Induction of apoptosis by tanshinone I via cytochrome c release in activated hepatic stellate cells.
Hepatic stellate cells play central roles in hepatic fibrosis. The therapeutic goal in hepatic fibrosis is to halt or reverse fibrosis. Apoptosis is suggested to eliminate activated hepatic stellate cells in fibrosis. Salvia miltiorrhiza is a traditional medicine used to improve blood circulation and treat chronic hepatitis and hepatic fibrosis. We investigated the effect of tanshinone I, an ingredient of Salvia miltiorrhiza, on the apoptotic death of rat hepatic stellate cells transformed by simian virus 40 (T-HSC/Cl-6), which retains the features of activated stellate cells. Treatment of T-HSC/Cl-6 cells with tanshinone I resulted in the induction of typical DNA fragmentation and DNA ladder formation in a concentration- and time-dependent manner. The induction of apoptosis was confirmed by flow cytometric analysis. Treatment of T-HSC/Cl-6 cells with tanshinone I caused activation of caspase-3 and subsequent proteolytic cleavage of poly(ADP-ribose) polymerase. Tanshinone I induced mitochondrial membrane dipolarization and the release of cytochrome c from mitochondria into the cytosol. In conclusion, our results demonstrate that tanshinone I induces apoptosis of T-HSC/Cl-6 cells and that tanshinone I-induced apoptosis involves caspase activation through cytochrome c release and loss of mitochondrial membrane potential.
Kim
Ji Young
JY
College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, South Korea.
Kim
Kyoung Mi
KM
Nan
Ji-Xing
JX
Zhao
Yu Zhe
YZ
Park
Pil-Hoon
PH
Lee
Sang Jun
SJ
Sohn
Dong Hwan
DH
D045784:Abietanes; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism*; D053938:DNA Fragmentation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005434:Flow Cytometry; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D010616:Phenanthrenes / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry; D013539:Simian virus 40
D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D003574:Cytochrome c Group; D004365:Drugs, Chinese Herbal; D004792:Enzyme Precursors; D010616:Phenanthrenes; C021751:tanshinone; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases