The latest Cancer Council Australia figures for cancer rates in Australia show that one in three men and one in four women will be directly affected by cancer before the age of 75. And while more than half of the 88,000 new cases of cancer diagnosed in Australia each year will be successfully treated, cancer is still the leading cause of death in this country. The most common cancers in Australia (excluding non-melanoma skin cancer) are colorectal, breast, prostate, melanoma and lung cancer.
Traditionally, cancer treatment includes therapies such as chemotherapy, radiation therapy and surgery. However, all these therapies can have devastating side effects and they are not always successful. One of the most frequent causes of shortened survival time in cancer patients is metastasis, which is the spread of cancer cells from the primary site of the tumour to normal tissue elsewhere in the body via the bloodstream or lymph system. Although surgery can often successfully reduce the tumour mass, and chemotherapy or radiation therapy can sometimes further reduce the mass, these toxic therapies damage the immune system, and small clumps of malignant cells may survive despite best efforts to eradicate them.
Immunotherapy is another approach to cancer treatment whereby the body is revitalised to carry out its natural functions of eliminating abnormal tissues after its immune defences have been diminished by cancer and the toxic therapies used against cancer. Immunotherapy is also used in the treatment of allergies, HIV and other immune-related diseases.
What are mushroom immunoceuticals?
One class of immunotherapy yet to gain popularity in the West but commonly used in Asia is mushroom immunoceuticals. Immunoceuticals are dietary supplements that have an immune-boosting effect. They are used in conjunction with conventional cancer therapies to strengthen the body’s natural immune system ability.
Immunoceuticals obtained from certain mushrooms have become popular in Asia because they have been shown to lessen the adverse side effects of conventional therapies and assist in boosting the immune system to fight tumours. The Japanese Health and Welfare Ministry has approved three different anti-cancer drugs extracted from mushrooms: Lentinan, derived from Lentinus edodes; Schizophyllan, from Schizophyllum commune; and Polysaccharide-K (PSK), from Coriolus versicolor.
PSK, which is sold in Europe and Japan, is the best-selling anti-cancer drug in the world. In Japan, only 30 per cent of cancer treatment includes radiation, chemotherapy and/or surgery; that is, an individual with cancer is treated with 30 per cent traditional therapies and 70 per cent complementary therapies. More than 500 scientific papers over the past 30 years, predominantly from Japan, have looked at the anti-tumour and anti-bacterial effects of mushrooms. However, despite this research and Asia’s long history of using medicinal mushrooms, authorities in the West are still slow to move to human trials with such remedies.
The medicinal properties of mushrooms have been recognised in Asia for 2000 years. However, scientists have only been able to study the therapeutically active chemicals (immunoceuticals) of these mushrooms since the technological advances of the last 30 years. Once identified, these chemical substances have been isolated, concentrated and tested on animals, with more than 30 mushroom species showing anti-cancer action. However, only a handful of these have been taken to the next step and tested on humans. At this stage, the mushroom immunoceuticals with the most promise in helping fight cancers are Lentinan, Schizophyllan, Active Hexose Correlated Compound (AHCC), Maitake D-Fraction, Polysaccharide-K (PSK) and Polysaccharide-P (PSP).
But despite the lack of human clinical trials, there is a tremendous amount of data on the chemistry of mushroom immunoceuticals. In fact, what all these mushrooms have in common is their chemical structure. Research has shown that the most effective immunoceuticals are nearly always chemically defined as beta-glucans or proteoglycans. Beta-glucans are long polysaccharide chains with sugar molecules branching off the backbone of the chain, giving them a three-dimensional appearance. Proteoglycans are also long polysaccharide chains, but they have proteins rather than sugar molecules branching off the backbone of the chain. It is the branching side-chains that allow interaction with the receptors of various immune cells, thereby regulating their action. (At this stage, it is understood that the branching side-chains correlate with anti-cancer effects, but the precise mechanisms are not fully understood.) As a rule, proteoglycans have greater immune-boosting potential than beta-glucans.
How do they work?
The mechanism behind the immune-boosting effect of mushroom immunoceuticals is thought to be their stimulating effect on dendritic, or Langerhans, cells. Dendritic cells are widespread in the body and are capable of sensing foreign or threatening material and then mobilising an appropriate and timely immune response. Basically, they are the immune system’s first line of defence.
Another way immunoceuticals work is by activating natural killer cells (NK cells). NK cells are a type of white blood cell that destroys foreign cells, including tumour cells, when they enter the body. NK cells also play a primary role in regulating immune responses.
In 2002, researchers at Kobe Pharmaceutical University in Japan monitored levels of NK cell activity in cancer patients receiving D-Fraction extracted from maitake mushrooms (Grifola frondosa). They found that NK cell activity levels were not only initially elevated, they also remained elevated for one year after the treatment stopped.
To determine the mechanisms underlying the long-term activation of NK cells, the researchers also administered the extract to mice for 19 days. What they found was that as well as significantly increasing NK cells and markedly suppressing tumour growth, there was a corresponding increase in immune-regulating proteins released from the spleen cells of the mice. In addition, the maitake mushroom extract increased macrophage-derived interleukin (IL)-12, which activates NK cells.
Another way that immunoceuticals are thought to elevate the immune system is by stimulating the secretion of cytokines and various interferons to levels as high as five to 120 times their normal levels. Cytokines are proteins produced by white blood cells that act as a messenger between cells. Basically, cytokines are released by one cell or group of cells and then bind to other cells in order to tell them what to do. In this way they help coordinate the immune system. Interferons are proteins that increase the resistance of surrounding cells to attacks by viruses.
Despite this promising biochemical research, many details of mushroom immunoceutical actions are still unclear. In China and Japan, the trend is to combine immunoceutical treatment with current cancer therapies such as surgery, chemotherapy and radiation therapy. In these countries, this form of integrated cancer treatment is very advanced.
Lentinan
Lentinan is produced from Lentinus edodes, which is also known as the shiitake mushroom, or “oak mushroom”, and is usually grown outdoors on oak logs in forests. However, because it takes three to five years before the mushrooms can be harvested, a more intensive cultivation technique has recently been developed that involves synthetic logs, sawdust and agricultural by-products. The shiitake is largely grown in Japan, China and South Korea and accounts for 10 per cent of the world’s production of cultivated mushrooms. It is the most researched mushroom with regard to its immunological activity.
“Take” is Japanese for mushroom and “shii” refers to the shii tree (Quercus cuspidata), an oak of central and southern Japan on which the shiitake most often grows. In China, the shiitake’s history dates back to the Ming Dynasty (1368-1644 AD). The mushroom was not only used as a food but also taken as a remedy for upper respiratory diseases, poor blood circulation, liver trouble, exhaustion and weakness, and to boost chi (life energy). It was also believed to prevent premature ageing.
In 1969, Tetsuro Ikekawa of Purdue University in West Lafayette, Indiana, with the aid of colleagues at the National Cancer Center Research Institute in Tokyo, was the first person to research the anti-tumour effect of the shiitake mushroom. The researchers found that extracts of the shiitake and several other mushrooms collected in the wild produced high rates (72 to 92 per cent) of tumour inhibition in mice. Ikekawa later identified a polysaccharide in the shiitake — Lentinan — as having powerful anti-tumour activity.
Clinical studies indicate that Lentinan can assist in prolonging the life of patients with gastric or colorectal cancer; however, because the molecules of Lentinan are extremely large, it cannot be absorbed and utilised by the body when taken orally. Lentinan therefore needs to be injected.
Schizophyllan
Schizophyllan, from Schizophyllum commune, is also ineffective when taken orally, so it is usually injected into muscle. Schizophyllan has been found to be rather ineffective against gastric cancer, but it has been shown to assist in extending the survival time of patients with head and neck cancers. In cervical cancer trials, Schizophyllan was most effective when it was injected directly into the tumour mass.
Active Hexose Correlated Compound
Active Hexose Correlated Compound (AHCC) is a proprietary (undisclosed) extract from several species of mushroom, including the shiitake. Unlike Lentinan and Schizophyllan, this extract is effective when taken orally and preliminary research indicates that AHCC has anti-cancer activity.
The AHCC Research Association was formed in Japan in 1996 to foster the development of AHCC as an anti-cancer therapy. Reports from the association claim that out of the 300 cancer patients given AHCC, 58 were effectively treated, with 46 showing complete or partial regression and 12 experiencing no further increase in tumour size. Among these 58 cases were cancers of the lung, breast, stomach, oesophagus, colon, liver and several other sites. Research on AHCC is still at a comparatively early stage and further investigation is required before its effectiveness can be declared.
Maitake D-Fraction
Maitake D-Fraction is a mixture of beta-glucans prepared from the maitake mushroom and it can be taken orally. Maitake has been used in Japan for hundreds of years in doses as high as several hundred grams per day, and its safety is well established. It has been found to be highly potent against cancer cells in laboratory and animal tests. However, this does not necessarily mean it will have the same effect in humans, and further research is needed. Nonetheless, several US physicians have reported good results with Maitake D-Fraction in their practices, and an Investigative New Drug Approval was obtained in 1998 in the US to begin a Phase II pilot study with advanced breast and prostate cancers.
Proteoglycans from Coriolus versicolor
As mentioned earlier, proteoglycans are polysaccharide chains bound to proteins and they have greater potential in boosting the immune system than beta-glucans. Polysaccharide-K (PSK) and Polysaccharide-P (PSP) are the only two proteoglycans that have been systematically investigated in human cancers.
Both PSK and PSP come from the mushroom Coriolus versicolor (also known in Australia as Trametes versicolor). Coriolus versicolor is known in Japan as kawaratake (“mushroom by the river bank”) and in China as yun zhi (“cloud fungus”). PSK was first discovered in 1965 in Japan by a chemical engineer whose neighbour attributed the successful treatment of his life-threatening cancer to self-administered kawaratake. PSP was first isolated in China some time later, around 1983.
PSK
The first clinical trial research with PSK began around 1970. Decades of clinical experience indicate that PSK is very gentle on cancer patients: its only significant side effect is occasional darkening of the fingernails. PSK is mostly used for cancers of the stomach, oesophagus, nasopharynx, colon, rectum and lungs. It also shows promise in some breast cancers.
PSK has been researched for longer than PSP and has therefore undergone more thorough laboratory, animal and clinical testing. Studies suggest that the effect of PSK can be attributed to its ability to improve the “host versus tumour response”; in other words, to increase the ability of the patient to defend themself from tumour progression. In addition to increasing the activation of white blood cells and NK cells and immune protein responses, PSK has demonstrated anti-metastatic action. This can perhaps be attributed to its potential to inhibit metalloproteinases and other enzymes involved in metastatic activity.
PSK has also been shown to cause changes in the physiology of leukemic cells (abnormal white blood cells in leukaemia patients), and this effect has been attributed to the increased production of cytokines. However, this has only been demonstrated in cell cultures, not in living patients, and results from human trials have been less encouraging.
Furthermore, PSK has been shown to have antioxidant capacity, which may enable it to protect normal tissue from chemotherapy and radiation therapy when it is used as an immunoceutical. Interestingly, studies have also shown that PSK may stop cancer developing by preventing various cancer-causing substances found in tobacco and asbestos from having an effect on vulnerable cells. This action of PSK may also prevent secondary malignancies in cancer-treatment patients, which sometimes occur because of the toxic effects of radiotherapy and chemotherapy.
Another very important aspect of immunotherapy in general is that it may be used on debilitated patients, such as those with AIDS and the elderly, so further research is certainly warranted in this area.
While PSK is not a magical solution, for some cancers it can assist in doubling the survival time of patients — perhaps by as much as 15 years — and it has virtually no side effects.
PSP
Phase I, II and III human trials with PSP are now complete. PSP has been proven to be non-toxic and can markedly help to improve the survival rate and quality of life in cancer patients. In trials using up to six grams of PSP per day, patients reported increased appetite and reduced rates of unpleasant side effects caused by the toxic therapies employed to treat cancer. PSP benefits patients with stomach, oesophageal and non-small-cell lung cancers.
Although PSP is less thoroughly researched than PSK, it is fast gaining respect as an anti-cancer immunoceutical. In strictly controlled double-blind trials, PSP has demonstrated improved quality of life in more than 70 per cent of patients with cancer.
PSK and PSP’s extremely high tolerability, proven benefits for survival and quality of life, and compatibility with chemotherapy and radiation therapy make them well suited for cancer-management regimes.
Ganoderma lucidum
Like other mushroom immunoceuticals, Ganoderma lucidum, also known as the lingzhi or reishi mushroom, contains the polysaccharide chemical structures that are thought to contribute to its immune-boosting potential. Historically, Chinese royalty seeking longevity held the lingzhi in high esteem. It was also listed among the superior tonics in the most famous of all Chinese medicine texts, the Shen Nong Ben Cao Jing, written between 206BC and 8AD.
Despite Ganoderma lucidum’s very long history of use in Chinese medicine, most of the clinical studies conducted with this mushroom have been performed on animals, limiting our understanding of its effectiveness in humans. Nonetheless, the mushroom has potential as a cancer adjuvant.
Preventative health
People without cancer will also benefit from taking mushroom immunoceuticals. A study published in the International Journal of Food Sciences and Nutrition looked at the antioxidant content of the reishi mushroom. The researchers found that the FRAP value (a measure of antioxidant power) of the reishi was 360mmol/g. This value was then compared with the FRAP value of other common antioxidant sources, including tea. The FRAP value of black tea was found to be between 132mmol/g and 654mmol/g, with the value of green tea between 272mmol/g and 1144mmol/g. The reishi mushroom’s fairly high antioxidant content may support claims that it has a protective role against age-related diseases.
The shiitake mushroom provides various essential amino acids (isoleucine, leucine, lysine, methionine, phenylalanine, threonine and valine), vitamins B1, B2 and B12, mineral salts and the provitamin ergosterol, which is converted to vitamin D in the presence of sunlight. In addition, the shiitake contains adenine and choline, which may prevent cirrhosis of the liver and vascular sclerosis. It also contains tyrosinase, which tends to lower blood pressure, and two other constituents that tend to reduce serum cholesterol.
The reishi mushroom has also shown cholesterol-lowering effects. Interestingly, chemical structures have been identified in the reishi that are similar to lanosterol, one of the substances involved in cholesterol synthesis in the body.
If you’re looking for a way to boost your immune system and manage the side effects of traditional cancer therapies, discuss using mushroom immunoceuticals with your doctor. If you’re simply seeking to improve your overall health and wellbeing, consider adding mushrooms to your menu, or order a mushroom dish whenever you eat out at your local Chinese or Japanese restaurant.
References
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Kodama, N., et al. “Effects of D-Fraction, a polysaccharide from Grifola frondosa on tumor growth involve activation of NK cells.” Biological and Pharmaceutical Bulletin 25, no. 12 (Dec 2002): 1647-50.
Mokhtar M.I.H. “Potential of Fungi Used in Traditional Chinese Medicine: Shiitake/shiang-gu (Lentinula edodes).” 2000. Available from www.world-of-fungi.org
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Wachtel-Galor, S., et al. “Ganoderma lucidum (‘Lingzhi’): acute and short-term biomarker response to supplementation.” International Journal of Food Sciences and Nutrition 55, no. 1 (Feb 2004): 75-83.
Wachtel-Galor, S., B. Tomlinson, and I.F.F. Benzie. “Ganoderma lucidum (‘Lingzhi’), a Chinese medicinal mushroom: biomarker responses in a controlled human supplementation study.” British Journal of Nutrition 91 (2004): 263–69.
Kizzy Gandy (BHSc, Chinese herbal medicine) works in regulatory affairs consultancy for complementary medicines and previously worked as a herbalist.
