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Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways

  • Pirouzpanah, Mohammad Bagher (International Branch of Tabriz University of Medical Sciences (Aras)) ;
  • Sabzichi, Mehdi (Drug Applied Research Center, Tabriz University of Medical Sciences) ;
  • Pirouzpanah, Saeed (Drug Applied Research Center, Tabriz University of Medical Sciences) ;
  • Chavoshi, Hadi (Drug Applied Research Center, Tabriz University of Medical Sciences) ;
  • Samadi, Nasser (Drug Applied Research Center, Tabriz University of Medical Sciences)
  • Published : 2015.03.18

Abstract

Nowadays herbal-derived medicines are attracting attention as new sources of drugs with few side effects. Silibinin is a flavonoid compound with chemotheraputic effects on different cancers such as examples in the prostate, lung, colon and breast. In the present study, the cytotoxic effects of silibinin on MCF7 breast cancer cells were investigated. Apoptosis was determined by flow cytometry and the impact of silibinin on the expression of pivotal genes including Bak, P53, P21, BRCA1, BCL-X1 and ATM was analyzed. Treatment for 24h had a significant dose-dependent inhibitory effect on cell growth (p<0.05) with dose- and time- dependent induction of apoptosis (p<0.05). In addition, there were significant increases in BRCA1, ATM, Bak and Bcl-XL gene expression at the mRNA level with different concentrations of silibinin for 24 or 48 h (p<0.05). Taken together, the results suggest that silibinin inhibits the proliferation and induces apoptosis of MCF-7 cells by down-regulating Bak, P53, P21, BRCA1, BCL-Xl and thus may be considered as an effective adjuvant drug to produce a better chemopreventive response for the cancer therapy.

Keywords

Silibinin;MCF-7;cell-cycle arrest;apoptosis

Acknowledgement

Supported by : Tabriz University of Medical Sciences

References

  1. Akhtar R, Ali M, Mahmood S, et al (2014). Anti-proliferative action of silibinin on human colon adenomatous cancer HT-29 cells. Nutr Hosp, 29, 388-92.
  2. Alhazmi MI, Hasan TN, Shafi G, et al (2014). Roles of p53 and caspases in induction of apoptosis in MCF-7 breast cancer cells treated with a methanolic extract of Nigella sativa seeds. Asian Pac J Cancer Prev, 15, 9655-60. https://doi.org/10.7314/APJCP.2014.15.22.9655
  3. Cecen E, Dost T, Culhaci N, et al (2010). Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac J Cancer Prev, 12, 2697-704.
  4. Chhabra N, Kaur J, Singh R, et al (2013). Silibinin: A promising anti-neoplastic agent for the future? A critical reappraisal. Intern J Nutrition, Pharmacol Neurological Diseases, 3, 206. https://doi.org/10.4103/2231-0738.114836
  5. Dhanalakshmi S, Agarwal C, Singh RP, et al (2005). Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. J Biol Chem, 280, 20375-83. https://doi.org/10.1074/jbc.M414640200
  6. Fan S, Qi M, Yu Y, et al (2012). P53 activation plays a crucial role in silibinin induced ROS generation via PUMA and JNK. Free Radic Res, 46, 310-9. https://doi.org/10.3109/10715762.2012.655244
  7. Farooqi AA, Mansoor Q, Ismail M, et al (2010). Therapeutic effect of epigallocatechin-3-gallate (EGCG) and silibinin on ATM dynamics in prostate cancer cell line LNCaP. World J Oncol, 1, 242-6.
  8. Ghasemi R, Ghaffari SH, Momeny M, et al (2013). Multitargeting and antimetastatic potentials of silibinin in human HepG-2 and PLC/PRF/5 hepatoma cells. Nutr Cancer, 65, 590-9. https://doi.org/10.1080/01635581.2013.770043
  9. Gu M, Dhanalakshmi S, Mohan S, et al (2005). Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signaling, and associated biological responses in SKH-1 mouse skin. Carcinogenesis, 26, 1404-13. https://doi.org/10.1093/carcin/bgi096
  10. Hagelgans A, Nacke B, Zamaraeva M, et al (2014). Silibinin down-regulates expression of secreted phospholipase A2 enzymes in cancer cells. Anticancer Res, 34, 1723-9.
  11. Kauntz H, Bousserouel S, Gosse F, et al (2012). Silibinin, a natural flavonoid, modulates the early expression of chemoprevention biomarkers in a preclinical model of colon carcinogenesis. Int J Oncol, 41, 849-54.
  12. Kauntz H, Bousserouel S, Gosse F, et al (2011). Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells. Apoptosis, 16, 1042-53. https://doi.org/10.1007/s10495-011-0631-z
  13. Liu W, Otkur W, Zhang Y, et al (2013). Silibinin protects murine fibroblast L929 cells from UVB-induced apoptosis through the simultaneous inhibition of ATM-p53 pathway and autophagy. FEBS J, 280, 4572-84. https://doi.org/10.1111/febs.12426
  14. Mateen S, Raina K, Jain AK, et al (2012). Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics, 7, 1161-72. https://doi.org/10.4161/epi.22070
  15. Nasiri M, Zarghami N, Koshki KN, et al (2013). Curcumin and silibinin inhibit telomerase expression in T47D human breast cancer cells. Asian Pac J Cancer Prev, 14, 3449-53. https://doi.org/10.7314/APJCP.2013.14.6.3449
  16. Noh EM, Yi MS, Youn HJ, et al (2011). Silibinin enhances ultraviolet B-induced apoptosis in mcf-7 human breast cancer cells. J Breast Cancer, 14, 8-13. https://doi.org/10.4048/jbc.2011.14.1.8
  17. Ramos S (2008). Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res, 52, 507-26. https://doi.org/10.1002/mnfr.200700326
  18. Roy S, Deep G, Agarwal C, et al (2012). Silibinin prevents ultraviolet B radiation-induced epidermal damages in JB6 cells and mouse skin in a p53-GADD45alpha-dependent manner. Carcinogenesis, 33, 629-36. https://doi.org/10.1093/carcin/bgr299
  19. Roy S, Gu M, Ramasamy K, et al (2009). p21/Cip1 and p27/Kip1 Are essential molecular targets of inositol hexaphosphate for its antitumor efficacy against prostate cancer. Cancer Res, 69, 1166-73. https://doi.org/10.1158/0008-5472.CAN-08-3115
  20. Roy S, Kaur M, Agarwal C, et al (2007). p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells. Mol Cancer Ther, 6, 2696-707. https://doi.org/10.1158/1535-7163.MCT-07-0104
  21. Sabzichi M, Hamishehkar H, Ramezani F, et al (2014). Luteolinloaded phytosomes sensitize human breast carcinoma MDAMB 231 cells to doxorubicin by suppressing Nrf2 mediated signalling. Asian Pac J Cancer Prev, 15, 5311-6. https://doi.org/10.7314/APJCP.2014.15.13.5311
  22. Sharifi S, Barar J, Hejazi MS, et al (2014). Roles of the bcl-2/bax ratio, caspase-8 and 9 in resistance of breast cancer cells to Paclitaxel. Asian Pac J Cancer Prev, 15, 8617-22. https://doi.org/10.7314/APJCP.2014.15.20.8617
  23. Tyagi A, Singh RP, Agarwal C, et al (2006). Silibinin activates p53-caspase 2 pathway and causes caspase-mediated cleavage of Cip1/p21 in apoptosis induction in bladder transitional-cell papilloma RT4 cells: evidence for a regulatory loop between p53 and caspase 2. Carcinogenesis, 27, 2269-80. https://doi.org/10.1093/carcin/bgl098
  24. Wang Q, Liu W, Zeng H, et al (2013). p53-mediated autophagy adjustment is involved in the protection of silibinin against murine dermal inflammation and epidermal apoptosis induced by UVB irradiation. J Asian Nat Prod Res, 15, 117-29. https://doi.org/10.1080/10286020.2012.739616
  25. Wang Y-X, Cai H, Jiang G, et al (2014). Silibinin inhibits proliferation, induces apoptosis and causes cell cycle arrest in human gastric cancer MGC803 Cells Via STAT3 pathway inhibition. Asian Pac J Cancer Prev, 15, 6791-8. https://doi.org/10.7314/APJCP.2014.15.16.6791

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