15,16‐Dihydrotanshinone I, a Compound of Salvia miltiorrhiza Bunge, Induces Apoptosis through Inducing Endoplasmic Reticular Stress in Human Prostate Carcinoma Cells

Abstract

5,16-dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge (tanshen root) and was found to be the most effective compound of tanshen extracts against breast cancer cells in our previous studies. However, whether DHTS can induce apoptosis through an endoplasmic reticular (ER) stress pathway was examined herein. In this study, we found that DHTS significantly inhibited the proliferation of human prostate DU145 carcinoma cells and induced apoptosis. DHTS was able to induce ER stress as evidenced by the upregulation of glucose regulation protein 78 (GRP78/Bip) and CAAT/enhancer binding protein homologous protein/growth arrest- and DNA damage-inducible gene 153 (CHOP/GADD153), as well as increases in phosphorylated eukaryotic initiation factor 2α (eIF2α), c-jun N-terminal kinase (JNK), and X-box-binding protein 1 (XBP1) mRNA splicing forms. DHTS treatment also caused significant accumulation of polyubiquitinated proteins and hypoxia-inducible factor (HIF)-1α, indicating that DHTS might be a proteasome inhibitor that is known to induce ER stress or enhance apoptosis caused by the classic ER stress-dependent mechanism. Moreover, DHTS-induced apoptosis was reversed by salubrinal, an ER stress inhibitor. Results suggest that DHTS can induce apoptosis of prostate carcinoma cells via induction of ER stress and/or inhibition of proteasome activity, and may have therapeutic potential for prostate cancer patients.

The Anticancer Properties of Salvia Miltiorrhiza Bunge (Danshen): A Systematic Review

“…It also inhibits cell proliferation in MDA‐MB‐231 (IC 50 85.1 μM), HeLa (IC 50 27.7 μM), SiHa (IC 50 63.5 μM), and MCF‐7 (IC 50 250 μg/mL) cells. Similar inhibitory effect is also reported in DU145 and HUVECs (IC 50 1.28 μg/mL) …”

“…To cause apoptosis, DHT I decreases the Bcl‐xL level and increases the loss of Δψm and the release of cytochrome c , which activate caspase‐9, caspase‐3, and caspase‐7 . Moreover, recent study showed that DHT I induced apoptosis in DU145 cells through induction of ER as evidenced by the fact that DHT I induced apoptosis was reversed by the ER stress inhibitor salubrinal …”

Cytotoxic and apoptogenic properties of three isolated diterpenoids from Salvia chorassanica through bioassay-guided fractionation

“…Considering the growth inhibitory effect of the different ingredients isolated from Salvia species on tumor cell lines, the plant has become popular for anticancer evaluations. 5,16-Dihydrotanshinone I (Chuang et al, 2011), tanshinone IIA (Sung et al, 1999;Liu et al, 2012) compounds of Salvia miltiorrhiza, rosmarinic acid from Salvia fruticosa and Salvia officinalis (Xavier et al, 2009), royleanone, horminone, and acetyl horminone from the roots of S. officinalis (Slamenová et al, 2004); 6a-hydroxysalvinolone, 6a-hydroxytaxodone, aethiopinone, microstegiol, ferruginol, saprorthoquinone, 11,12-dioxoabieta-8,13-diene, taxodione, hypargenin A, hypargenin D isolated from Salvia hypargeia (Ulubelen et al, 1999;Topçu and Gören, 2007;Topcu, 2008) were effective in inhibiting proliferation and had cytotoxic activity against a panel of cell lines including human breast cancer, human lung cancer, human colon cancer, human prostate cancer and mouse lymphocytic leukemia.…”

15,16-Dihydrotanshinone I from the Functional Food Salvia miltiorrhiza Exhibits Anticancer Activity in Human HL-60 Leukemia Cells: in Vitro and in Vivo Studies

“…DHTS also significantly induced apoptosis in colorectal cancer cells, and ATF-3 might be involved in inducing apoptosis [ 4 ]. In addition, 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. In human hepatoma cells, DHTS also induced cell apoptosis through inducing reactive oxygen species (ROS) and the p38 pathway [ 6 ].…”