Isocryptotanshinone Induced Apoptosis and Activated MAPK Signaling in Human Breast Cancer MCF-7 Cells

다국어 초록 (Multilingual Abstract)

Purpose: Isocryptotanshinone (ICTS) is a natural bioactive product that is isolated from the roots of the widely used medical herb Salvia miltiorrhiza. However, few reports exist on the mechanisms underlying the therapeutic effects of ICTS. Here, we report that ICTS has anticancer activity and describe the mechanism underlying this effect. Methods: The antiproliferative effect of ICTS was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5- diphenyl-2-H-tetrazolium bromide (MTT) and clonogenic assays.
The effect of ICTS on the cell cycle was measured using flow cytometry. Apoptosis was determined by Hoechst 33342 staining, DNA fragmentation assays, and Western blotting for apoptotic proteins. Finally, the effect of ICTS on mitogen-activated protein kinases (MAPKs) was determined by Western blotting.
Results: ICTS significantly inhibited proliferation of MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 human liver cancer cells, and A549 human lung cancer cells in vitro. Among the tested cell lines, MCF-7 cells showed the highest sensitivity to ICTS. ICTS significantly inhibited colony formation by MCF-7 cells. Furthermore, exposure of MCF-7 cells to ICTS induced cell cycle arrest at the G1 phase and decreased mitochondrial membrane potential. Hoechst 33342 staining and Western blot analysis for apoptotic proteins suggested that ICTS induced apoptosis in MCF-7 cells. In addition, ICTS activated MAPK signaling in MCF-7 cells by inducing time- and concentration-dependent phosphorylation of JNK, ERK, and p38 MAPK. Conclusion: Our results suggest that ICTS inhibited MCF-7 cell proliferation by inducing apoptosis and activating MAPK signaling pathways.

참고문헌 (Reference)

1 Sui X, "p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents" 344 : 174-179, 2014

2 Chen X, "The anticancer properties of Salvia miltiorrhiza Bunge(Danshen) : a systematic review" 34 : 768-794, 2014

3 Cory S, "The Bcl-2 family : roles in cell survival and oncogenesis" 22 : 8590-8607, 2003

4 Badr CE, "Targeting cancer cells with the natural compound obtusaquinone" 105 : 643-653, 2013

5 Zhang Y, "Tanshinones: sources, pharmacokinetics and anti-cancer activities" 13 : 13621-13666, 2012

6 Cheng CY, "Tanshinone IIA may inhibit the growth of small cell lung cancer H146 cells by up-regulating the Bax/Bcl-2 ratio and decreasing mitochondrial membrane potential" 3 : 645-650, 2010

7 Jiao JW, "Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells" 25 : 781-788, 2011

8 Nizamutdinova IT, "Tanshinone I effectively induces apoptosis in estrogen receptor-positive(MCF-7)and estrogen receptor-negative(MDA-MB-231)breast cancer cells" 33 : 485-491, 2008

9 Kakisawa H, "Structures of isotanshinones" 10 : 301-304, 1969

10 Tsujimoto Y, "Role of the mitochondrial membrane permeability transition in cell death" 12 : 835-840, 2007

11 Ola MS, "Role of Bcl-2 family proteins and caspases in the regulation of apoptosis" 351 : 41-58, 2011

12 Lee WY, "Reactive oxygen species-mediated kinase activation by dihydrotanshinone in tanshinones-induced apoptosis in HepG2 cells" 285 : 46-57, 2009

13 Glassmann A, "Pharmacological targeting of the constitutively activated MEK/MAPK-dependent signaling pathway in glioma cells inhibits cell proliferation and migration" 39 : 1567-1575, 2011

14 Griffin C, "Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts" 10 : 57-68, 2011

15 Han YM, "PTP1B inhibitory effect of abietane diterpenes isolated from Salvia miltiorrhiza" 28 : 1795-1797, 2005

16 Chaveli-López B, "Oral toxicity produced by chemotherapy: a systematic review" 6 : e81-e90, 2014

17 Saha SK, "Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs : current trends" 714 : 239-248, 2013

18 Himeji M, "Difference of growth-inhibitory effect of Scutellaria baicalensis-producing flavonoid wogonin among human cancer cells and normal diploid cell" 245 : 269-274, 2007

19 Park IJ, "Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation" 298 : 88-98, 2010

20 Chen L, "Cryptotanshinone inhibits lung tumorigenesis and induces apoptosis in cancer cells in vitro and in vivo" 9 : 2447-2452, 2014

21 Lu L, "Cryptotanshinone inhibits human glioma cell proliferation by suppressing STAT3 signaling" 381 : 273-282, 2013

22 Shin DS, "Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells" 69 : 193-202, 2009

23 Zhou J, "Cryptotanshinone induces inhibition of breast tumor growth by cytotoxic CD4+ T cells through the JAK2/STAT4/ perforin pathway" 15 : 2439-2445, 2014

24 Ge Y, "Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E" 368 : 17-25, 2012

25 Park IJ, "Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma" 19 : 615-628, 2014

26 Park IJ, "Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells" 17 : 248-257, 2012

27 Chen L, "Cryptotanshinone has diverse effects on cell cycle events in melanoma cell lines with different metastatic capacity" 68 : 17-27, 2011

28 Chen W, "Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells" 5 : 778-787, 2012

29 Wei H, "Chalcone derivatives from the fern Cyclosorus parasiticus and their anti-proliferative activity" 60 : 147-152, 2013

30 Tan W, "Anti-cancer natural products isolated from Chinese medicinal herbs" 6 : 27-, 2011