Activation of c-Jun N-terminal kinase mediates tanshinone IIA-induced apoptosis in KBM-5 chronic myeloid leukemia cells.
Aim of this study was to identify the molecular mechanisms of tanshinone IIA-induced apoptosis in chronic myelogenous leukemia (CML) cells. Cytotoxicity of tanshinone IIA was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our data demonstrate that tanshinone IIA induced apoptosis by increasing the sub-G1 DNA contents and DNA fragmentation in KBM-5 CML cell line. In addition, tanshinone IIA significantly reduced mitochondrial membrane potential (MMP), mediated cytochrome c release from mitochondria and activated caspase-3 and 9, indicating mitochondria-dependent apoptosis by tanshinone IIA. Tanshinone IIA attenuated expression of several apoptosis-related proteins such as c-inhibitor of apoptosis protein (IAP) 2, Mcl-1(L) and Bcl-2. Interestingly, although tanshinone IIA notably enhanced the phosphorylation of both c-Jun N-terminal protein kinase (JNK) and p38, JNK inhibitor, but not p38 inhibitor, reversed tanshinone IIA-induced apoptosis. Our findings suggest that tanshinone IIA induces mitochondria-dependent apoptosis via activation of JNK in KBM 5 cells as a potent anti-cancer agent for CML therapy.
College of Oriental Medicine, Kyung Hee University, Seoul 130–701, Republic of Korea.
Sun-Mi
SM
Yun
Soo-Jin
SJ
Jeong
Ji-Hyun
JH
Kim
Ji Hoon
JH
Jung
Hyo-Jung
HJ
Lee
Eun Jung
EJ
Sohn
Min-Ho
MH
Lee
Sung-Hoon
SH
Kim
D045784:Abietanes / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000503:physiopathology; D007963:Leukocytes, Mononuclear; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; C021751:tanshinone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases