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220
CHAPTER 10 CONCLUSIONS
The effect of purified polysaccharides on immunostimulation and
cancer therapy
This Report has attempted to appraise, in particular but not exclusively, the
therapeutic functions of mushroom polysaccharides and polysaccharide-protein
complexes on animal and human systems. Amongst their many biopharmacological
activities the most intriguing are those associated with immunomodulatory and anticancer
effects. In mushrooms, they occur mostly as glucans with different types of
glycosidic linkages such as (1-3), (1-6)-β-glucans and (1-3)-α-glucans, as true
heteroglucans, while others bind to protein residues as polysaccharide-protein
complexes.
Why then do these mushroom polysaccharides display such an array of
biopharmacological activities? Polysaccharides, unlike proteins and nucleic acids,
contain repetitive structural features that are polymers of monosaccharide residues
joined to each other by glycosidic linkage. Consequently, these polysaccharides
offer a high capacity for carrying biological information because of their increased
potential for structural variability. The amino acids in proteins and the nucleotides in
nucleic acids can only interconnect in one way while the monosaccharide units in the
polysaccharides can interconnect at several points to create a wide array of linear
and branched molecules. It has been calculated that the number of possible
permutations from four different sugar monosaccharides could be up to 35, 560
unique tetrasaccharides, whereas four amino acids can form only 24 different
permutations. This, then, creates a vast potential flexibility for the precise regulatory
mechanisms of various cell-cell interactions in higher organisms. Is this then at least
221
a part explanation for the multivarious medical claims that have been made for the
extracts from medicinal mushrooms used in TCM?
A fundamental principle in Oriental medicine is to regulate homeostasis of the
whole body and to bring the diseased person to the normal state. Potentiating the
physiological constitution in favour of host defence results in the activation of many
vitally important T-cells for the maintenance of homeostasis. Of significant relevance
and importance is the reported ability of particular mushroom-derived compounds to
modulate human immune responses and to inhibit certain tumour growths. Currently,
and in marked contrast, medicinal mushrooms are not yet employed in Western
medicine practices despite the ongoing intensive research for new or complementary
therapeutic solutions such as for the treatments of cancer, immmunodeficiency
diseases, or for generalised immunosuppression following conventional treatment. A
significant hurdle to their non-introduction has been, until recently, the lack of
supporting scientific and medical data in peer-reviewed Western journals.
Medicinal mushroom research has focused on discovering compounds that
can modulate positively or negatively the biological response of immune cells.
Certain mushroom derived-glucans and polysaccharide-bound proteins have been
shown to act as immunomodulators or biological response modifiers (BRMs), where
these polymers interact with the immune system to upregulate or downregulate
specific aspects of the responses of the host and this may result in various
therapeutic effects. Whether certain compounds enhance or suppress immune
responses can depend on a number of factors including dosage, route of
administration, timing and frequency of administration, mechanism of action or the
site of activity. Many mushroom-derived polysaccharides appear to fit the accepted
criteria for BRM compounds. They cause no harm and place no additional stress on
222
the body, they assist the body to adapt to the various environmental and
psychological stresses, and they have a non-specific action on the body, supporting
all the major systems, including nervous, hormonal, and immune systems, as well as
regulatory functions.
In this report, a wide variety of mushroom polysaccharides, including Lentinan
(from L. edodes), Schizophyllan (from S. commune), PSK and PSP (from Trametes
versicolor), and Grifron-D (from the Maitake mushroom G. frondosa) and others are
described, and their properties are shown to satisfy the criteria for BRMs. Many of
these mushroom-derived polymers potentiate the host’s innate (non-specific) and
acquired (specific) immune responses in a similar manner, where they activate many
kinds of immune cells that are vitally important for the maintenance of homeostasis.
Key innate responses that are stimulated by these mushroom derived-β-glucans or
polysaccharide-protein complexes include host T-cells (such as cytotoxic
macrophages, monocytes, neutrophils, natural killer cells, and dendritic cells) and
chemical messengers (cytokines such as interleukins, interferon and colony
stimulating factors) that trigger complement and acute phase responses. Moreover,
mushroom polysaccharides or polysaccharide-protein complexes are considered as
multi-cytokine inducers that are able to induce gene expression of various
immunomodulatory cytokines and cytokine receptors. In addition, acquired
responses are also enlisted, where lymphocytes that govern antibody production (Bcells)
and cell-mediated cytotoxicity (T-cells) are stimulated. While the immune
system is shrouded in tremendous complexity, our current understanding shows that
it is regulated in an orchestrated dynamic manner.
Mushroom-derived polysaccharides have shown anti-tumour activities in both
pre-clinical models and in clinical trials. Although the mechanism of their anti-tumour
223
action is still not completely clear, Lentinan, Schizophyllan, PSP, PSK and other
mushroom polysaccharides appear to mediate their anti-tumour activity by activation
or augmentation of the host’s immune system (via stimulated cytotoxic
macrophages, cytotoxic T-cells and antibody-mediated cytoxicity of targeted cancer
cells), rather than direct cytotoxicity. Thus, both cell-mediated immune responses
against the target T-cells initiated by macrophage-lymphocyte interactions and
cytoxicity induced by antibodies to target T-cells are believed to contribute to the
elimination of targetted tumour cells. Recent evidence suggests that several
mushroom polysaccharides may also possess cytotoxic properties. Grifron-D from G.
fondosa mushroom was reported to induce apoptosis (programmed cell death) in
human prostate cancer cell-lines.
The likely mode of immunopotentiation by mushroom macromolecules
involves activation of cytotoxic macrophages, helper T-cells and NK cells, and the
promotion of T-cell differentiation. Macrophages are one of the many critical
components in the immune system, necessary for tumour rejection. Macrophages
have a highly selective cytotoxicity towards cancer cells in vitro; and there is
evidence that they may also destroy malignant T-cells in vivo. T-cell competence
appears necessary for selection of macrophage resistance, which suggests that
these two cell types interact in the intact host in response to a tumour challenge.
Neither Schizophyllan nor Lentinan demonstrated any anti-tumour activity against
Sarcoma 180 in in vivo experiments with cyclosporin A as a T-cell suppressor, which
suggests that an immunocompetent T-cell component is necessary for developing
anti-tumour activity. These results indicate that Schizophyllan and Lentinan are T-cell
oriented immunopotentiators and, therefore, require a functional T-cell component
for their biological activity and that the action of (1-3)-β-D-glucans on the host’s
224
immune system might increase helper T-cell production, increase macrophage
production, and bring about stimulation of acute phase proteins and colony
stimulating factors, which in turn effects proliferation of macrophages, neutrophils,
and lymphocytes and activation of the complement system. The immunopotentiating
activity of β (1-3)-D-glucans would appear to depend on the presence of a helical
conformation with hydrophilic groups located on the outside surface of the helix.
By way of further examples, both PSK and PSP are potent immunostimulators
with specific activity for T-cells and for antigen-presenting cells such as monocytes
and macrophages. The biological activity is characterized by their ability to increase
white blood cell counts, interferon-γ and interleukin-2 production and delayed type
hypersensitivity reactions. Numerous reports have documented the ability of PSK
and PSP to activate cellular (helper and cytotoxic T-cells) and humoral (antibody)
components of the host immune system. In addition, these polysaccharides have
been shown to inhibit the growth of tumour cell lines and to have in vivo anti-tumour
activity. Recently, the anti-tumour activity of medicinal mushrooms has been
evaluated in Japan for the prevention of oesophageal, gastric, and lung cancer in
humans with promising results. In Phase II and Phase III trials in China, PSP
significantly enhanced immune status in 70 to 97% of patients with these cancers. In
these studies, PSK and PSP increased the number of immune cells and facilitated
dendritic cell (antigen-presenting cell) and cytotoxic T-cell infiltration of tumours.
The proprietary mushroom polysaccharides such as Lentinan, Schizophyllan,
PSK and PSP, and Grifon-Dare not miracle drugs but can increase the quality of life
of cancer patients and may offer increased survival rates for some types of cancer,
especially when they are used as adjuncts to conventional forms of treatment. The
enhanced survival rates with such compounds appear very promising and it is to be
225
hoped that Western oncologists will now look more carefully and appreciatively at the
wealth of information set out in this document, and assess the potential for
incorporating some aspects into current cancer research. The Maitake compound,
Grifron-D, is now undergoing extensive clinical trials in the US. Many thousands of
US physicians now use proprietary mushroom polysaccharides in treatment
programmes, possibly aided by a much higher Asian-derived populace.
These compounds have been shown to be safe when taken over long periods
of treatment; and significantly, these compounds appear to reduce the adverse
effects of radiotherapy and chemotherapy. These results are in contrast to the welldocumented
adverse side-effects associated with most chemotherapeutic
compounds and also, but to a lesser extent, certain immunotherapeutics. Such
compounds have been shown to be capable of causing fevers, chills, rash, eodema,
arthralgia, hypotension, congestive heart failure or CNS toxicities.
Almost all of the current cancer rearch studies utilising mushroom
polysaccharides have been performed using only individual components. Only a few
studies have applied mixtures of proprietary compounds. This is to be expected
since the purified compounds such as Lentinan, PSK and Grifron-D are produced
by different companies. It could be expected that by utilising mixtures of these
proven compounds the immune system would receive multiple stimuli possibly
leading to stronger anti-cancer effects. At the recent Kiev Conference on Medicinal
Mushrooms, Professor Ikekawa strongly advocated the use of mixtures of the
accepted anti-cancer mushroom-derived compounds for clinical cancer treatments
(personal communication). Some recent clinical studies have been mentioned in
Chapter 7.
226
As stated by Kidd (2000), “glucan and proteoglycan mushroom
immunoceuticals offer hope for cancer patients. These substances are prohomeostatic,
uniquely effective immune boosters, which pose no threat of
autoimmune backlash. As dietary supplements, they are safe, and exhibit nearperfect
benefit-risk profiles. Mushroom immunoceuticals are a potential boon to
individuals afflicted with cancer living with impaired immunity, or merely descending
into ill-health with the passing of time.”
The effect of whole medical mushrooms and concentrated extracts
(dietary supplements) as functional foods
Scientific and medical studies with the medicinal mushrooms have mainly
concentrated on the application of purified polysaccharide compounds such a
Lentinan, Schizophyllan, Grifron-D, PSK and PSP on animal and human systems.
What then can be surmised on potential health benefits from consuming fresh
mushrooms or crude concentrates derived from them?
As a source of nutrients, mushrooms continue to be under-valued in the UK
where many believe that mushrooms are low in nutrients and are of little or no value
to health. In truth, most edible and culinary mushrooms (e.g. Agaricus bisporus –
the button mushroom, and Lentinus edodes – the Shiitake), are very rich in minerals
(e.g. potassium, calcium and magnesium), various vitamins (D2, B2, C and niacin),
dietary fibres, proteins and all the essential amino acids and yet are extremely low in
calories, fat and cholesterol. The potential nutritional value of mushrooms ranked by
internationally-accepted tests compares well with meat and milk and more so than
some common vegetables. Many wild edible mushrooms are often more
flavoursome than their cultivated relatives (e.g. the Chanterelle). In Japan,
mushrooms are highly rated and recommended by doctors and nutritionists, together
227
with green vegetables, to promote good health. Edible mushrooms must, therefore,
be considered foremost as ‘healthy’ foods and their consumption should be
encouraged in healthy eating programmes especially where the levels of fats and
cholesterol are to be minimilised, e.g. with respect to cardiovascular diseases.
In Traditional Chinese Medicine, many mushrooms have long been part of a
wide range of treatment regimes mostly used in the form of dried powders of the
mushroom fruit-bodies or as hot water extracts of the same. While many of these
medicinal mushrooms were both medicinal and nutritious, others were inedible and
only used for their medicinal qualities (how these qualities were first identified will
forever be a mystery). When used for medicinal purposes the medicinal properties
are derived from a relatively large quantity of fresh mushrooms, not normally
consumed in the average eating portion. The question, then, arises on how valuable
to the individual is the consumption of fresh medicinal mushrooms? In murine
studies, regular feeding of certain whole medicinal mushrooms stimulated aspects of
the immune system and did inhibit growth of existing tumours. There has been no
research on the prophylactic effects of medicinal mushroom intake on, for instance,
the development of spontaneous tumours in humans. However, in this respect, a
survey conducted among Japanese mushroom workers in the Nagano Prefecture in
Japan, implied that the regular eating of mushrooms (mostly the edible, medicinal
variety Flammulina velutipes) was associated with a lower death rate from cancer
than of other people in the Prefecture (Table 1). This study strongly suggests that
quantity and frequency of intake of the mushrooms were related to the lowered
cancer death rate. A detailed large-scale epidemiological study is ongoing
conducted by the NCC Research Institute of Japan, Nagamo Agricultural Technology
228
Institute, and Hospitals as a cohort study of the Japanese Ministry of Health and
Welfare.
Table 1 Comparison of Cancer Death Rate (Ikekawa, 2001)
Average cancer death rate in Nagano Prefecture
Total 160.1
Man 90.8
Woman 69.3
Average cancer death rate of farmers producing an edible mushroom in Nagano
Prefecture
Total 97.1
Man 57.5
Woman 39.7
Cancer death rate: rate per 100,000 age-adjusted rates.
Total population: 174,505. Years investigated 1972-1986.
The cancer date rate of the farmers producing Flammulina velutipes as a main
occupation was remarkably lower than that of the total Nagano Prefecture, Japan
(p<0.01).
Agaricus blazei has become an important source of antitumour
polysaccharides and is now being artificially grown in Japan and studied
pharmacologically. This fungus is native to a small mountainous area near Sao
Paulo, Brazil. Epidemiologists when studying the native population of this small area
found that such people had a very low incidence of several illnesses, including
cancer, viral and bacterial diseases, together with a disproportionally higher number
enjoying longevity. This has been correlated with the constant consumption of this
mushroom in their normal diet. In recent years there has been extensive research
on the medicinal properties of this mushroom, mostly in Japan, clearly demonstrating
immunostimulatory activity and antitumour action (Reshetnikov et al., 2001).
In Asia, several medicinal/edible mushrooms are regularly (often daily)
consumed in the average diet. Whether the amount consumed by this route can be
229
expected to have a limited or a significant effect on the immune system in sick or
healthy people must be the subject of future research. In this respect the final
outcome of the Nagano epidemiological study could have tremendous significance.
As previously discussed, oral ingestion of concentrates of L. edodes and G.
frondosa can modulate certain murine immune functions. The consumption of L.
edodes concentrates as part of a regular diet had immune stimulatory as well as
immunosuppressive effects in mice depending on the strain and the specific immune
function studied. Could regular ingestion of medicinal mushroom concentrates as
dietary supplements be of significance to human health? The huge, world-wide sale
of such products, can testify to the beliefs of many, of their efficacy. Proof of efficacy
must surely be the defining factor for those who remain sceptical. Again, the
previous statement of Kidd (2000) extolling the value of partially purified mushroom
polysaccharides as immune system modulators must also be relevant to some
extent with whole medicinal mushrooms and, more especially, with crude
concentrates.
There is now increasing evidence with experimental animals that regular
feeding of powdered medicinal mushrooms can have a cancer prevention effect,
demonstrating both high antitumour activity and restriction of tumour metastasis. A
recent study by Professor Ikekawa (2001) demonstrated the preventive effects of the
edible mushroom Hypsizygus marmoneus. Control mice were bred on an ordinary
feed and the treated mice on the feed also containing 5% dried fruit-bodies of the
mushroom. All mice were injected i.p. with a strong carcinogen, methylcholanthrene,
and carcinogenesis of the mice recorded. After 76 weeks, 21 of 36 mice developed
tumours in the control mice but only 3 of 36 mice in the treated group had tumours.
Thus, the intake of this medicinal mushroom proved to be effective in cancer
230
prevention and tumour growth inhibition. This study confirms previous studies with
Lentinus edodes and Pleurotus ostreatus.
Yet another interesting study on cancer chemoprevention using mushroom
polysaccharides is the yet unpublished paper by Shon and Nam (2002) using the
mouse skin carcinogenesis model (Holden et al., 1997) to study changes involved in
tumour promotion. In these studies 12-0-tetradicanoylphorbol-13-acetate (TPA)-
induced tumour promotion in mouse epidermis previously initiated with 7, 12-
dimethylbenz[a] anthracene (DMBA) was used. The effects of polysaccharides
derived from the medicinal mushrooms Phellinus igniarius and Agrocybe cylindracea
applied topically were then studied. Topical application of polysaccharides from
either P. igniarius or A. cylindracea together with TPA twice weekly for 12 weeks
inhibited the number of skin tumours per mouse by 69.7 or 88.2% respectively and
the percentage of mice with tumours was lowered by 70.0 or 30.0% respectively.
It is tempting to draw an analogy between the medicinal/edible mushrooms,
with their proven medicinal properties when applied in purified and crude concentrate
forms, and the anticancer phytochemicals of fruit and vegetables. However, it is
perhaps unlikely that there will be a major increase in fresh or processed medicinal
mushroom consumption in the UK in line with Asian culinary practice. The
imbalance could be reduced by the consumption of medicinal mushrooms as dietary
supplements in the form of capsules or elixirs. Notwithstanding, the value of the
medicinal mushrooms as true functional foods/dietary supplements can no longer be
in doubt. Indeed, the abundance of scientific evidence confirms the role of certain
mushrooms as valuable functional foods/dietary supplements in the human diet. The
very considerable historical evidence with edible medicinal mushrooms would
strongly suggest that they are the very first truly functional foods.
231
When the British public become more aware of the significant medical and
flavour attributes of the edible medicinal mushrooms, perhaps there will be a positive
change in consumer acceptance and consumption. Such a change has already
occurred in the US with the recognition of certain medical mushrooms, with ‘healthy’
food and ‘healthy’ medicine. Perhaps the major supermarkets will take a lead and
promote mushrooms in general and medicinal mushrooms in particular as novel,
scientifically and medically proven functional foods. Sadly, so many products now
being sold as functional foods, are mere marketing ploys and have dubious and,
indeed, unproven efficacy – not so the medicinal mushrooms!
The vast majority of medicinal mushrooms are cultivated in the Far East
though production of the Shiitake (L. edodes) and the Oyster mushroom (P.
ostreatus) are now increasing in the UK and Europe. Recent studies in Japan have
shown that the concentration of the polysaccharide Lentinan (L. edodes) and
Grifron-D (G. frondosa) remain relatively stable in the fruit-bodies when the
harvested mushrooms are stored at 4oC for up to one week. In contrast, these
same polysaccharides are greatly reduced by endogenous enzyme activity at 20oC
over the same time period as measured by reduced tumour necrosis factor (TNF)-α
and nitric oxide production from macrophages. Clearly, time from harvesting to
consumption is of critical importance to retain the important medicinal properties of
these mushrooms and should certainly be a significant factor for fresh mushroom
production and also for the production of concentrates or dietary supplements.
In final summary this Report has demonstrated that many mushroom species
(the medicinal mushrooms) contain some unique and intriguing biochemical
compounds that have undergone controlled clinical studies in Asian and some
Western research institutions and hospitals demonstrating considerable
232
effectiveness in the treatment of many diseases, especially cancer. In cancer
treatment they have largely been used as adjuncts to traditional chemotherapy and
radiotherapy. In addition, the remarkable ability of many of these non-toxic and
compatible compounds to reduce the debilitating effects of traditional
chemotheropeutic drugs is notable. Indeed, there are also many examples where
the use of these compounds allows the reduction in dose level of the toxic
chemotherapeutic compound without reduced efficacy. Chemotherapy can severely
impair immune function. By limiting this ‘iatrogenic’ or ‘physician-induced’
immunosuppression by means of mushroom polysaccharides could be the great
benefit to physicians.
There is now increasing evidence that whole mushroom powders and extracts
can exert cancer chemoprevention when incorporated into the diet or applied
topically to experimental animals. Human epidemiological studies in Japan and
Brazil strongly suggest that regular consumption of certain medicinal mushrooms
over prolonged periods of time significantly reduce the levels of cancer incidence.
In Asia, mushrooms occupy an important and regular part of the daily diet
whereas in the West this does not happen to the same extent. Perhaps as the
edible medicinal mushrooms such as the Shiitake and Enoke become more readily
available to the Western customer and their culinary and medicinal values become
more appreciated then the level of uptake will increase. In the meantime, dietary
supplements consisting of whole mushroom extracts are becoming increasingly
popular. Unlike most dietary supplements mushroom dietary supplements contain a
veritable Pandora’s box of compounds with variable medical claims. What level of
consumption or intake can exert healthy benefits is still a matter of debate and
warrants some level of clinical study.
233
The edible medicinal mushroom must be considered as the ultimate functional
food when consumed in the whole fresh form or as concentrates or dietary
supplements. Non-edible medicinal mushrooms will be consumed only as dietary
supplements.
As Mark Twain said:
“Good health is not just the absence of disease”
234
References
Holden, P.P., Mcguire, B., Stoler, A., Belman, A. and Pitts, J.D. 1997. Changes in gap junctional
intercellular communication in mouse skin carcinogenesis. Carcinogenesis 18, 15-21.
Ikekawa, T. 2001. Beneficial effects of edible and medicinal mushrooms on health care. International
Journal of Medicinal Mushrooms 3, 291-298.
Reshetnikov, S.V., Wasser, S.P. and Tan, K.K. 2001. Higher Basidiomycetes as a source of
antitumour and immunostimulating polysaccharides (Review). International Journal of
Medicinal Mushrooms 3, 361-394.
Shon, Y-H. and Nam, K-S. 2002. Inhibitory effect of soybeans fermented with basidiomycetes on
DMBA/TPA—induced mouse skin carcinogenesis. Biotechnology Letters (in press).
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