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Life Extension Magazine

LE Magazine June 2000


imageCan Silibinin Arrest Cancer Cells Growth?

The last decade has brought many discoveries about the natural ways to prevent breast cancer and prostate cancer. Certain supplements, such as potent extracts of green tea, have been shown to be effective in lowering cancer risk, and even in fighting cancer, particularly when used together with other therapeutic agents. Since flavonoids of various kinds have antiproliferative properties, they have emerged in a starring role. Epidemiological studies have confirmed that diets rich in flavonoids appear to lower the risk of many kinds of cancer, including breast and prostate cancer.

Startling new
discoveries about a popular herb

In February 1991, The Life Extension Foundation introduced a German drug called silymarin to its members. The primary known benefit of silymarin at the time was to protect the liver. Since 1991, a plethora of newly published research reveals additional
life-saving benefits that can be attributed to this herbal extract from milk thistle.
One of these new discoveries has prompted The Life Extension Foundation to participate in an investigation to ascertain whether a silymarin concentrate called silibinin is effective in the treatment of prostate cancer. In this article, we present some startling new findings about this herbal extract that is sold in Europe as a prescription drug. We will restrict the information in this report to the effects of silymarin/silibinin outside the liver and kidneys. For those concerned about liver/kidney health, the article that follows this report will review the effects of silymarin/silibinin on various hepatic and renal diseases.

A recent in vitro study by Zi and Agarwal (1999) found that silibinin was able to arrest cell growth in prostate cancer lines, probably through inhibiting various kinase enzymes. Silibinin helped arrest cell growth in the early phase of the cell cycle, known as G1. The researchers found a 20% increase in G1 cell population when the culture was treated with silibinin. It is well known that potent flavonoids have an antiproliferative effect on tumor tissue, so this was not surprising. But this is not the end of the story. It turned out that the growth arrest did not lead to apoptosis (programmed cell death), but to cell differentiation. As the authors put it:

"The silibinin-treated [cancer] cells that are unable to grow follow a differentiation pathway as evidenced by neuroendocrine-like morphology, elevated prostate tissue differentiation markers... and altered cell-cycle regulatory molecules."

Differentiated cells are the mature cells that perform specialized tasks appropriate to the organ. In this study, silibinin transformed a significant proportion of malignant cells to normal, differentiated prostate cells. Silibinin treatment also resulted in a large decrease in PSA secretion. The authors conclude that silibinin "has strong potential to be developed as an antiproliferative differentiating agent for the intervention of hormone-refractory human prostate cancer."

Another study found that silibinin inhibits proliferation in both drug-sensitive and drug-resistant breast cancer and ovarian cancer lines. The suggested mechanism of action involves silibinin's ability to bind to nuclear type II estrogen receptors, which are thought to mediate the antiproliferative effects of flavonoids (Scambia 1996). Comparing the properties of silymarin and silibinin, two investigators, Zhao and Agarwal (1999) state:

"Studies from our laboratory have shown that silibinin, the major active constituent of silymarin, has comparable [to silymarin] inhibitory effects towards human prostate, breast and cervical carcinoma cell growth, DNA synthesis and cell viability, and is as strong an antioxidant as silymarin."

Silibinin also showed synergy with two common chemotherapy drugs, cisplatin and doxorubicin. By arresting tumor cell division at a vulnerable stage, silibinin can apparently make tumor cells more sensitive to chemotherapy. Because of its effectiveness, silibinin is now in phase I clinical trials in patients with advanced ovarian cancer (Scambia 1996).

Likewise, silibinin has been shown to protect the kidneys during chemotherapy with certain extremely toxic drugs such as cisplatin (Bokemayer 1996). This is also fairly typical for effective alternative therapies for cancer: They often synergize with the mainstream treatment, and at least partly protect against its devastating effects on normal tissue. Thus, there is much to say for the combination of mainstream treatment with potent flavonoids such as silibinin.

Can silibinin slow aging?

The authors of a recent study (Onat 1999) concluded that silymarin's and silibinin's antiproliferative mechanism of action is not yet fully known, but it may involve modulating signal transduction pathways. These signaling pathways are involved in aging, atherosclerosis and cancer. Compounds that can inhibit excess proliferation involved in aging-related disorders are of great clinical interest. Onat found that both alpha tocopherol and silibinin had a similar inhibitory action on the proliferation of skin fibroblasts. Insofar as excess fibroblast proliferation is one of the phenomena of aging, silibinin could become one of the agents used to slow the aging of the skin.

What is silibinin?

Standardized milk thistle extract usually consists of a minimum 35% silibinin (by HPLC analysis). Silibinin is regarded as the most biologically active ingredient of silymarin. A new pharmaceutical concentrate contains a minimum of 80% silibinin, thus ensuring a higher concentration of silymarin's most potent component to the body. Being able to obtain enough silibinin is of particular importance for those who need to ensure effective dosage for the treatment of various diseases.

One of the ways in which silibinin protects against the development of cancer is by enhancing the activity of protective Phase II enzymes, glutathione transferase and quinone reductase. These two extremely important enzymes detoxify the various pro-carcinogenic metabolites that result from the initial stage of detoxification. Zhao and Agarwal (1999) found that in mice the activity of glutathione transferase in particular was enhanced by oral treatment with silibinin. This enhancement was especially evident in the small bowel, but was found also in liver, lungs, stomach, skin and prostate. Garrido's earlier finding in relation to acetaminophen indicates that silibinin can also inhibit the cytochrome P-450 system, which constitutes the main group of Phase I enzymes (Garrido 1991). This suggests that silibinin lowers the levels of toxic metabolites through a mechanism that may involve the inhibition of certain Phase I enzymes, and simultaneous enhancement of Phase II enzymes.

Silibinin and silymarin have also been shown to inhibit an enzyme called beta-glucuronidase, which catalyzes the breakdown of glucuronides, compounds created in the liver for the purpose of safely disposing of various toxic chemicals. Liver damage causes an increase in beta-glucuronidase; it has been suggested that it is a factor in liver cancer. Toxins such as carbon tetrachloride increase serum beta-glucuronidase. Likewise, our intestinal bacteria produce this enzyme; scientists suspect that it is related to colon cancer. Kim (1994) found that both silymarin and silibinin inhibited beta-glucuronidase to a similar degree in rats treated with carbon tetrachloride. The potential for reducing the risk of colon cancer and liver cancer is worth further exploration.

Cardiovascular health and the brain

An early German study (Schriewer and Rauen 1977) showed that silibinin dose-dependently inhibits the biosynthesis of cholesterol in vitro. This has been confirmed by more recent studies (reviewed by Skottova 1998). Another interesting effect is faster removal of low-density lipoproteins by the liver in the presence of silymarin. Studies have also shown that silymarin and silibinin inhibit the development of diet-related excess cholesterol levels in rats. Supplementing the diet with silymarin or silibinin resulted in an increase in HDL levels and a decrease in liver cholesterol content.

A recent study by Skottova (1999) compared the effectiveness of silymarin with that of silibinin in inhibiting copper-induced oxidation of low-density lipoproteins in vitro.

Silymarin and silibinin were found to be equally effective in prolonging the initial "lag phase" (the stage of oxidation when the process is proceeding slowly). In Skottova's study, silichristin and silidianin appeared to act instead as pro-oxidants when tested at the same concentrations as silibinin. Consequently, Skottova concludes, "silibinin is the most important compound of silymarin in protecting the LDL from oxidation."

Another in-vitro study of copper-induced oxidation of LDLs found that silibinin could prolong the lag phase by more than 50%. The authors suggest that silibinin binds to LDL particles and prevents the oxidation of polyunsaturated fatty acids (Locher 1998). Altogether, silibinin shows a potential for being used as an effective hypocholesterolemic and anti-atherogenic agent. It may yet emerge as an important supplement for the prevention of atherosclerosis.

Silibinin may also prove useful as a drug helping the survival of hypertensive patients who suffer a heart attack. In a rat model of acute coronary artery blockage combined with hypertension, intravenous administration of silibinin was found to reduce blood pressure and arrhythmias, decrease ventricular hypertrophy, and reduce mortality (Chen 1993). Fewer heart cells died in the silibinin-treated hypertensive rats. The finding that silibinin was able to reduce the size of the infarct zone is especially important, since the extent of heart cell death is an important predictor of mortality or subsequent congestive heart failure.

Of related interest is the ability of silibinin to protect the brain under conditions of ischemia (insufficient oxygen). Here the chief mechanisms of action include the scavenging of free radicals and the inhibition of lipoxygenase pathways, lowering the production of cell-damaging leukotrienes (Rui 1990). This is no surprise, considering that silibinin has been shown to help protect the liver and the kidneys from ischemic damage, including ischemia due to exposure to low temperatures (Gower 1989), and has been shown to be an effective inhibitor of leukotriene production. The potential of silibinin as adjuvant therapy for stroke remains to be explored. At The Life Extension Foundation's Critical Care Research Facility in Southern California, silymarin is one component of a neuro-protective "cocktail" used to successfully protect against experimentally induced ischemia.

Silibinin may also help counteract the greater oxidative stress in pregnant diabetic women, which threatens the normal development of the fetus, particularly in regard to the cardiovascular and nervous system. When pregnant diabetic rats were given silibinin, markers of neural development showed considerable normalization (Germani 1999).

Silibinin's effect on diabetes

Silibinin is of considerable interest in the treatment of diabetes, since preliminary evidence indicates that it may prove helpful in normalizing the action of insulin. A Chinese study found that rats subjected to heat injury (scalding) showed elevated blood glucose and high insulin levels due to stress-induced insulin resistance. The function of insulin receptors in the liver was shown to be impaired. Treatment with silibinin significantly enhanced the binding of insulin to the receptors (Tang 1991).

Silibinin was also found to help normalize pancreatic function in the presence of cyclosporin A, an immunosuppressive drug that is damaging to the pancreas (Schonfeld 1997). This included a lowering of insulin secretion without raising serum glucose, possibly indicating that silibinin improves insulin sensitivity.

Schonfeld and colleagues suggest that silibinin should be investigated as a potential treatment for Type II diabetics, who overproduce insulin due to insulin resistance. The authors also suggest that the protective effect of silibinin on the pancreas is non-specific, and is probably due to its antioxidant and membrane-stabilizing properties. Very likely, silibinin protects the pancreas not only against cyclosporin A, but also against alcohol and other toxins, and against free radicals in general.

Glycation, or the damage of proteins by simple sugars, is one of the greatest problems in diabetes. Glycation is a major causal factor leading to diabetic retinopathy, a frequent cause of blindness, and diabetic neuropathy (peripheral nerve degeneration, leading to axon atrophy and eventual loss of sensation). One of the simple sugars involved in this damage is ribose. Exposure to high glucose levels induces increased ribosylation of at least five proteins. It also suppresses the sodium-pump activity (an active transport of sodium ions across cell membranes in exchange for potassium ions) and the maintenance of neural tissue.

A recent in vitro study showed that silibinin can normalize the degree of ribosylation and the sodium pump activity even in the presence of abnormally high glucose levels (Di Giulio 1999). A similar protective effect of silibinin against ribosylation was found in the retina (Gorio 1997). Thus, silibinin may be able to decrease the extent of diabetic neuropathy and retinopathy, two extremely serious complications of diabetes. Considering that silibinin has also been shown to protect the kidneys, another organ seriously damaged by glycation (kidney failure is a frequent cause of death in diabetics), silibinin should be seriously explored as an adjunct treatment in diabetes.

A potent antioxidant

It has been established that silibinin is an effective scavenger of various free radicals, including hydroxyl and peroxyl radicals, and the hypochlorite ion that originates in neutrophils (Mira 1994). While it constitutes an important antibacterial defense, the hypochlorite radical is also extremely damaging to normal cells, and must be quickly "disarmed." Unchecked, the hypochlorite ion can even chlorinate DNA bases. In the presence of iron, it creates the hydroxyl radical, which can also directly attack DNA. The presence of powerful flavonoids such as silibinin helps prevent the damage from this "friendly fire."

Silibinin has been found to protect red blood vessels and stabilize their membranes through inhibition of lipid peroxidation. In addition, silibinin increases the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase in human red blood cells (Altorjay 1992). Another study found that silymarin normalized low SOD activity and altered immunoreactivity in the lymphocytes (a common type of white blood cell) of patients with alcoholic liver cirrhosis (Feher 1989).

Finally, silibinin has been found to protect against iron-mediated tissue damage. Iron overload is a dangerous condition, since iron catalyzes various free radical reactions with resulting lipid peroxidation in the membranes. The liver is a primary site of iron-induced damage. Silibinin's antioxidant activities help protect against iron toxicity. In addition, there is evidence suggesting silibinin acts as an iron chelator, binding the free iron for safe excretion in the bile (Pietrangelo 1995; Mira 1994). Thus, iron overload states are another condition during which treatment with silibinin might be helpful. Pietrangelo points out that in fact the high antioxidant activity of flavonoids might be partly due to their ability to form inactive iron chelates, thus reducing the formation of peroxides. Pietrangelo and colleagues found that silibinin was able to protect the rat liver mitochondria against abnormalities caused by iron-induced oxidative stress, such as lipid peroxidation, ATP depletion and abnormal calcium cycling.

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