Abstract
15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with 1.5 μg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, thus leading to poly ADP ribose polymerase (PARP) cleavage and resulting in cell apoptosis. DHTS induced sustained c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. The anti-Fas blocking antibody reversed the DHTS-induced cell death, and the JNK-specific inhibitor, SP600125, inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a great effect in attenuating HL-60 tumor growth. Taken together, these results suggest that DHTS can induce HL-60 cell apoptosis in vitro and inhibit HL-60 cell growth in vivo; the underlying mechanisms might be mediated through activation of the JNK and FasL signal pathways.
Highlights
15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia
5 μM SP600125 reversed increases in cleaved caspase-3, -8, and -9, and poly ADP ribose polymerase (PARP) in DHTS-treated cells. These results suggest that DHTS-induced apoptosis might be mediated through increases in Fas ligand (FasL) expression and Jun N-terminal kinase (JNK)
We showed that DHTS significantly induced apoptosis of human HL-60 leukemia cells at very low concentrations, as evidenced by a decrease in viable cell numbers and an increase in propidium iodide (PI)/annexin
Summary
15,16-Dihydrotanshinone I (DHTS) is extracted from the Salvia miltiorrhiza Bunge (Tanshen), which is used as a dietary supplement or as an ingredient in functional foods in Asian countries. Among the compounds of Tanshen, DHTS has the strongest inhibitory activity against breast cancer cells through inducing G1-phase arrest and increasing loss of the mitochondrial membrane potential and cytochrome c release [3]. DHTS can induce apoptosis of prostate carcinoma cells via induction of endoplasmic reticular stress and/or inhibition of proteasome activity [5], and may have therapeutic potential for prostate cancer patients. The mitochondrial membrane plays a crucial role in initiating the intrinsic apoptosis pathway, which can occur by decreasing antiapoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, and increasing proapoptotic Bcl-2 family proteins, such as Bad and. A decrease in the antiapoptotic protein/proapoptotic protein ratio results in cytochrome c release into the cytosol and causes pro-caspase-9 cleavage. The extrinsic apoptotic pathway is activated by various death receptors, such as Fas, and induces pro-caspase-8 cleavage. Cleaved caspase-9 and -8 can subsequently activate downstream effector caspases, including caspase-3, which destroys the cellular machinery and leads to eventual cell death [13]
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