Photo courtesy of JHS Natural Products.

Maitake mushrooms (Grifola frondosa) are native to Northern Japan, growing wild in cool hardwood forests. It is said that in ancient times, people would dance for joy to find these large, tasty, medicinal mushrooms growing in clusters of 100 pounds or more. This, of course, is why they were called “the dancing mushroom.”

Modern biomedical scientists may not quite be moved to dancing over this fascinating fungus, but some of them are certainly turning an interested eye to its therapeutic possibilities.

Maitake has been used for centuries as a food and as a medicinal source in Asia, where it is used to treat such varied conditions as high blood pressure, elevated serum cholesterol, and as treatment of cancer, according to the American Cancer Society (www.cancer.org). Recently, some excellent basic research and clinical trials have been carried out at US institutions. This work has shed light on the identification of active fractions, methods of extraction, as well as modes of action.

A high profile study scheduled to begin at Memorial Sloan-Kettering Cancer Center in New York City involves a product called Maitake Gold 404 (AKA MD-fraction), which will be tested against breast cancer. Barrie Cassileth, MD, has received approval for an important mechanistic study and clinical trial using this formula, among the most potent and best studied of the available Maitake extracts. The aim is to determine just how this product acts against cancer cells both in vitro and in cancer patients. Maitake Gold 404 was recently licensed for distribution in the US, and is now marketed by seven high-end nutraceutical companies including JHS Natural Products (www.jhspro.com), Thorne Research (www.thorne.com); Integrative Therapeutics (www.integrativeinc.com), Threshold/Source Naturals (www.sourcenaturals.com), Natural Factors (www.naturalfactors.com), Zand (www.zand.com), and Megafoods (www.megafood.com).

Other recent clinical findings regarding Maitake extract are its effects on glucose/insulin metabolism in diabetics. Studies ongoing in Dr. Harry Preuss’ laboratory at Georgetown University in Washington DC have looked at Maitake-derived beta-glucans in the reduction of serum glucose in diabetic rats. Statistically significant reductions in serum glucose were seen at 8 and 16 hours post Maitake extract administration (Manohar et al. Diabetes Obes Metab 2002; 4: 43), suggesting potency in stabilization of blood sugars in diabetics. The Maitake extract also resulted in reductions of hemoglobin A1c in these animals.

Speaking at the recent Nutracon natural products conference, Dr. Preuss said he believes the water soluble fractions of Maitake have tremendous potential for the management of Syndrome X, pre-diabetic insulin resistance, and diabetes itself (Konno S, et al. Diabet Med 2001; 18(12): 1010).

The Georgetown research team has studied a Maitake product called D-fraction (Maitake Products, Paramus, NJ; www.maitake.com) in three different animal tumor models, and showed significant tumor growth inhibition. Researchers in the department of urology, New York Medical College, Valhalla, NY, using the same compound, showed that it can induce apoptosis in human prostate cancer cell lines (Fullerton SA, et al. Molecular Urol 2000; 4(1): 7–13). This D-fraction product is marketed in the US as Grifron D-fraction by Maitake Products Inc. (Paramus, NJ; www.maitake.com).

A Cornucopia of Immunomodulators

Biological Response Modifiers (BRMs) are molecules that activate the innate immune system. Natural sources of BRMs have been used by folk practitioners as well as homeopaths, naturopaths and many allopathic physicians for centuries. Plant polysaccharides, consisting of bacterial cell wall glucans (long chain glucose molecules), are important botanical BRMs, and Maitake appears to be very rich in them.

Most polysaccharides derived from fungi have a backbone structure of linear glucose molecules with variously complicated side chains that confer secondary structure and biological function. Dr. Gary Ostroff, vice-president of research and development at Biopolymer Engineering (http://www.biopolymer.com) classifies plant BRMs into four categories according to the type of side chains they possess: the simplest, found in bacteria, is a smooth, linear (1,3) polysaccharide without branched side chains. These have been shown to have action against certain strains of HIV (http://www.niaid.nih.gov/daids/dtpdb/000726.htm). Increasingly more complex are the glucans isolated from fungi, such as Shiitake or Reishi, which have single glucose side chains attached in (1,6) configuration. These “bristly” fungal glucans are well studied, and they have been shown to have anticancer as well as anti bacterial effects in vivo and in vitro (Diamond, WJ. 1997. An alternative medicine definitive guide to cancer. Tiburon CA. Future Medicine Publishing in 113: 483; Ontario Breast Cancer Information Exchange Project 1994. 166).

Still more complex are the yeast glucans, in which the (1,6) side branches are longer, more “floppy,” and can form complicated secondary structures with profound effects on biological function. The most complex are the glucans derived from cereals, such as oats and barley. These have side chains in (1,4) as well as (1,3) configuration, differing in frequency and distribution.

Glucans 101

	Chemical structures of β-(1→6) glucan (upper) and β-(1→3) glucan (lower).

The biological functions of various glucans depend on their side chains, frequency, linkage and distribution. Dr. Ostroff has shown that glucans bind to several classes of cellular receptors to mediate specific biological functions. Among them is the Complement Receptor-3 (CR3), as well as other macrophage receptors including Toll-Like Receptor-2 (TLR-2) and CD17 (also known as lactosylceramide, a marker for some leukemias).

Their major action is to activate the innate immune system, an ancient system of defense that we shared with such diverse species as lobsters, mice, and earthworms. The innate immune system is relatively antigen nonspecific and includes primitive cells which, when activated, secrete certain cytokines (interferon, complement, tumor necrosis factor (TNF)-alpha, Interleukin (IL) 1 and 6. Glucans also activate cellular components of the innate immune system (granulocytes, macrophages, natural killer cells), and increase cellular internal toxic molecules such as nitric oxide (NO), which are able to kill engulfed bacteria. There is increasing evidence that the innate immune system plays an important role in the defenses against infection and cancer, and can be important in certain autoimmune conditions such as asthma.

According to Gordon D Ross, PhD, of the University of Louisville in Kentucky, mushroom and yeast glucans active against tumors have a particular structure, including beta (1,3) linkages. (http://www.louisville.edu/medschool/pathology/research/immuno/glucans.htm; Yan, J., et al. J Immunol 1999; 163: 3045). Dr. Ross has shown that molecular weight of the glucans plays an important role in their biological functions. Small glucans (5–20 kDa) bind to the CR3 receptor and prime immune cells for further activation. Because tumor cells may be coated with antibody and complement (from an ineffective anti-tumor response), they are prime targets for activated CR3 cells; the latter efficiently kill off the former.

Larger molecular size glucans (>500 kDa) are effective in cross-linking the CR3 receptor, and can activate immune cells nonspecifically. This kind of activation can lead to cellular degranulation, production of NO, and release of cytokines.

Modern Maitake Medicines

Maitake extract is made by hot water extraction followed by further purification. A number of products are now on the market, each made through unique patented processes, and possessing different glucan fractions. So far, there have been no head to head trials comparing them in any disease state.

Dr. Hiroaki Nanba, a mycologist at the Pharmaceutical University of Kobe, Japan, developed a product called MD-fraction, now renamed Maitake Gold 404 for the US market. This is a hot water extraction followed by precipitation in ethanol, acidification and extraction in alkali, and it is the compound to be used in the MSKCC trials. What is unique about Dr. Nanba’s extract, is that the glucans are a 1→6 structure rather than a 1→3 structure, which has been recognized as a BRM. Although variations exist in the different patented forms, the fundamental useful agents in all of them are long chain branched polysaccharides with a molecular size of one million or more.

Experiments from Dr. Nanba’s laboratory have shown that tumor bearing mice treated with his extract generate not only enhanced nonspecific immunity as mentioned above for fungal extracts, but also tumor specific T cell dependent immunity (K Adachi, H Nanba and H Kuroda. Chem Pharm Bull 1987; 35: 262).

This type of immunity has not been observed in other models of immune enhancement with extracts from other mushrooms. According to Dr. Suzanne McNeary of Tradeworks (www.tradeworks.com), the company licensing Dr. Nanba’s extract for the US market, perhaps the 1→6 structure is responsible in some fashion for the activation of T-cell immunity, so important in the elimination of certain types of cancer.

Nanba’s Maitake Gold 404 has been less effective in the elimination of certain cancers (bone, blood and brain), which have a weak immune response component, but appears highly effective in breast, prostate, liver and lung cancers which are strongly immunogenic, suggesting that T-cell activation may be as important as the nonspecific immunity mentioned above. Exactly how these various structures affect cellular mechanisms of cancer protection is unknown.

Current Cancer Trials

There are several ongoing or projected clinical trials using glucans against a variety of cancers. Trials of Coriolus versicolor fungus at MD Anderson in Texas have suggested that treatment in tandem with radiation or chemotherapy led to greater disease free periods in patients with colon cancer (American Cancer Society: http://www.cancer.org; Mitomi T, et al. Dis Colon Rectum 1992; 35: 123; Torisu M, et al. Cancer Immunol Immunother 1990; 31: 261).

A glucan trial against neuroblastoma (childhood brain cancer) is being carried out by Dr. Nai-Kong Cheung at MSKCC. The goal of this study is to determine if glucans from barley can function as immune enhancers when given in conjunction with a neuroblastoma-specific antibody (http://www.mskcc.org). Barley glucans are thought to super-activate cells so that they are more active against tumors which have been coated (opsonized) with the 3F8 antibody. Because the barley glucan is given orally, the possibility of side effects for the polysaccharide is very low. According to University of Louisville’s Dr. Ross, plans are underway to test yeast glucans similarly in future clinical trials.

The MSKCC Maitake trial in breast cancer patients involves a three-stage approach. In Stage 1, Maitake Gold 404 will be tested in models of cancer to determine if it interferes with conventional chemotherapy agents. In Stage 2, healthy volunteers will be given extract to determine its bioavailability. Blood samples from these normal volunteers will be examined to determine if there is an increase in molecules active against breast cancer cells (MCF-7) in tissue culture. In Stage 3, breast cancer patients will be recruited to determine if Maitake extract is able to work with traditional chemotherapy to eliminate the tumors (http://cdmrp.army.mil/cgi-bin/search/search_results.pl).

In summary, mushroom extracts containing high levels of glucans have activity in several animal models of disease, as well as in clinical trials. The active fraction seems to be a linear polysaccharide with short side branches, which folds into a complex secondary structure capable of activating immune cells. These activated cells increase the innate immunity against certain cancers by increasing soluble cytokine secretion and activating internal toxic molecules such as nitric oxide. Some glucans derived from other plants are also active against tumors in an adjuvant fashion, when administered with specific anti-tumor antibodies which coat the tumors and make them more susceptible to engulfment by immune cells.