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Can Silibinin Arrest Cancer Cell Growth?

June 2000

Flavonoids, lignans and the importance of glutathione

The extract of milk thistle seed is commonly referred to as silymarin. Silymarin is a collective name for a mixture of flavonoids or, more technically, flavolignans. Both flavonoids and lignans are often loosely grouped together with isoflavonoids (soy), phytosterols and coumestans into a category of compounds known as phytoestrogens. Structural and chemical similarities between flavonoids and human steroid hormones, and thyroid hormone are particularly intriguing. Molecular biologists have begun studying the complex hormone-like actions of flavonoids, including the modulation of various enzyme activities and signaling pathways. Eventually this may lead to a fuller understanding of how diets rich in phytoestrogens help protect against a variety of cancers, including breast cancer, prostate cancer and colon cancer.

Lignans have potent hormone-like properties and are now beginning to be studied in relation to cancer and immunomodulation. The most commonly used natural sources of lignans are flaxseed and stinging nettle (Urtica dioica). Flavonoids are part of a larger group of important compounds known as polyphenols, widely distributed in the plant world. Together with chlorophyll and carotenoids, flavonoids are the most common pigments in plants. The reason that vegetables, fruit (especially berries), and beverages such as tea and wine are so protective against cancer, cardiovascular disease and many other disorders of aging is due in large part to their content of flavonoids.

More than 4000 flavonoids have been identified so far.

Depending on molecular structure, all flavonoids show various degrees of antioxidant activity. Some are in fact very powerful antioxidants, more potent by far than vitamins C or E. Potent flavonoids such as proanthocyanidins in grape seed extract, quercetin and various other compounds in ginkgo or catechins in green tea enter our antioxidant network to regenerate vitamin C and glutathione to their antioxidant status (for more information on antioxidant networks, see Dr. Lester Packer's excellent recent book, The Antioxidant Miracle). By restoring ascorbic acid and glutathione to the reduced (antioxidant) state, flavonoids greatly potentiate the action of these primary antioxidant compounds.

Dr. Lester Packer states that all flavonoids are antioxidants; their antioxidant potency depends on their molecular structure. Those flavonoids that are strong antioxidants can quench the particularly dangerous hydroxyl radical. Flavonoids stabilize cell membranes, probably thanks to their ability to protect lipids against peroxidation. Typically, flavonoids also decrease the production of nitric oxide. In excess, nitric oxide promotes chronic inflammation and the generation of more free radicals.

There is also evidence that indicates that certain flavonoids (including those found in wine, tea, and coffee) can chelate iron, which can act as a powerful catalyst of free radical induced damage. The ability to chelate iron further enhances the ability of flavonoids to decrease oxidative stress.

Taking a variety of flavonoids is a must for life extensionists. Because they lower oxidative stress and inflammation, two conditions very prominently associated with aging, flavonoids have the potential to retard the aging process. The most potent flavonoids may even extend life span. Very likely, their mechanism of action extends beyond the scavenging of free radicals and reducing inflammation. It may involve an inhibition of certain genes that affect aging.

Because of their hormone-like character, flavonoids affect many fundamental aspects of our physiology. We have barely begun to investigate these amazingly potent compounds. Evolved by plants for their own protection against DNA damage, viruses and bacteria, flavonoids have turned out to be effective guardians of human health as well, indicating an essential commonality of biological mechanisms at the molecular level.

One of the primary anti-aging properties of flavonoids is their ability to boost the levels of glutathione, our main endogenous antioxidant and detoxifier. It is present in all cells, but particularly abundant in the liver. Liver poisons act chiefly by depleting glutathione. When glutathione is essentially used up due to toxic overload, and the levels of glutathione in the liver fall below a certain threshold, glutathione-dependent detoxification cannot proceed, and toxins accumulate. It has been shown that silymarin can raise the levels of glutathione in a rat liver by as much as 35%, and that this glutathione-raising action is selective for the liver, intestine and stomach.

Simply raising glutathione levels produces a whole cascade of physiological benefits. But this is not the end of the story. Flavonoids also modulate the action of various enzymes, such as lipoxygenase, which catalyzes the oxidation of polyunsaturated fatty acids, leading to the production of harmful inflammatory compounds known as leukotrienes. Some flavonoids slow the activity of the main Phase I enzymes, the Cytochrome P-450 system. This means a slower conversion of various pro-carcinogens into carcinogenic metabolites. Since these metabolites need to be detoxified by glutathione, slowing down their production prevents rapid glutathione depletion. At the same time, certain potent flavonoids, including silymarin and its chief ingredient silibinin, induce the detoxifying Phase II enzymes, glutathione peroxidase and quinone reductase.

Taking various methylating agents, lipoic acid (which has also been shown to raise glutathione levels) and a mix of various antioxidants are all important ways of helping the liver in its huge task of detoxification. We should try to keep liver glutathione levels as high as possible-and this is where silymarin and silibinin appear to be particularly effective.

In addition to their well-known role in promoting liver health, silymarin (milk thistle extract) and silibinin have now joined grape seed extract, green tea extract, bilberry and ginkgo as phytonutrients that provide a wide range of antioxidant, anti-inflammatory, anticarcinogenic and cardiovascular benefits.

Milk thistle through the ages

Milk thistle (Silybum marianum) is a member of the aster family, which also includes the artichoke, a close relative. A handsome plant with milky white veins on spiky leaves, milk thistle is native to the Mediterranean region, but it is now widely grown for medicinal use in the United States, Africa and South America. Its extract has been used as folk medicine for more than 2000 years. It was first mentioned in writing by the ancient Greek scholar Theophrastus (372-287 B.C.). Interestingly, the physicians of the ancient world recommended milk thistle root mixed with honey as a cough medicine.

Medieval monks and nuns spread the use of milk thistle throughout Europe; it was one of the most common herbs grown in cloister gardens, and was known as Heal Thistle or Saint Mary's Thistle. Various parts of the plant were used for medicinal extracts, including flowers and leaves. Mystical properties were ascribed to the Heal Thistle; it is one of the symbolic plants that appear in medieval paintings.

The use of milk thistle for bronchitis persisted for many centuries; only in the fifteen hundreds it became known that milk thistle was an excellent detoxifier. It was also established that the seed had the most potent medicinal properties, and that the extract of crushed milk thistle seeds was effective in many cases of indigestion, liver problems and toxic liver damage. Later milk thistle was recommended as a remedy against gallstones, jaundice and spleen disorders.

Modern science has validated many of these medicinal uses. The active ingredients of milk thistle extract were identified in 1960. The main active ingredient, silibinin, was extracted in 1980, making higher doses more affordable. As potent antioxidants and anticarcinogens, milk thistle extract (silymarin) and silibinin are now attracting more and more attention as effective adjuvant therapy for various liver disorders, including cirrhosis and hepatitis C. In Germany, where herbal products are required to be tested for effectiveness, milk thistle extract has been officially approved for the treatment of both chronic and acute liver disorders by the world-renowned Commission E. Some American alternative clinicians favor the standardized German product for the treatment of hepatitis and cirrhosis. Research on silibinin, however, seems to confirm that silibinin is approximately equivalent to silymarin in effectiveness.

The ability of milk thistle extract and silibinin to protect organs other than liver, especially the kidneys and the pancreas, against toxic and ischemic damage is now well documented. More recently, both silymarin and silibinin have also emerged as promising natural agents in the prevention and treatment of cardiovascular disorders, diabetes, and cancer, including breast and prostate cancer.

One exciting discovery is that milk thistle appears to be a "smart herb," able to enhance new cell growth where needed for repair, but arresting cell division in tumor tissue; likewise, it can enhance the activity of certain enzymes, but inhibit others. The flavonoids in milk thistle seem to have special affinity for Type II estrogen receptors. There is also emerging evidence that milk thistle extract is a COX-2 inhibitor-another example of its "smart," selective action. We are discovering more and more about the multiple benefits of this ancient healing herb.

Anti-inflammatory properties

Image with Caption
Silibinin inhibits the
production of nitric
oxide, a destructive
compound that can
trigger chronic

Like many other flavonoids, silibinin can also inhibit the production of nitric oxide (Dehmlow 1996). Excess nitric oxide can be very destructive. It triggers chronic inflammation and promotes the generation of more free radicals.

Silibinin's anti-inflammatory properties are also of great interest. Silibinin can inhibit the formation of pro-inflammatory prostaglandins (PGE-2), but there is some evidence that in the liver this takes place only at very high concentrations. On the other hand, silibinin excels at inhibiting the lipoxygenase pathway, thus reducing the generation of harmful inflammatory compounds called leukotrienes (Dehmlow 1996). The inhibition was remarkably strong. At higher concentrations, silibinin lowered the leukotriene levels to 28% of the control values.

The powerful reduction of leukotriene levels by silibinin is of great clinical interest in the treatment of inflammatory disorders. The commonly used non-steroidal anti-inflammatories (NSAIDs) reduce the production of inflammatory prostaglandins, but are notoriously ineffective at controlling leukotrienes. Leukotrienes are a major culprit in inflammation-induced damage to the tissues. The fact that even low concentrations of silibinin strongly inhibits leukotriene production is potentially of great clinical importance in preventing gallstone formation, as well as tissue damage in liver and kidneys.

In skin cells, the flavonoids in silymarin appear to inhibit the cyclooxygenase-2 enzyme, thus leading to a lower production of inflammatory prostaglandins (Zhao 1999). COX-2 inhibitors are gaining more and more attention in cancer prevention and therapy, especially in the prevention of stage I tumor promotion. Demlow, on the other hand, stresses that in the liver at least, selective lowering of leukotrienes may be one of silibinin's main hepatoprotective properties, since in the liver prostaglandins are essentially protective, and silibinin has little effect on prostaglandin production in the liver.

Demlow also found that silibinin is a potent scavenger of the hypochlorite ion. She concludes, "The deleterious effects of [hypochlorite] that can lead to cell death, and those of leukotrienes that are especially important in inflammatory reactions, can be inhibited by silibinin in concentrations that are reached in vivo after the usual clinical dose. Silibinin is thought not only to display hepatoprotective properties but might also be cytoprotective in other organs and tissues."


"Toxic overload" is one way to describe our modern environment. If you are worried about the health of your liver, chemical allergies, carcinogen-induced cancer, pancreas health and blood sugar, there is good news: silibinin, the main active ingredient of milk thistle, an herb used since ancient times can help protect you and keep your vital organs in top shape. It can even reverse liver damage. And the most recent research findings broaden silibinin's range of potential applications to include cancer, cardiovascular disease, kidney and pancreatic health, and other age-related conditions.

Recent research has shown that silymarin and silibinin should be rightfully placed with ginkgo, green tea and grape seed extract as an indispensable anti-aging herbal supplement.

The following article discusses the effects of silymarin-silibinin on liver and kidney function and also provides suggested doses to prevent or treat various diseases.