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Background: Icariin is a major component isolated from Epimedium brevicornum Maxim and has been reported to exhibit anti-tumor activity. However, whether icariin could reverse the acquired drug resistance in breast cancer remains largely unclear. Therefore, this study was designed to explore the antitumor effects of icariin and its underlying mechanisms in a tamoxifen-resistant breast cancer cell line MCF-7/TAM.

Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Lactate dehydrogenase (LDH) assay were performed to determine the effects of icariin on cell viability and cell death. Cell cycle progression and apoptosis were detected by flow cytometry analysis. Transmission electron microscopy (TEM) assay was utilized to observe cell autophagy. The downstream protein levels were measured using western blotting.

Results: Here, we observed that icariin treatment not only inhibited the growth of MCF-7 but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Moreover, icariin significantly induced cell cycle G0/G1 phase arrest and apoptosis, as well as suppressed autophagy. At molecular levels, icariin treatment remarkably down-regulated the expression levels of CDK2, CDK4, Cyclin D1, Bcl-2, LC3-1, LC3-II, AGT5, Beclin-1, but upregulated the expression levels of caspase-3, PARP and p62. Most importantly, we found inhibition of autophagy via 3-MA treatment could significantly enhance the effects of icariin on cell viability and apoptosis. Enhanced autophagy via autophagy related 5 (ATG5) overexpression could partially reverse the effects of icariin on cell viability and apoptosis.

Conclusion: These results revealed that icariin might potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen through suppression of autophagy in vitro and provide insight into the therapeutic potential of icariin for the treatment of chemo-resistant breast cancer.

Titel:	Icariin induces apoptosis by suppressing autophagy in tamoxifen-resistant breast cancer cell line MCF-7/TAM.
Autor/in / Beteiligte Person:	Cheng, X ; Tan, S ; Duan, F ; Yuan, Q ; Li, Q ; Deng, G
Link:	Zum Volltext
Zeitschrift:	Breast cancer (Tokyo, Japan), Jg. 26 (2019-11-01), Heft 6, S. 766-775
Veröffentlichung:	Tokyo : Maruzen Co.,, 2019
Medientyp:	academicJournal
ISSN:	1880-4233 (electronic)
DOI:	10.1007/s12282-019-00980-5
Schlagwort:	Autophagy-Related Protein 5 genetics Autophagy-Related Protein 5 metabolism Breast Neoplasms drug therapy Caspase 3 metabolism Cell Cycle Checkpoints drug effects Cell Survival drug effects Epimedium chemistry Female Humans MCF-7 Cells Poly(ADP-ribose) Polymerases metabolism Proto-Oncogene Proteins c-bcl-2 metabolism Selective Estrogen Receptor Modulators adverse effects Selective Estrogen Receptor Modulators therapeutic use Signal Transduction drug effects Tamoxifen therapeutic use Transfection Apoptosis drug effects Autophagy drug effects Breast Neoplasms pathology Drug Resistance, Neoplasm drug effects Flavonoids pharmacology Plant Extracts pharmacology Tamoxifen adverse effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Breast Cancer] 2019 Nov; Vol. 26 (6), pp. 766-775. <i>Date of Electronic Publication: </i>2019 Jun 06. MeSH Terms: Apoptosis / drug effects ; Autophagy / drug effects ; Breast Neoplasms / pathology ; Drug Resistance, Neoplasm / drug effects ; Flavonoids / pharmacology ; Plant Extracts / pharmacology ; Tamoxifen / *adverse effects ; Autophagy-Related Protein 5 / genetics ; Autophagy-Related Protein 5 / metabolism ; Breast Neoplasms / drug therapy ; Caspase 3 / metabolism ; Cell Cycle Checkpoints / drug effects ; Cell Survival / drug effects ; Epimedium / chemistry ; Female ; Humans ; MCF-7 Cells ; Poly(ADP-ribose) Polymerases / metabolism ; Proto-Oncogene Proteins c-bcl-2 / metabolism ; Selective Estrogen Receptor Modulators / adverse effects ; Selective Estrogen Receptor Modulators / therapeutic use ; Signal Transduction / drug effects ; Tamoxifen / therapeutic use ; Transfection References: Curr Opin Cell Biol. 2010 Apr;22(2):140-9. (PMID: 20097051) ; Biomed Pharmacother. 2019 Jan;109:2456-2463. (PMID: 30551506) ; Int Immunopharmacol. 2014 Jan;18(1):55-65. (PMID: 24262302) ; J Histochem Cytochem. 2009 Apr;57(4):289-300. (PMID: 19029405) ; Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961-5. (PMID: 1871110) ; J Cell Physiol. 2019 Feb 19;:null. (PMID: 30784063) ; Nat Rev Cancer. 2005 Sep;5(9):726-34. (PMID: 16148885) ; Braz J Med Biol Res. 2018 Aug 06;51(10):e7151. (PMID: 30088538) ; Int J Oncol. 2019 Jun;54(6):1933-1942. (PMID: 31081049) ; J Ethnopharmacol. 2011 Dec 8;138(3):731-6. (PMID: 22027446) ; Toxicol Pathol. 2007 Jun;35(4):495-516. (PMID: 17562483) ; Sci Rep. 2016 Feb 19;6:21145. (PMID: 26892033) ; Autophagy. 2016 Jun 2;12(6):1029-46. (PMID: 27166522) ; Pharmacogenomics J. 2015 Feb;15(1):84-94. (PMID: 25091503) ; CA Cancer J Clin. 2017 Nov;67(6):439-448. (PMID: 28972651) ; Genes Dev. 2007 Nov 15;21(22):2861-73. (PMID: 18006683) ; Clin Cancer Res. 2009 Apr 1;15(7):2433-41. (PMID: 19318480) ; Cell Mol Biol (Noisy-le-grand). 2016 Apr 30;62(4):123-9. (PMID: 27188746) ; Oncol Rep. 2015 Jun;33(6):2829-36. (PMID: 25845681) ; Mol Pain. 2018 Jan-Dec;14:1744806918768970. (PMID: 29623757) ; Curr Top Dev Biol. 2015;114:67-91. (PMID: 26431564) ; J Pharm Pharmacol. 2004 Dec;56(12):1557-62. (PMID: 15563763) ; Breast Cancer Res Treat. 2010 Feb;119(3):575-91. (PMID: 19288272) ; Cell Death Differ. 1999 Feb;6(2):99-104. (PMID: 10200555) ; Cell Biochem Biophys. 2014 Jul;69(3):523-30. (PMID: 24435883) ; Arch Androl. 2004 Jan-Feb;50(1):27-32. (PMID: 14660168) ; Front Pharmacol. 2019 Mar 19;10:271. (PMID: 30941046) ; Planta Med. 1995 Dec;61(6):523-6. (PMID: 8824946) ; Phytomedicine. 2013 Aug 15;20(11):975-9. (PMID: 23746958) ; Cancer Lett. 2011 Jan 28;300(2):105-14. (PMID: 21036469) ; Exp Cell Res. 2013 Jun 10;319(10):1505-14. (PMID: 23524143) ; Cell Biochem Biophys. 2014 Jun;69(2):303-10. (PMID: 24590261) ; Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3:220-34. (PMID: 26455641) ; Cell Death Differ. 2004 Apr;11(4):448-57. (PMID: 14713959) ; Oncol Lett. 2018 Aug;16(2):1405-1410. (PMID: 30008817) ; Exp Cell Res. 2016 Sep 10;347(1):222-31. (PMID: 27515002) ; Acta Pharmacol Sin. 2013 Feb;34(2):301-8. (PMID: 23274410) ; Nature. 2015 Dec 17;528(7582):413-7. (PMID: 26649828) ; Oncol Rep. 2019 Apr;41(4):2321-2328. (PMID: 30720119) ; Cell Syst. 2016 Jan 27;2(1):27-37. (PMID: 27136687) ; Nat Cell Biol. 2010 Mar;12(3):207-9. (PMID: 20190829) ; Curr Opin Gastroenterol. 2010 Jul;26(4):302-9. (PMID: 20571384) ; Carcinogenesis. 2011 Apr;32(4):629-35. (PMID: 21258042) ; Science. 2004 Nov 5;306(5698):1037-40. (PMID: 15528445) ; Neuroscience. 2015 May 21;294:193-205. (PMID: 25791226) ; Cancer Discov. 2015 Sep;5(9):909-11. (PMID: 26334046) ; Pharmazie. 2014 Mar;69(3):198-202. (PMID: 24716409) ; Mol Oncol. 2013 Jun;7(3):611-24. (PMID: 23499324) ; Annu Rev Plant Biol. 2018 Apr 29;69:173-208. (PMID: 29539270) ; Curr Opin Genet Dev. 2014 Jun;26:16-23. (PMID: 24907664) Grant Information: 317605403 National Natural Science Foundation of China; 2016FB068 National Natural Science Foundation of Yunnan; 2017FB108 National Natural Science Foundation of Yunnan Contributed Indexing: Keywords: Apoptosis; Autophagy; Breast cancer; Drug resistance; Icariin Substance Nomenclature: 0 (ATG5 protein, human) ; 0 (Autophagy-Related Protein 5) ; 0 (BCL2 protein, human) ; 0 (Flavonoids) ; 0 (Plant Extracts) ; 0 (Proto-Oncogene Proteins c-bcl-2) ; 0 (Selective Estrogen Receptor Modulators) ; 094ZI81Y45 (Tamoxifen) ; EC 2.4.2.30 (Poly(ADP-ribose) Polymerases) ; EC 3.4.22.- (CASP3 protein, human) ; EC 3.4.22.- (Caspase 3) ; VNM47R2QSQ (icariin) Entry Date(s): Date Created: 20190608 Date Completed: 20200226 Latest Revision: 20200226 Update Code: 20231215 PubMed Central ID: PMC6821666

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Icariin induces apoptosis by suppressing autophagy in tamoxifen-resistant breast cancer cell line MCF-7/TAM.