RSS-Feed abonnieren
DOI: 10.1055/a-1013-1439
Yuanhuatine from Daphne genkwa selectively induces mitochondrial apoptosis in estrogen receptor α-positive breast cancer cells in vitro
Publikationsverlauf
received 24. April 2019
revised 14. August 2019
accepted 12. September 2019
Publikationsdatum:
18. Oktober 2019 (online)
Abstract
Breast cancer is one of the most common cancers diagnosed among women worldwide. Estrogen receptor alpha (ERα) is a transcriptional factor that plays an important role in the development and progression of breast cancer. Yuanhuatine, a natural daphnane-type diterpenoid extracted from Daphne genkwa, was reported to exhibit significant cytotoxicity against breast cancer cells. However, the underlying mechanism is still unclear. In this study, we evaluated the cytotoxicity of yuanhuatine on two breast cancer cell lines that are ERα-positive and -negative. The results show that yuanhuatine inhibits the growth of ERα-positive cells (MCF-7) with much stronger inhibitory activity (IC50 = 0.62 µM) compared with positive control tamoxifen (IC50 = 14.43 µM). However, no obvious cytotoxicity was observed in ERα-negative cells (MDA-MB-231). Subsequent experiment also indicated that yuanhuatine markedly induced mitochondrial dysfunction, leading to apoptosis in MCF-7 cells. Molecular docking studies suggest the potential interactions between yuanhuatine and ERα. Immunofluorescence staining and Western blot analysis indicated that yuanhuatine down-regulated the expression of ERα in MCF-7 cells. MPP, a specific ERα inhibitor, significantly enhanced yuanhuatine-induced mitochondrial dysfunction and apoptosis in MCF-7 cells. On the contrary, the treatment with yuanhuatine causes no apoptosis in MM231 cells. Altogether, in vitro and in silico results suggested that ERα down-regulation was involved in yuanhuatine-induced mitochondrial dysfunction and apoptosis in ERα-positive breast cancer cells. Thus, yuanhuatine could be a potential candidate for treating ERα-positive breast cancer.
Supporting Information
- Supporting Information
Additional information about the induction of cells apoptosis by yuanhuatine treatment of MM231 cells and the pharmacokinetic properties of yuanhuatine predicted by PreADMET web server are available in Supporting Information section.
-
References
- 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69: 7-34
- 2 Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001; 344: 276-285
- 3 Ali S, Coombes RC. Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia 2000; 5: 271-281
- 4 Tong CWS, Wu M, Cho WCS, To KKW. Recent advances in the treatment of breast cancer. Front Oncol 2018; 8: 227
- 5 Ballinger TJ, Meier JB, Jansen VM. Current landscape of targeted therapies for hormone-receptor positive, HER2 negative metastatic breast cancer. Front Oncol 2018; 8: 308
- 6 Li S, Chou G, Hseu Y, Yang H, Kwan H, Yu Z. Isolation of anticancer constituents from flos genkwa (Daphne genkwa Sieb.et Zucc.) through bioassay-guided procedures. Chem Cent J 2013; 7: 159
- 7 Van Minh N, Han BS, Choi HY, Byun J, Park JS, Kim WG. Genkwalathins A and B, new lathyrane-type diterpenes from Daphne genkwa . Nat Prod Res 2018; 32: 1782-1790
- 8 Hong JY, Nam JW, Seo EK, Lee SK. Daphnane diterpene esters with anti-proliferative activities against human lung cancer cells from Daphne genkwa . Chem Pharm Bull (Tokyo) 2010; 58: 234-237
- 9 Park BY, Min BS, Ahn KS, Kwon OK, Joung H, Bae KH, Lee HK, Oh SR. Daphnane diterpene esters isolated from flower buds of Daphne genkwa induce apoptosis in human myelocytic HL-60 cells and suppress tumor growth in Lewis lung carcinoma (LLC)-inoculated mouse model. J Ethnopharmacol 2007; 111: 496-503
- 10 Shao ZY, Shang Q, Zhao NX, Zhang SJ, Xia GP, Bai XX, Dong HL, Han YM. Daphnane diterpene esters from flower buds of Daphne genkwa and their cytotoxic effects on cancer cells. Zhong Cao Yao 2013; 44: 128-132
- 11 Li F, Sun Q, Hong L, Li L, Wu Y, Xia M, Ikejima T, Peng Y, Song S. Daphnane-type diterpenes with inhibitory activities against human cancer cell lines from Daphne genkwa . Bioorg Med Chem Lett 2013; 23: 2500-2504
- 12 Zhang Y, Chen X, Gueydan C, Han J. Plasma membrane changes during programmed cell deaths. Cell Res 2018; 28: 9-21
- 13 Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol 2003; 15: 725-731
- 14 Pero ME, Zullo G, Esposito L, Iannuzzi A, Lombardi P, De Canditiis C, Neglia G, Gasparrini B. Inhibition of apoptosis by caspase inhibitor Z-VAD-FMK improves cryotolerance of in vitro derived bovine embryos. Theriogenology 2018; 108: 127-135
- 15 Fan S, Li L, Chen S, Yu Y, Qi M, Tashiro S, Onodera S, Ikejima T. Silibinin induced-autophagic and apoptotic death is associated with an increase in reactive oxygen and nitrogen species in HeLa cells. Free Radic Res 2011; 45: 1307-1324
- 16 Dharmaraja AT. Role of reactive oxygen species (ROS) in therapeutics and drug resistance in cancer and bacteria. J Med Chem 2017; 60: 3221-3240
- 17 Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47-59
- 18 Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Ignatiadis M, Dancey JE, Piccart-Gebhart MJ. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev 2013; 39: 935-946
- 19 Zheng N, Zhang P, Huang H, Liu W, Hayashi T, Zang L, Zhang Y, Liu L, Xia M, Tashiro S, Onodera S, Ikejima T. ERα down-regulation plays a key role in silibinin-induced autophagy and apoptosis in human breast cancer MCF-7 cells. J Pharmacol Sci 2015; 128: 97-107
- 20 Klinge CM. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 2001; 29: 2905-2919
- 21 Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011; 11: 597-608
- 22 Sommer S, Fuqua SA. Estrogen receptor and breast cancer. Semin Cancer Biol 2001; 11: 339-352
- 23 Jang SY, Jang SW, Ko J. Celastrol inhibits the growth of estrogen positive human breast cancer cells through modulation of estrogen receptor α. Cancer Lett 2011; 300: 57-65
- 24 Kim KH, Cho SJ, Kim BO, Pyo S. Differential pro-apoptotic effect of allicin in oestrogen receptor-positive or -negative human breast cancer cells. J Funct Foods 2016; 25: 341-353
- 25 Lim MS, Choung SY, Jeong KW. Germacrone Inhibits Estrogen Receptor α-Mediated Transcription in MCF-7 Breast Cancer Cells. Phytother Res 2016; 30: 2036-2043
- 26 Sun Y, Wang Y, Fan C, Gao P, Wang X, Wei G, Wei J. Estrogen promotes stemness and invasiveness of ER-positive breast cancer cells through Gli1 activation. Mol Cancer 2014; 13: 137
- 27 Min JB, Gupta SD, Wahler J, Suh N. Role of dietary bioactive natural products in estrogen receptor-positive breast cancer. Semin Cancer Biol 2016; 40 – 41: 170-191
- 28 Liao SG, Chen HD, Yue JM. Plant orthoesters. Chem Rev 2009; 109: 1092-1140