Meme Kanseri Hücre Hattında Hypericum perforatum Ekstresinin Apoptotik Etkilerinin Araştırılması

Abstract

Kantaron otu (Hypericum perforatum), programlanmış hücre ölümü olarak bilinen apoptoza aracılık eden kaspaz-3, bax ve bcl-2 gibi çeşitli proteinleri etkileyen ve antiinflamatuar etki gösteren biyolojik aktif içeriğe sahiptir. Apoptotik yolaklar kanserler, kemoterapötik direnç ve kanser gelişimi için önemlidir. Ayrıca, antiinflamatuar ajanlar kanser için bir potansiyel hedeftir. Bundan dolayı, bu çalışmada H. perforatum ekstresi ile muamele edilmiş meme kanseri hücrelerinde kaspaz-3'ün aktivitesinin ve bax, bcl-2, wee 1, gadd153, grp78, AIF, iNOS, COX-2, cPLA2 ve NF-κB ekspresyonlarının araştırılması amaçlandı. Hücrelerde kaspaz-3'ün aktivitesi ve proteinlerin ekspresyonları ELISA ile belirlendi. Ekstrakt, göğüs kanseri hücrelerinde kaspaz-3 aktivitesini ve bax, wee 1, gadd153, grp78 ve AIF ekspresyonunu arttırdı ve bcl-2, iNOS, COX-2, cPLA2 ve NF-κB ekspresyonunu azalttı. Bu bulgular ışığında, H. perforatum ekstresi, meme kanseri hücrelerinin büyümesini önlemeye yardımcı olabilir ve ekstrenin antiinflamatuar etkisi, bu etkiye katkıda bulunabilir.

Keywords

• Hypericum perforatum,Meme kanseri,Apoptozis,İnflamasyon

Investigation of Apoptotic Effects of Hypericum perforatum Extract on Breast Cancer Cell Line

Abstract

Hypericum perforatum has biological active contents affecting a variety of proteins such as caspase-3, bcl-2, and bax, which mediate apoptosis known as programmed cell death and exerting anti-inflammatory effect. Apoptotic pathways are important for cancers, chemotherapeutic resistance, and cancer development. Anti-inflammatory agents are also a potential target for cancer. Therefore, it was aimed to investigate the activity of caspase-3 and the expressions of bcl-2, bax, wee 1, gadd153, grp78, AIF, iNOS, COX-2, cPLA2, and NF-κB in H. perforatum extract-treated breast cancer (BC) cells in this study. The activity of caspase-3 and the expressions of these proteins were determined in the cells by ELISA. The HP extract increased the activity of caspase-3 and the expressions of bax, wee 1, gadd153, grp78 and AIF, and decreased the expressions of bcl-2, COX-2, iNOS, cPLA2 and NF-κB in the BC cells. In the light of these findings, HP extract could help to inhibit grow of BC cells and its anti-inflammatory effect may contribute this effect.

Keywords

• Hypericum perforatum,Breast cancer,Apoptosis,Inflammation

References

1. Albert D, Zundorf I, Dingermann T, Muller WE, Steinhilber D, Werz O, 2002: Hyperforin is a Dual Inhibitor of Cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol, 64(12), 1767-1775.
2. Baldwin AS, 2001: Series introduction: the transcription factor NF-κB and human disease. J Clin Invest, 107(1), 3-6.
3. Berköz M, Allahverdiyev O, Yıldırım M, 2018: Investigation of the Effect of Hyperforin and Hypericin on Inflammatory Response in RAW 264.7 Macrophages. Van Tıp Derg, 25(2), 124-131.
4. Butterweck V, 2003: Mechanism of action of St John’s wort in depression. CNS Drugs, 17(8), 539-562.
5. Cakir A, Mavi A, Yildirim A, Duru ME, Harmandar M, Kaza C, 2003: Isolation and Characterization of Antioxidant Phenolic Compounds from the Aerial Parts of Hypericum hyssopifolium L. by Activity-guided Fractionation. J Ethnopharmacol, 87(1), 73-83.
6. Chan TA, 2002: Nonsteroidal Anti-inflammatory Drugs, Apoptosis, and Colon-cancer Chemoprevention. Lancet Oncol, 3(3), 166-174.
7. Efferth T, Koch E, 2011: Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy. Current Drug Targets, 12(1), 122-132.
8. Ferguson A, Morris C, Curley J, 2011: Hypericum perforatum extracts and hypericin treatment of a mouse mammary cancer cell line induces growth inhibition in a dose dependent manner. J Exp Sec Sci, 3, 14-18.

9. Gupta S, Hastak K, Afaq F, Ahmad N, Mukhtar H, 2004: Essential Role of Caspases in Epigallocatechin-3-gallate-mediated Inhibition of Nuclear Factor KappaB and Induction of Apoptosis. Oncogene, 23(14), 2507-2522.
10. Henson PM, Bratton DL, 2013: Antiinflammatory Effects of Apoptotic Cells. J Clin Invest, 123(7), 2773-2774.
11. Izol V, Arıdoğan IA, Tansuğ Z, Doran F, Erdoğan KE, Kaplan HM, Şingirik E, Ertuğ P, Pazarci P, 2019: Hypericum perforatum Extract Against Oxidative Stress, Apoptosis and Oedema in Kidney Induced by Gentamicin. Int J Pharmacol, 15, 66-73.
12. Jakubikova J, Duraj J, Takacsova X, Hunakova L, Chorvath B, Sedlak J, 2001: Non-steroidal Anti-inflammatory Agent Ibuprofen-induced Apoptosis, Cell Necrosis and Cell Cycle Alterations in Human Leukemic Cells in vitro. Neoplasma, 48(3), 208-213.
13. Lu HP, Chie YJ, Yang MS, Lee CS, Fu JJ, Yang JS, Tan TW, Wu SH, Ma YS, Ip SW, Chung JG, 2010: Apigenin Induces Caspase-dependent Apoptosis in Human Lung Cancer A549 Cells Through Bax- and Bcl-2-triggered Mitochondrial Pathway. Int J Oncol, 36(6), 1477-1484.
14. Ma YQ, Ma ZH, Yin SQ, Yan X, Wang J, 2017: Arsenic and Fluoride Induce Apoptosis, Inflammation and Oxidative Stress in Cultured Human Umbilical Vein Endothelial Cells. Chemosphere, 167, 454-461.
15. Madunić IV, Madunić J, Antunović M, Paradžik M, Garaj-Vrhovac V, Breljak D, Marijanovic I, Gajski G, 2018: Apigenin, a dietary flavonoid, induces apoptosis, DNA damage, and oxidative stress in human breast cancer MCF-7 and MDA MB-231 cells. Naunyn-Schmiedebergs Arch Pharmacol, 391(5), 537-550.
16. Martarelli D, Martarelli B, Pediconi D, Nabissi MI, Perfumi M, Pompei P, 2004: Hypericum perforatum Methanolic Extract Inhibits Growth of Human Prostatic Carcinoma Cell Line Orthotopically Implanted in Nude Mice. Cancer Lett, 210(1), 27-33.
17. Merhi F, Tang R, Piedfer M, Mathieu J, Bombarda I, Zaher M, Kolb JP, Billard C, Bauvois B, 2011: Hyperforin Inhibits Akt1 Kinase Activity and Promotes Caspase-Mediated Apoptosis Involving Bad and Noxa Activation in Human Myeloid Tumor Cells. Plos One, 6(10), e25963.
18. Milosevic T, Solujic S, Sukdolak S, 2007: In vitro study of ethanolic extract of Hypericum perforatum L. on growth and sporulation of some bacteria and fungi. Turkish Journal of Biology, 31(4), 237-241.
19. Mirmalek SA, Azizi MA, Jangholi E, Damavandi SY, Javidi MA, Parsa Y, Tabatabaee SAS, Kolagar HG, Navaei RA, 2016: Cytotoxic and Apoptogenic Effect of Hypericin, The Bioactive Component of Hypericum perforatum on The MCF-7 Human Breast Cancer Cell Line. Cancer Cell Int, 16(3), 1-9.
20. Moore BC, Simmons DL, 2000: COX-2 Inhibition, Apoptosis, and Chemoprevention by Nonsteroidal Anti-inflammatory Drugs. Curr Med Chem, 7(11), 1131-1144.
21. Mosmann T, 1983: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 65, 55-63.
22. Oliveira AI, Pinho C, Sarmento B, Dias AC, 2016: Neuroprotective activity of Hypericum perforatum and its major components. Front Plant Sci, 7, 1004.
23. Pia Schiavone BI, Verotta L, Rosato A, Marilena M, Gibbons S, Bombardelli E, Franchini C, Corbo F, 2014: Anticancer and antibacterial activity of hyperforin and its derivatives. Anticancer Agents Med Chem, 14(10), 1397-1401.
24. Power EJ, Chin ML, Haq MM, 2018: Breast Cancer Incidence and Risk Reduction in The Hispanic Population. Cureus, 10(2), e2235.
25. Shiverick KT, Nseyo OU, Medrano TA, Mejia MC, Stavropoulos N, Tsimaris I, Skalkos D, 2008: The Dual Effects of Polar Methanolic Extract of Hypericum perforatum L in Human Bladder Cancer Cells. J Urol , 179(4), 371.
26. Sivalingam S, Tharmarajah L, 2018: Complementary and Alternative Therapies for Breast Cancer Worldwide. Lett Health Biol Sci, 3(2), 27-32.
27. Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A, 2018: Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines, 5(3), 93-109.
28. Tutun H, Özmen Ö, Aktaş I, Yalçınn A, Türk A, 2019: Investigation of the effects of artemisinin on testis and kidney injury induced by doxorubicin. Acta Veterinaria-Beograd, 69(2), 177-191.
29. WCRF, 2018: Word Cancer Research Fund: Breast cancer statistics. Breast Cancer is The Most Common Cancer in Women Worldwide. https://www.wcrf.org/dietandcancer/ cancer-trends/breast-cancer-statistics, Erişim tarihi; 12.11.2018.
30. van Kempen LCL, de Visser KE, Coussens LM, 2006: Inflammation, Proteases and Cancer. Eur J Cancer, 42(6), 728-734.
31. Yarla NS, Satyakumar K, Srinivasu D, Dsvgk KAG, Dharmapuri G, Putta GRSS, Jagarlapoodi S, Bheeram V, Sadu SP, Duddukuri GR, 2015: Phospholipase A2: a potential therapeutic target in inflammation and cancer (In silico, In vitro, In vivo and clinical approach). J Cancer Sci Ther, 7(7), 249-252.
32. You MK, Kim HJ, Kook J, Kim HA, 2018: St. John’s wort regulates proliferation and apoptosis in MCF-7 human breast cancer cells by inhibiting AMPK/mTOR and activating the mitochondrial pathway. Int J Mol Sci, 19(4), 966.
33. Zaher M, Tang R, Bombarda I, Merhi F, Bauvois B, Billard C, 2012: Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa. Int J Oncol, 40(1), 269-276.