Journal of Breast Cancer

Korean Breast Cancer Society (한국유방암학회)
권호 표지
DOI QR코드

DOI QR Code

Silibinin Enhances Ultraviolet B-Induced Apoptosis in MCF-7 Human Breast Cancer Cells

  • Noh, Eun-Mi (Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School) ;
  • Yi, Mi-Suk (Division of Breast.Thyroid Surgery, Department of Surgery, Chonbuk National University Medical School) ;
  • Youn, Hyun-Jo (Division of Breast.Thyroid Surgery, Department of Surgery, Chonbuk National University Medical School) ;
  • Lee, Byoung-Kil (Division of Breast.Thyroid Surgery, Department of Surgery, Chonbuk National University Medical School) ;
  • Lee, Young-Rae (Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School) ;
  • Han, Ji-Hey (Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School) ;
  • Yu, Hong-Nu (Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School) ;
  • Kim, Jong-Suk (Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School) ;
  • Jung, Sung-Hoo (Division of Breast.Thyroid Surgery, Department of Surgery, Chonbuk National University Medical School)
  • Published : 2011.03.31
⟨ Previous Next ⟩

Abstract

Purpose: Chemotherapies for breast cancer generally have strong cellular cytotoxicity and severe side effects. Thus, significant emphasis has been placed on combinations of naturally occurring chemopreventive agents. Silibinin is a major bioactive flavonolignan extracted from milk thistle with chemopreventive activity in various organs including the skin, prostate, and breast. However, the mechanism underlying the inhibitory action of silibinin in breast cancer has not been completely elucidated. Therefore, we investigated the effect of silibinin in MCF-7 human breast cancer cells and determined whether silibinin enhances ultraviolet (UV) B-induced apoptosis. Methods: The effects of silibinin on MCF-7 cell viability were determined using the MTT assay. The effect of silibinin on PARP cleavage, as the hallmark of apoptotic cell death, and p53 protein expression in MCF-7 cells was analyzed using Western blot. The effect of silibinin on UVB-induced apoptosis in MCF-7 cells was analyzed by flow cytometry. Results: A dose- and time-dependent reduction in viability was observed in MCF-7 cells treated with silibinin. Silibinin strongly induced apoptotic cell death in MCF-7 cells, and induction of apoptosis was associated with increased p53 expression. Moreover, silibinin enhanced UVB- induced apoptosis in MCF-7 cells. Conclusion: Silibinin induced a loss of cell viability and apoptotic cell death in MCF-7 cells. Furthermore, the combination of silibinin and UVB resulted in an additive effect on apoptosis in MCF-7 cells. These results suggest that silibinin might be an important supplemental agent for treating patients with breast cancer.

Keywords

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-49. https://doi.org/10.3322/caac.20006
  2. Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS. Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochem Biophys Res Commun 2007;354:165-71. https://doi.org/10.1016/j.bbrc.2006.12.181
  3. Tyagi AK, Agarwal C, Chan DC, Agarwal R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB 468 cells. Oncol Rep 2004;11:493-9.
  4. Li L, Gao Y, Zhang L, Zeng J, He D, Sun Y. Silibinin inhibits cell growth and induces apoptosis by caspase activation, down-regulating survivin and blocking EGFR-ERK activation in renal cell carcinoma. Cancer Lett 2008;272:61-9. https://doi.org/10.1016/j.canlet.2008.06.033
  5. Kaur M, Agarwal R. Silymarin and epithelial cancer chemoprevention: how close we are to bedside? Toxicol Appl Pharmacol 2007;224:350-9. https://doi.org/10.1016/j.taap.2006.11.011
  6. Singh RP, Agarwal R. Prostate cancer chemoprevention by silibinin: bench to bedside. Mol Carcinog 2006;45:436-42. https://doi.org/10.1002/mc.20223
  7. Wellington K, Jarvis B. Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs 2001;15:465-89. https://doi.org/10.2165/00063030-200115070-00005
  8. Singh RP, Dhanalakshmi S, Tyagi AK, Chan DC, Agarwal C, Agarwal R. Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res 2002;62:3063-9.
  9. Katiyar SK, Korman NJ, Mukhtar H, Agarwal R. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 1997;89:556-66. https://doi.org/10.1093/jnci/89.8.556
  10. Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 2002;101:461-8. https://doi.org/10.1002/ijc.10625
  11. Flaig T, Agarwal R, Su L, Harrison GS, Gustafson DL, Glode LM. A phase I study of silibinin in hormone refractory prostate cancer. 2005 ASCO Annual Meeting. 2005;23. Abstract #4698.
  12. Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Kim JS, et al. Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells. Phytomedicine 2009;16:573-80. https://doi.org/10.1016/j.phymed.2008.11.006
  13. Yarosh DB, Boumakis S, Brown AB, Canning MT, Galvin JW, Both DM, et al. Measurement of UVB-induced DNA damage and its consequences in models of immunosuppression. Methods 2002;28:55-62. https://doi.org/10.1016/S1046-2023(02)00209-8
  14. Kulms D, Schwarz T. Molecular mechanisms of UV-induced apoptosis. Photodermatol Photoimmunol Photomed 2000;16:195-201. https://doi.org/10.1034/j.1600-0781.2000.160501.x
  15. John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study, 1971-1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 1999;8:399-406.
  16. Ferguson HA, Marietta PM, Van Den Berg CL. UV-induced apoptosis is mediated independent of caspase-9 in MCF-7 cells: a model for cytochrome c resistance. J Biol Chem 2003;278:45793-800. https://doi.org/10.1074/jbc.M307979200
  17. Dhanalakshmi S, Mallikarjuna GU, Singh RP, Agarwal R. Dual efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in HaCaT human immortalized keratinocytes. Carcinogenesis 2004;25:99-106.
  18. Vogel G, Trost W, Braatz R, Odenthal KP, Brüsewitz G, Antweiler H, et al. Pharmacodynamics, site and mechanism of action of silymarin, the antihepatoxic principle from Silybum mar. (L) Gaertn. 1. Acute toxicology or tolerance, general and specific (liver-) pharmacology. Arzneimittelforschung 1975;25:82-9.
  19. Mereish KA, Bunner DL, Ragland DR, Creasia DA. Protection against microcystin-LR-induced hepatotoxicity by Silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991;8:273-7. https://doi.org/10.1023/A:1015868809990
  20. Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol Cancer Ther 2005;4:207-16. https://doi.org/10.4161/cbt.4.2.1442
  21. Bhatia N, Zhao J, Wolf DM, Agarwal R. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 1999;147:77-84. https://doi.org/10.1016/S0304-3835(99)00276-1
  22. Ellis RE, Yuan JY, Horvitz HR. Mechanisms and functions of cell death. Annu Rev Cell Biol 1991;7:663-98. https://doi.org/10.1146/annurev.cb.07.110191.003311
  23. Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science 1993;262:695-700. https://doi.org/10.1126/science.8235590
  24. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000;21:485-95. https://doi.org/10.1093/carcin/21.3.485
  25. Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene can act as a suppressor of transformation. Cell 1989;57:1083-93. https://doi.org/10.1016/0092-8674(89)90045-7
  26. Dhanalakshmi S, Agarwal C, Singh RP, Agarwal R. Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. J Biol Chem 2005;280:20375-83. https://doi.org/10.1074/jbc.M414640200
  27. Gu M, Dhanalakshmi S, Mohan S, Singh RP, Agarwal R. Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signaling, and associated biological responses in SKH-1 mouse skin. Carcinogenesis 2005;26:1404-13. https://doi.org/10.1093/carcin/bgi096
  28. Tonks NK, Myers MP. Structural assets of a tumor suppressor. Science 1999;286:2096-7. https://doi.org/10.1126/science.286.5447.2096
  29. Mohan S, Dhanalakshmi S, Mallikarjuna GU, Singh RP, Agarwal R. Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun 2004;320:183-9. https://doi.org/10.1016/j.bbrc.2004.05.153

Cited by

  1. A Triterpenoid from Thalictrum fortunei Induces Apoptosis in BEL-7402 Cells Through the P53-Induced Apoptosis Pathway vol.16, pp.11, 2011, https://doi.org/10.3390/molecules16119505
  2. P53 activation plays a crucial role in silibinin induced ROS generation via PUMA and JNK vol.46, pp.3, 2011, https://doi.org/10.3109/10715762.2012.655244
  3. Silibinin inhibits VEGF secretion and age-related macular degeneration in a hypoxia-dependent manner through the PI-3 kinase/Akt/mTOR pathway : Silibinin inhibits retinal neovascularization vol.168, pp.4, 2013, https://doi.org/10.1111/j.1476-5381.2012.02227.x
  4. Molecular Mechanisms of Silibinin-Mediated Cancer Chemoprevention with Major Emphasis on Prostate Cancer vol.15, pp.3, 2011, https://doi.org/10.1208/s12248-013-9486-2
  5. Silibinin Inhibits Tumor Growth through Downregulation of Extracellular Signal-Regulated Kinase and Akt in Vitro and in Vivo in Human Ovarian Cancer Cells vol.61, pp.17, 2013, https://doi.org/10.1021/jf400192v
  6. Silibinin induced the apoptosis of Hep-2 cells via oxidative stress and down-regulating survivin expression vol.270, pp.8, 2013, https://doi.org/10.1007/s00405-013-2444-x
  7. Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways vol.16, pp.5, 2011, https://doi.org/10.7314/apjcp.2015.16.5.2087
  8. Silibinin affects tumor cell growth because of reduction of stemness properties and induction of apoptosis in 2D and 3D models of MDA-MB-468 vol.26, pp.5, 2015, https://doi.org/10.1097/cad.0000000000000205
  9. Beneficial effects of the naturally occurring flavonoid silibinin on the prostate cancer microenvironment: role of monocyte chemotactic protein-1 and immune cell recruitment vol.37, pp.6, 2011, https://doi.org/10.1093/carcin/bgw039
  10. Effect of silibinin-loaded nano-niosomal coated with trimethyl chitosan on miRNAs expression in 2D and 3D models of T47D breast cancer cell line vol.46, pp.3, 2018, https://doi.org/10.1080/21691401.2017.1326928
  11. Functional Role of p53 in the Regulation of Chemical-Induced Oxidative Stress vol.2020, pp.None, 2011, https://doi.org/10.1155/2020/6039769
  12. Path of Silibinin from diet to medicine: A dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance vol.73, pp.None, 2011, https://doi.org/10.1016/j.semcancer.2020.09.014