cells (HSCs)
KW - Liver fibrosis
UR - http://www.scopus.com/inward/record.url?scp=84921449688&partnerID=8YFLogxK
U2 - 10.3390/molecules20011277
DO - 10.3390/molecules20011277
M3 - Article
C2 - 25594342
AN - SCOPUS:84921449688
SN - 1420-3049
VL - 20
SP - 1277
EP - 1292
JO - Molecules
JF - Molecules
IS - 1
ER -