Thymoquinone induces apoptosis via targeting the Bax/BAD and Bcl-2 pathway in breast cancer cells

Yıl 2019, Cilt: 46 Sayı: 3, 411 - 417, 16.09.2019

İbrahim Halil Yıldırım Ali Ahmed Azzawri Tuğçe Duran

https://doi.org/10.5798/dicletip.620329

Cited By: 4

Öz

Objective: Nigella sativa, commonly known as the black seed, has been used since ancient times in folk medicine, and its various therapeutic benefits have been mentioned in some ancient medical sources and confirmed by modern science. Thymoquinone is the major compound and essential active ingredient of Nigella sativa seed oil. Thymoquinone has been reported to have high biological activity and broad therapeutic potential through several mechanisms that affect cells including anti-oxidant, anti-inflammatory, and anti-tumor properties. Although it has been widely reported that Thymoquinone inhibits cell growth and proliferation and stimulates apoptosis in various types of cancer cells, the mechanisms and signaling pathways are not fully understood. The aim of this study was to determine the effect of Thymoquinone on apoptosis in both tumor and non-tumor cells. 

Methods: In this study, breast cancer cell line (MCF-7) was used as tumor cells and Human Embryonic Kidney Cell line (HEK293) was used as non-tumor cells. Cells were treated with Thymoquinone and viability test performed by MTT assay.Gene expression of apoptosis markers such as Bax, BAD, Bcl-2, and p53 was determined by Real-Time PCR. HEK293 cells were used as non-tumor control.  

Results and Conclusion: Results suggest that Thymoquinone has a strong effect on cell proliferation and vitality. Thymoquinone has increased the expression of BAD, Bax genes which induce apoptosis and decreased the p53 gene in breast cancer cells. Therefore Thymoquinone promotes apoptosis and enhances anti-cancer efficacy in breast cancer cells. 

Anahtar Kelimeler

Thymoquinone, breast cancer

Kaynakça

• 1. Yeo B, Turner NC, Jones A. An update on the medical management of breast cancer. BMJ 2014; 348: g3608.
• 2. Becker S. A historic and scientific review of breast cancer: The next global healthcare challenge. Int J Gynecol Obstet. 2015; 131: 36-9.
• 3. Beresford MJ, Wilson GD, Makris A. Measuring proliferation in breast cancer: practicalities and applications. Breast Cancer Res. 2006; 8: 216.
• 4. Chen MC, Lee NH, Hsu HH, et all. Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38. J. Agric. Food Chem. 2015; 63: 1540-6.
• 5. Gali-Muhtasib HU, Abou Kheir WG, Kheir LA, Darwiche N, Crooks PA. Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes. Anticancer Drugs, 2004; 15: 389-99.
• 6. Banerjee S, Padhye S, Azmi A, et all. Review on molecular and therapeutic potential of thymoquinone in cancer. Nutr Cancer. 2010; 62: 938-46.
• 7. Burits M, Bucar F. Antioxidant activity of Nigella sativa essential oil. Phytother Res. 2000; 14: 323-8.
• 8. Ali B, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 2003; 17: 299-305.
• 9. Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol. 2003; 26: 87-98.
• 10. El Gazzar M, El Mezayen R, Marecki JC, et all. Anti-inflammatory effect of thymoquinone in a mouse model of allergic lung inflammation. Int Immunopharmacol. 2006; 6: 1135-42.
• 11. Worthen DR, Ghosheh OA, Crooks PA. The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L. Anticancer Res. 1998; 18: 1527–32.
• 12. Jafri SH, Glass J, Shi R, et all. Thymoquinone and cisplatin as a therapeutic combination in lung cancer: in vitro and in vivo. J Exp Clin Cancer Res. 2010; 29: 87.
• 13. Li F, Rajendran P, Sethi G. Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br J Pharmacol. 2010; 161: 541–54.
• 14. El-Mahdy MA, Zhu Q, Wang QE, Wani G, Wani AA. Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myoloblastic leukemia HL-60 cells. Int J Cancer. 2005; 117: 409-17.
• 15. Gali-Muhtasib H, Diab-Assaf M, Boltze C, et all. Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Onco. 2004; 25: 857-66.
• 16. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001; 2: 533-43.
• 17. Demain AL, Vaishnav P. Natural products for cancer chemotherapy. Microb Biotechnol. 2011; 4: 687-99.
• 18. Hata AN, Engelman JA, Faber AC. The BCL-2 family: key mediators of the apoptotic response to targeted anti-cancer therapeutics. Cancer Discov. 2015; 5: 475-87.
• 19. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995; 80: 285–91
• 20. Scheid MP, Schubert KM, Duronio V. Regulation of Bad Phosphorylation and Association with Bcl-xL by the MAPK/Erk Kinase. The Journal of Biological Chemistry. 1999; 274: 31108-13.
• 21. Kocak N, Yildirim IH, Yildirim Cing S, Cellular functions of p53 and p53 gene family members p63 and p73, Dicle Medical Journal, 2011; 38: 530-35.
• 22. Marjaneh M, Narazah MY, Shahrul H. Apoptosis pathway targeted by thymoquinone in MCF7 breast cancer cell line. International Scholarly and Scientific Research & Innovation 2015; 9: 87-91.
• 23. Arafa ESA, Zhu Q, Shah ZI, et all.,Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutat. Res. 2011; 706: 128–35.
• 24. Woo CC, Hsu A, Kumar AP, Sethi G, Tan KH. Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS. PLoS One. 2013 Oct 2; 8: e75356. doi: 10.1371/journal.pone.0075356. eCollection 2013.
• 25. Shanmugam MK, Ahn KS, Hsu A, et all., Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis. Front Pharmacol. 2018 Dec 4; 9: 1294. doi: 10.3389/fphar.2018.01294
• 26. Mostofa AGM, Hossain MK, Basak D, Bin Sayeed MS. Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies. Front Pharmacol. 2017 Jun 12; 8: 295. doi: 10.3389/fphar.2017.00295. eCollection 2017.
• 27. Kabel AM, El-Rashidy MA, Omar MS (2016) Ameliorative Potential of Tamoxifen/Thymoquinone Combination in Patients with Breast Cancer: A Biochemical and Immunohistochemical Study. Cancer Med Anticancer Drug 1:102. doi:10.4172/cmacd.1000102
• 28. Bashmail HA, Alamoudi AA, Noorwali A, et all., Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities. Scientific Reports 2018; volume 8, Article number: 11674.
• 29. Alobaedi OH, Talib WH, Basheti IA. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pasific Journal of Tropical Medicine 2017; 10: 400-8.