Milk Thistle (Silybum Marianum) as a Supportive Phytotherapeutic Agent in Oncology

Česká verzia

Authors: Z. Frassová; J. Rudá-Kučerová
Authors place of work: Farmakologický ústav, LF MU, Brno
Published in the journal: Klin Onkol 2017; 30(6): 426-432
Category: Přehled
doi: https://doi.org/10.14735/amko2017426

Summary

Background:
Milk thistle (Silybum marianum) has been traditionally used in medicine, particularly in the treatment of liver diseases. Today, it is used for the same purpose in evidence-based medicine (EBM). Its main active ingredient is a complex of flavonolignans, known as silymarin. Silymarin is used as a hepatoprotective agent, but its potential therapeutic use in oncology patients has drawn attention only recently.

Purpose:
The aim of this review is to provide comprehensive information on the potential therapeutic effects of milk thistle in oncology patients and potential indications for its use as a supportive therapy either as an anticarcinogenic agent or as an agent that attenuates the side effects of oncological treatments. Evidence of its effects and its safety, and possible interactions with other cancer treatments are emphasized. Available findings are supported mainly by in vitro studies and the results of animal research, but the number of clinical trials in oncology patients is increasing. Based on the results of these studies, milk thistle or silymarin could be beneficial in oncology patients, especially for the treatment of the side effects of anticancer chemotherapeutics. Evidence from clinical studies shows that it has mainly beneficial effects in hepatotoxicity and radiotherapy-induced skin and mucosa damage at dosages of 160–600 mg daily.

Key words:
phytotherapy – drug-herb interactions – cancer – adverse effects – milk thistle – Silybum marianum

This publication was written at Masaryk University as part of the project „Experimental and translational pharmacological research and development“, number MUNI/A/1063/2016 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2017.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
4. 6. 2017

Accepted:
18. 9. 2017

Zdroje

1. Comelli MC, Mengs U, Schneider C et al. Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy. Integr. Cancer Ther 2007; 6 (2): 120–129. doi: 10.1177/1534735407302349.

2. Veprikova Z, Zachariasova M, Dzuman Z et al. Mycotoxins in Plant-Based Dietary Supplements: Hidden Health Risk for Consumers. J Agric Food Chem 2015; 63 (29): 6633–6643. doi: 10.1021/acs.jafc.5b02105.

3. ADC. sk. FLAVOBION tbl flm 70 mg (liek.skl.hnedá) 1x50 ks. [online] Dostupné na: https: //www.adc.sk/databazy/produkty/spc/flavobion-565959.html.

4. SÚKL. cz. LEGALON SIL 350MG INJ PLV SOL 4. [online]. Dostupné na: http: //www.sukl.cz/modules/medication/detail.php?code=0014380&tab=info.

5. European Medicines Agency – Science medicines health. EU/3/10/828 [online]. Dostupné na: http: //www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2011/01/human_orphan_000877.jsp&mid=WC0b01ac058001d12b.

6. Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integr Cancer Ther 2007; 6 (2): 104–109. doi: 10.1177/1534735407301632.

7. Barzaghi N, Crema F, Gatti G et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990; 15 (4): 333–338.

8. Mastron JK, Siveen KS, Sethi G et al. Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review. Anticancer. Drugs 2015; 26 (5): 475–486. doi: 10.1097/CAD.0000000000000211.

9. Ramakrishnan G, Elinos-Báez CM, Jagan S et al. Silymarin downregulates COX-2 expression and attenuates hyperlipidemia during NDEA-induced rat hepatocellular carcinoma. Mol Cell Biochem 2008; 313 (1–2): 53–61. doi: 10.1007/s11010-008-9741-5.

10. Ramakrishnan G, Jagan S, Kamaraj S et al. Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis. Invest New Drugs 2009; 27 (3): 233–240. doi: 10.1007/s10637-008-9163-y.

11. Imamoto R, Okano JI, Sawada S et al. Null anticarcinogenic effect of silymarin on diethylnitrosamine-induced hepatocarcinogenesis in rats. Exp Ther Med 2014; 7 (1): 31–38. doi: 10.3892/etm.2013.1391.

12. Brandon-Warner E, Eheim AL, Foureau DM et al. Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice. Cancer Lett 2012; 326 (1): 88–95. doi: 10.1016/j.canlet.2012.07.028.

13. Wu YF, Fu SL, Kao CH et al. Chemopreventive Effect of Silymarin on Liver Pathology in HBV X Protein Transgenic Mice. Cancer Res 2008; 68 (6): 2033–2042. doi: 10.1158/0008-5472.CAN-07-2450.

14. Hogan FS, Krishnegowda NK, Mikhailova M et al. Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res 2007; 143 (1): 58–65. doi: 10.1016/j.jss.2007.03.080.

15. Eo HJ, Park GH, Song HM et al. Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol 2015; 24 (1): 1–6. doi: 10.1016/j.intimp.2014.11.009.

16. Kauntz H, Bousserouel S, Gossé F et al. Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells. Apoptosis 2011; 16 (10): 1042–1053. doi: 10.1007/s10495-011-0631-z.

17. Kauntz H, Bousserouel S, Gossé F et al. The flavonolignan silibinin potentiates TRAIL-induced apoptosis in human colon adenocarcinoma and in derived TRAIL-resistant metastatic cells. Apoptosis 2012; 17 (8): 797–809. doi: 10.1007/s10495-012-0731-4.

18. Kauntz H, Bousserouel S, Gosse F et al. Silibinin, a natural flavonoid, modulates the early expression of chemoprevention biomarkers in a preclinical model of colon carcinogenesis. Int J Oncol 2012; 41 (3): 849–854. doi: 10.3892/ijo.2012.1526.

19. Kohno H, Tanaka T, Kawabata K et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 2002; 101 (5): 461–468. doi: 10.1002/ijc.10625.

20. Kaur G, Athar M, Alam MS. Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response. Invest New Drugs 2010; 28 (5): 703–713. doi: 10.1007/s10637-009-9289-6.

21. Lee SO, Jeong YJ, Im HG et al. Silibinin suppresses PMAinduced 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 (1): 165–171. doi: 10.1016/j.bbrc.2006.12.181.

22. Kim S, Choi JH, Lim HI 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 (6–7): 573–580. doi: 10.1016/j.phymed.2008.11.006.

23. Kim S, Han J, Kim JS et al. Silibinin suppresses EGFR ligand-induced CD44 expression through inhibition of EGFR activity in breast cancer cells. Anticancer Res 2011; 31 (11): 3767–3773.

24. Bayram D, Çetin ES, Kara M et al. The apoptotic effects of silibinin on MDA-MB-231 and MCF-7 human breast carcinoma cells. Hum Exp Toxicol 2016; 36 (6): 573–586. doi: 10.1177/0960327116658105.

25. Molavi O, Narimani F, Asiaee F et al. Silibinin sensitizes chemo-resistant breast cancer cells to chemotherapy. Pharm Biol 2017; 55 (1): 729–739. doi: 10.1080/13880209.2016.1270972.

26. Malewicz B, Wang Z, Jiang C et al. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis 2006; 27 (9): 1739–1747. doi: 10.1093/carcin/bgl032.

27. Dong XY, Lang TQ, Yin Q et al. Co-delivery of docetaxel and silibinin using pH-sensitive micelles improves therapy of metastatic breast cancer. Acta Pharmacol Sin 2017. doi: 10.1038/aps.2017.74.

28. Kil WH, Kim SM, Lee JE et al. Anticancer effect of silibinin on the xenograft model using MDA-MB-468 breast cancer cells. Ann Surg Treat Res 2014; 87 (4): 167–173. doi: 10.4174/astr.2014.87.4.167.

29. Thelen P, Jarry H, Ringert RH et al. Silibinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer cells. Planta Med 2004; 70 (5): 397–400. doi: 10.1055/s-2004-818965.

30. Jung HJ, Park JW, Lee JS et al. Silibinin inhibits expression of HIF-1alpha through suppression of protein translation in prostate cancer cells. Biochem Biophys Res Commun 2009; 390 (1): 71–76. doi: 10.1016/j.bbrc.2009.09.068.

31. Cufí S, Bonavia R, Vazquez-Martin A et al. Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food Chem Toxicol 2013; 60: 360–368. doi: 10.1016/j.fct.2013.07.063.

32. Singh T, Prasad R, Katiyar SK. Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression. Am J Cancer Res 2016; 6 (6): 1287–1301.

33. Li W, Mu D, Song L et al. Molecular mechanism of silymarin-induced apoptosis in a highly metastatic lung cancer cell line anip973. Cancer Biother Radiopharm 2011; 26 (3): 317–324. doi: 10.1089/cbr.2010.0892.

34. Son YG, Kim EH, Kim JY et al. Silibinin sensitizes human glioma cells to TRAIL-mediated apoptosis via DR5 up-regulation and down-regulation of c-FLIP and survivin. Cancer Res 2007; 67 (17): 8274–8284. doi: 10.1158/0008-5472.CAN-07-0407.

35. Gándara L, Sandes E, Di Venosa G et al. The natural flavonoid silybin improves the response to Photodynamic Therapy of bladder cancer cells. J Photochem Photobiol B 2014; 133: 55–64. doi: 10.1016/j.jphotobiol.2014.03.006.

36. Svobodová A, Zdarilová A, Walterová D et al. Flavonolignans from Silybum marianum moderate UVA-induced oxidative damage to HaCaT keratinocytes. J Dermatol Sci 2007; 48 (3): 213–224. doi: 10.1016/j.jdermsci.2007.06.008.

37. Katiyar SK. Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin. Int J Oncol 2002; 21 (6): 1213–1222.

38. Feng N, Luo J, Guo X. Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway. Mol Med Rep 2016; 13 (4): 3243–3248. doi: 10.3892/mmr.2016.4887.

39. Faezizadeh Z, Mesbah-Namin SA, Allameh A. The effect of silymarin on telomerase activity in the human leukemia cell line K562. Planta Med 2012; 78 (9): 899–902. doi: 10.1055/s-0031-1298464.

40. Siegel AB, Narayan R, Rodriguez R et al. A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma. Integr Cancer Ther 2014; 13 (1): 46–53. doi: 10.1177/1534735413490798.

41. Hoh C, Boocock D, Marczylo T et al. Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences. Clin Cancer Res 2006; 12 (9): 2944–2950. doi: 10.1158/1078-0432.CCR-05-2724.

42. Lazzeroni M, Guerrieri-Gonzaga A, Gandini S et al. A Presurgical Study of Oral Silybin-Phosphatidylcholine in Patients with Early Breast Cancer. Cancer Prev Res Phila Pa 2016; 9 (1): 89–95. doi: 10.1158/1940-6207.CAPR-15-0123.

43. Flaig TW, Gustafson DL, Su LJ et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs 2007; 25 (2): 139–146. doi: 10.1007/s10637-006-9019-2.

44. Flaig TW, Glodé M, Gustafson D et al. A study of highdose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 2010; 70 (8): 848–855. doi: 10.1002/pros.21118.

45. Grossmann M, Hoermann R, Weiss M et al. Spontaneous regression of hepatocellular carcinoma. Am J Gastroenterol 1995; 90 (9): 1500–1503.

46. Moroni M, Zanlorenzi L. Complete regression following sorafenib in unresectable, locally advanced hepatocellular carcinoma. Future Oncol 2013; 9 (8): 1231–1237. doi: 10.2217/fon.13.86.

47. Bosch-Barrera J, Corominas-Faja B, Cuyàs E et al. Silibinin administration improves hepatic failure due to extensive liver infiltration in a breast cancer patient. Anticancer Res 2014; 34 (8): 4323–4327.

48. Ladas EJ, Kroll DJ, Oberlies NH et al. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Cancer 2010; 116 (2): 506–513. doi: 10.1002/cncr.24723.

49. Psotová J, Chlopcíková S, Grambal F et al. Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res 2002; 16 (Suppl 1): S63–S67.

50. Shahbazi F, Sadighi S, Dashti-Khavidaki S et al. Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res 2015; 29 (7): 1046–1053. doi: 10.1002/ptr.5345.

51. Tiwari P, Kumar A, Ali M et al. Radioprotection of plasmid and cellular DNA and Swiss mice by silibinin. Mutat Res 2010; 695 (1–2): 55–60. doi: 10.1016/j.mrgentox.2009.11.007.

52. Son Y, Lee HJ, Rho JK et al. The ameliorative effect of silibinin against radiation-induced lung injury: protection of normal tissue without decreasing therapeutic efficacy in lung cancer. BMC Pulm Med 2015; 15: 68. doi: 10.1186/s12890-015-0055-6.

53. Elyasi S, Hosseini S, Niazi Moghadam MR et al. Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res 2016; 30 (11): 1879–1885. doi: 10.1002/ptr.5704.

54. Yasueda A, Urushima H, Ito T. Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment: A Systematic Review. Integr Cancer Ther 2016; 15 (1): 17–39. doi: 10.1177/1534735415610 427.

55. Becker-Schiebe M, Mengs U, Schaefer M et al. Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients. Strahlenther Onkol 2011; 187 (8): 485–491. doi: 10.1007/s00066-011-2204-z.

56. van Erp NP, Baker SD, Zhao M et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 2005; 11 (21): 7800–7806. doi: 10.1158/1078-0432.CCR-05-1288.

57. Ben-Arye E, Samuels N, Goldstein LH et al. Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals. Cancer 2016; 122 (4): 598–610. doi: 10.1002/cncr.29 796.

58. Gufford BT, Chen G, Vergara AG et al. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction. Drug Metab Dispos 2015; 43 (9): 1353–1359. doi: 10.1124/dmd.115.065086.