Milk Thistle Silymarin Silybin for Cancer

Questions and Answers About Milk Thistle

    What is milk thistle?

    Milk thistle is a plant whose fruit and seeds have been used for more than 2,000 years as a treatment for disorders of the liver, bile ducts, and gallbladder. Milk thistle is native to Europe but can also be found in the United States and South America.

    The medicinal ingredient found in milk thistle is silymarin, an extract of milk thistle seeds. It is an antioxidant that protects against cell damage. Silymarin contains 4 compounds: silybin (the most active), isosilybin, silychristin, and silydianin. Most research has studied silymarin or its major compound silybin, instead of the plant in its whole form.

    The botanical name for milk thistle is Silybum marianum. Milk thistle is also called holy thistle, Marian thistle, Mary thistle, St. Mary thistle, Our Lady's thistle, wild artichoke, Mariendistel (German), and Chardon-Marie (French).

    What is the history of the discovery and use of milk thistle as a complementary and alternative treatment for cancer?

    The ancient Greeks and Romans used milk thistle as a treatment for liver ailments and snake bites. During the Middle Ages, milk thistle was recommended to treat liver toxins.  The German Commission E, which studies the safety and efficacy of herbs for the German government, recommends milk thistle for liver damage due to toxins, cirrhosis of the liver, and as a supportive therapy for chronic inflammation of the liver.

    Despite milk thistle's long history of use for liver complaints, it was not until 1968 that researchers extracted silymarin from milk thistle seeds and suggested that it might be the plant's active ingredient. Silymarin was later discovered to be a mixture of flavonolignans, a family of plant-based substances with antioxidant effects.






Milk Thistle Shows Promising Applications in Treating Liver Disease, Cancer


When the Romans prescribed milk thistle 2,000 years ago, they did so for a variety of health concerns, including serpent bites, melancholy, plague and milk production, in addition to “carrying off bile.”1,2    Now, the popularity of milk thistle is soaring, not only for treating chronic liver problems for which it is best known, but also for its ability to protect other organs from the damaging effects of radiation, chemotherapy, other xenobiotics and chronic disease.3   For example, its antioxidant actions decrease gentamicin-induced nephrotoxicity in dogs;4   milk thistle also promotes kidney function in patients with end-stage diabetic nephropathy.5 
  
What’s in It
Milk thistle extract,  the first substance extracted from the crushed seeds, contains up to 80 percent silymarin, the main active constituent.6  In contrast, the silymarin content of unprocessed seeds may fall as low as 4 percent silymarin.7   Some manufacturers standardize the silymarin content to ensure equivalence between batches. Silibinin (or silybin), a semi-purified fraction of silymarin, acts as an important marker for research to track pharmacokinetics and ensure adequate plasma and target tissue concentrations.8  Monitoring pharmacokinetics becomes especially important when studying phytomedicinals exhibiting poor or erratic bioavailability, as do the flavonolignans comprising silymarin.  Complexing silibinin with phophatidylcholine dramatically improves oral availability; manufacturers may also add vitamin E and zinc to further manage liver dysfunction--doing so does not attenuate bioavailability .9

Working for the Liver
The plant stimulates liver repair and detoxification through four main avenues: 
1. antioxidation, free radical scavenging and glutathione regulation; 
2. stabilization of cell membranes and permeability, which limits hepatotoxin entry into hepatocytes; 
3. ribosomal RNA synthesis promotion, stimulating liver regeneration; and 
4. slowing transformation of stellate hepatocytes into myofibroblasts, slowing the onset of cirrhosis arising through collagen deposition.10

New Applications for Cancer
The most salient new applications for milk thistle arise in its role as an adjunct for cancer chemoprevention, treatment and to reduce side effects of treatment.11,12    Specifically, silymarin has led to reductions in tumor incidence and the number of chemically-induced tumors in rat models for colon, tongue and bladder cancer. It has also held back the growth of human prostate cancer and lung cancer xenografts in mice bred as immunodeficient.13  Milk thistle derivatives protect the kidneys from radiation injury and cisplatin nephrotoxicity14,15    and may protect the heart from doxorubicin-induced lipid peroxidation. When combined with omega 3 fatty acids, milk thistle has reduced the number of radionecrosis sites in cancer patients and prolonged survival.16  Milk thistle potentiated antitumor effects of drugs like cisplatin in both in vivo and in vitro studies.17   



Adverse Effects
Milk thistle’s ability to promote liver regeneration you might think it could conceivably stimulate tumor growth in cases of hepatocellular carcinoma,22  but  studies showed that milk thistle demonstrated strong anticancer (pro-apoptotic and growth-inhibiting) activity against human hepatocellular carcinoma cells.23   

Overall, the majority of patients tolerate even high doses of milk thistle; as with most herbs, adverse effects typically involve mild gastrointestinal upset at initial dosing.  





    What is the theory behind the claim that milk thistle is useful in treating cancer?

    To research the claim that milk thistle is useful in treating cancer, its active substance silymarin and its major compound silybin have been the most widely studied ingredients.

    Silymarin and silybin may protect the liver against damage from toxic chemicals by blocking toxins from entering the cell or by moving toxins out of the cell before damage begins.

    Silymarin and silybin have been studied in the laboratory in cancer cells as well as in animal tumors of the tongue, skin, bladder, colon, and small intestine. They have been tested for their potential to:

        Make chemotherapy less toxic.
        Make chemotherapy more effective.
        Stop or slow the growth of cancer cells and block tumors from starting or continuing to grow.
        Help to repair liver tissue.

    In Europe, the active compound silybin is given by intravenous infusion as the only effective antidote for Amanita phalloides, a rare mushroom toxin that causes deadly liver failure.

    Most milk thistle supplements are measured by how much silybin they contain. 

    Have any preclinical (laboratory or animal) studies been conducted using milk thistle?

    Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be useful in humans. Preclinical studies are done before clinical trials (in humans) are begun.

    Silymarin, the active substance found in milk thistle seeds, has been studied in laboratory research. These studies have shown that it acts as an antioxidant by:

        Strengthening cell walls to prevent toxins from crossing into the cell.
        Stimulating enzymes that make toxins less harmful to the body.
        Blocking damaging substances called free radicals from attacking cells.

    Silybin, the major compound found in silymarin, has been studied in laboratory experiments using cancer cell lines (cells adapted to grow in the laboratory). These studies show that silybin:

        May help cisplatin and doxorubicin (chemotherapy drugs) work better against ovarian and breast cancer cells.
        May have direct anticancer effects against prostate, breast, and cervical cancer cells.
        May slow down cell growth, as shown in prostate cancer cell lines.

    In laboratory tests using rat livers, silymarin and silybin have also been found to boost the regrowth of liver tissue.

    Tests on colorectal cancer cells transplanted into mice found that silybin given twice a day decreased tumor growth.

    Have any clinical trials (research studies with people) of milk thistle been conducted?

    There is 1 case report describing the use of silymarin in a patient with promyelocytic leukemia who required breaks in chemotherapy due to abnormal liver enzyme levels. During 4 months of treatment with silymarin, the patient had normal liver enzyme levels and was able to undergo chemotherapy without breaks. A second case report describes a patient with hepatocellular carcinoma whose symptoms improved when he took 450 milligrams of silymarin per day, without anticancer therapy.

    A randomized clinical trial in children with acute lymphoblastic leukemia found that silymarin decreased the harmful effects of chemotherapy on the liver without working against the cancer treatment. The children taking silymarin needed fewer chemotherapy dose reductions because of side effects than the children who did not take milk thistle.

    A number of clinical trials have studied milk thistle or silymarin in the treatment of patients with hepatitis, cirrhosis, or disorders of the bile ducts.  In a trial of biologic therapy for patients with chronic hepatitis, patients taking silymarin had fewer symptoms and a better quality of life compared to patients not taking silymarin. 


References

1. PDR® for Herbal Medicines™. 2nd ed. Montvale, NJ: Medical Economics, 2000. 
2. Lee DY, Liu Y: Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle). J Nat Prod 66 (9): 1171-4, 2003.  [PUBMED Abstract]
3. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983.  [PUBMED Abstract]
4. Wagner H, Hörhammer L, Münster R: [On the chemistry of silymarin (silybin), the active principle of the fruits from Silybum marianum (L.) Gaertn. (Carduus marianus L.)] Arzneimittelforschung 18 (6): 688-96, 1968.  [PUBMED Abstract]
5. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989.  [PUBMED Abstract]
6. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000.  [PUBMED Abstract]
7. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990.  [PUBMED Abstract]
8. Zhao J, Agarwal R: Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20 (11): 2101-8, 1999.  [PUBMED Abstract]
9. Valenzuela A, Guerra R, Videla LA: Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med (6): 438-40, 1986.  [PUBMED Abstract]
10. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987.  [PUBMED Abstract]
11. Valenzuela A, Aspillaga M, Vial S, et al.: Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 55 (5): 420-2, 1989.  [PUBMED Abstract]
12. Mira ML, Azevedo MS, Manso C: The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 4 (2): 125-9, 1987.  [PUBMED Abstract]
13. Mira L, Silva M, Manso CF: Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48 (4): 753-9, 1994.  [PUBMED Abstract]
14. Koch HP, Löffler E: Influence of silymarin and some flavonoids on lipid peroxidation in human platelets. Methods Find Exp Clin Pharmacol 7 (1): 13-8, 1985.  [PUBMED Abstract]
15. Garrido A, Arancibia C, Campos R, et al.: Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin. Pharmacol Toxicol 69 (1): 9-12, 1991.  [PUBMED Abstract]
16. Bosisio E, Benelli C, Pirola O: Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 25 (2): 147-54, 1992 Feb-Mar.  [PUBMED Abstract]
17. Altorjay I, Dalmi L, Sári B, et al.: The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung 80 (1-4): 375-80, 1992.  [PUBMED Abstract]
18. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996.  [PUBMED Abstract]
19. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999.  [PUBMED Abstract]
20. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999.  [PUBMED Abstract]
21. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997.  [PUBMED Abstract]
22. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993. 
23. Salmi HA, Sarna S: Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17 (4): 517-21, 1982.  [PUBMED Abstract]
24. Parés A, Planas R, Torres M, et al.: Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28 (4): 615-21, 1998.  [PUBMED Abstract]
25. Moscarella S, Giusti A, Marra F, et al.: Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholine complex in chronic liver disease: preliminary results. Current Therapeutic Research 53 (1): 98-102. 
26. Marena C, Lampertico M: Preliminary clinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med 57 (Suppl 2): A124-5, 1991. 
27. Marcelli R, Bizzoni P, Conte D, et al.: Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. European Bulletin of Drug Research 1 (3): 131-5, 1992. 
28. Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct.  [PUBMED Abstract]
29. Ferenci P: [Therapy of chronic hepatitis C] Wien Med Wochenschr 150 (23-24): 481-5, 2000.  [PUBMED Abstract]
30. Buzzelli G, Moscarella S, Giusti A, et al.: Therapeutic effects of a new silybin complex in chronic active hepatitis (CAH). [Abstract] Hellenic Journal of Gastroenterology 5 (Suppl): A-151, 38, 1992. 
31. Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.

Footnotes:

1. Mulrow C, Lawrence V, Jacobs B, et al. Milk thistle: effects on liver disease and cirrhosis and clinical adverse effects. Evid Rep Technol Assess. 2000. Chapter 1. Introduction. Obtained on 1-26-08 at http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.section.29172.

2. Post-White J, Ladas EJ, and Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integrative Cancer Therapies. 2007;6(2):104-109.

3. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

4. Varzi HN, Esmailzadeh S, Morovvati H, et al. Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs. J Vet Pharmacol Therap. 2007;30:477-481.

5. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

6. Kroll DJ, Shaw KS, and Oberlies NH. Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integrative Cancer Therapies. 2007;6(2):110-119.

7. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

8. Kroll DJ, Shaw KS, and Oberlies NH. Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integrative Cancer Therapies. 2007;6(2):110-119.

9. Filburn CR, Kettenacker R, and Griffin DW.  Bioavailability of a silybin-phosphatidylcholine complex in dogs.  J Vet Pharmacol Therap.  2007;30:132-138.

10. Sagar SM. Future directions for research on Silybum marianum for cancer patients. Integrative Cancer Therapies.  2007;6(2):166-173.

11. Kroll DJ, Shaw KS, and Oberlies NH.  Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integrative Cancer Therapies. 2007;6(2):110-119.

12. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

13. Malewicz B, Wang Z, Jiang C, et al. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis. 2006;27:1739-1747.

14. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies.  2007;6(2):158-166.

15. Gaedeke J, Fels LM, Bokemeyer C, et al. cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant. 1996;11(1):55-62.

16. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

17. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies.  2007;6(2):158-166.

18. Kroll DJ, Shaw KS, and Oberlies NH.  Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integrative Cancer Therapies. 2007;6(2):110-119.

19. Greenlee H, Abascal K, Yarnell E, and Ladas E. Clinical applications of Silybum marianum in oncology. Integrative Cancer Therapies.  2007;6(2):158-166.

20. Van Erp NPH, Baker SD, Zhao M et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res. 2005;11(21):7800-7805.

21. Chauret N, Gauthier A, Martin J, et al.  In vitro comparison of cytochrome P450-mediated metabolic activities in human, dog, cat, and horse.  Drug Metabolism and Disposition. 1997;25(10):1130-1136.

22. Greenlee H, Abascal K, Yarnell E, and Ladas E.  Clinical applications of Silybum marianum in oncology.  Integrative Cancer Therapies. 2007;6(2):158-166.

23. Varghese L, Agarwal C, Tyagi A, et al. Silibinin efficacy against human hepatocellular carcinoma. Clin Cancer Res.  2005;11(23):8441-8448.

24. Malewicz B, Wang Z, Jiang C, et al. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis. 2006;27:1739-1747.

I give Lucy 1 Milk Thistle capsule in her PM meal.