| Summary: | 碩士 === 臺北醫學大學 === 醫學科學研究所 === 97 === TSDH is a lipophilic compound extracted from traditional Chinese medicine
Salvia miltiorrhiza. Our recent studies have shown that TSDH possesses the ability of
inhibiting proliferation and can induce apoptosis in human breast cancer cells. First,
TSDH inhibited cell proliferation through down-regulation of G1 cyclins and cell
cycle dependent kinase activity and resulting in cell cycle arrest in G1 phase, and then
induced cell apoptosis through mitochondria-mediated pathway. Another study
reported that TSDH analogue, Tanshinone II A, induces AML cells apoptosis by
caspase-3 dependent pathway. In this study, we have investigated the apoptotic effect
of TSDH on the human AML type III cell line HL-60. We found that under 1.5 μg/ml
of TSDH significantly increased proapoptotic Bax, Bad proteins expression and
activated several caspases, thus led to PARP cleavage and resulted in HL-60 cell
apoptosis. The activation of caspase-8 and caspase-9 found in TSDH-treated cells
suggest that both death receptor and mitochondrion mediated pathways were induced.
Due to the AP-1 binding site sits on FasL promoter region, activation of JNK pathway
may mediates the regulation of FasL gene expression. Our results indicated that
TSDH time-dependently induced JNK phosphorylation and dose-dependently
upregulated Fas ligand (FasL) expression. By using JNK-specific inhibitor, SP600125,
can slightly inhibited TSDH-induced caspases activation. However, FasL expression
and cell death cannot be reversed. These results suggest that TSDH induced HL-60
cell apoptosis was partially through JNK activation, where the upregulation of FasL
may play a more important role. In vivo study of the TSDH effect on HL-60 bearing
nude mice indicated that, under TSDH 25 mg/kg treatment efficiently blocked tumor
formation. In conclusion, due to the proapoptotic effect in leukemia cells in vitro and
in vivo suggest that TSDH has the potential to develop as an anti-leukemia drug in the
future.
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