Polysaccharide-K

Overview
Polysaccharide-K, also known as PSK, is a proteoglycan found in the polypore fungus Trametes versicolor. The results obtained from a large number of published scientific studies and clinical trials show that PSK is a powerful immunomodulator capable of stimulating diverse immunological functions.

For instance, PSK can improve cancer survival by restoring and enhancing cellular immune functions in patients with depressed immunity due to radiation and/or chemotherapy or surgical stress after curative resection of cancer.

PSK does not interact with other drugs nor affect hepatic drug-metabolizing enzyme activities indicating that drug efficacy is not affected by PSK when used with other medications. PSK is most effective when combined with a front-line anticancer treatment regimen (chemotherapy, radiation therapy or surgery) for patients with many types of cancer. Randomized controlled clinical trials and meta-analysis showed that overall survival and disease-free survival are improved in patients treated with adjuvant immunotherapy plus PSK. PSK is also beneficial for maintaining general immune health with no reported adverse side effects.

PSK is extracted from Trametes versicolor, a polypore mushroom found all over the world.

In Japan, it is called (polysaccharopeptide-Krestin) and in China, it is called PS-P (polysaccharide-peptide). PSK is used as a generic term for PS-Krestin and PS-P, which have the same chemical and structural characteristics.

Background
The medicinal mushroom, Trametes versicolor has been used in traditional Chinese and Japanese medicine for centuries. Trametes versicolor (also known scientifically as Trametes versicolor, and Polystictus versicolor, and by the common names of Yun Zhi in China, Kawaratake in Japan and Turkey’s tail in North America), belongs to a class of traditionally used mushrooms known as Basidiomycetes. Of the 20,000 species recorded, Trametes versicolor is best known commercially for its medicinal applications. 1

Trametes versicolor contains active substances that belong to a class of immune-modulators known as biological response modifiers (BRM) or immunomodulators whose therapeutic effects are derived from their capacity to stimulate key effector pathways of the immune system. Trametes versicolor is visible by its characteristic fan-shape leathery body marked with concentric shades of color, and it is commonly found year round growing as overlapping clusters with a fruiting body on tree trunks and dead trees particularly in the wooded temperate climates of China, Japan and North America.

Trametes versicolor has been traditionally harvested, dried, ground and reconstituted as a tea. The extract is recorded as being a remedy for treating a variety of symptoms associated with liver dysfunction and respiratory tract infection and for generally promoting a healthy body and spirit (Compendium of Materia Medica, AD1590), Vol 28, pp19- 21 (reprint edition), China Press, Beijing). In recent times, the extract is best known in Japan for use as an adjunct in the treatment of gastric and colorectal cancer.

The known therapeutic benefits of Trametes versicolor led Japanese researchers in 1971 to isolate an active substance from shelf mushroom or cultured mycelia. 2 The substance was identified as a proteoglycan (also called a polysaccharopeptide) and the given name is polysaccharide-Krestin (PSK). PS-P (Polysaccharide-Peptide).3,4 was later isolated from a Chinese strain of Trametes versicolor around 1983. Both PSK and PSP are produced (in Japan and China, respectively) in commercial quantities by fermentation of the mushroom to the mycelium stage. The mycelium biomass is then extracted with hot water and the active substance isolated by precipitation.

PSK was commercialized under the name Krestinon the Japanese market and was ranked 19th on the list of the world’s best selling medications with an annual sale in Japan worth US$357 million.4 It is used primarily as an adjunct immunotherapeutic agent in combination with standard cancer treatments such as chemotherapy, radiotherapy and surgery.

Since its discovery in 1971, over 350 scientific and clinical studies have been published demonstrating its potential benefits to a variety of diseases, especially cancer. 5 Similar work has been performed in China with PSP.4 For simplicity in the following description, PSK has been used as a general term to include both PSK and PSP.

Composition
PSK is a light or dark brown odorless and tasteless powder which readily dissolves in water. It contains approximately 35% carbohydrate (91% beta-glucan), 35% protein and the remainder are free residues such as sugars, amino acids and moisture. 6 PSK is a mixture of polysaccharides covalently linked to various peptides with an average molecular weight of 100 kilodaltons.7

The polysaccharide component is in a class of beta-glucans which comprise of glucopyranose units. Structural analysis showed that PSK has a 1, 4–glucan configuration as the main glucoside portion with branches at positions 3 and 6 at a frequency of one branch per several residual groups of 1 - 4 bonds.

Immunomodulatory Effects
PSK activates both innate and adaptive immune systems in which inflammatory and immune cells are stimulated to proliferate and differentiate into effector cells via key pathways controlled by cytokines acting in an autocrine or paracrine manner.

Receptors for beta-glucan have been found on immune and inflammatory cells such as neutrophils,8 natural killer cells,9 monocyte/macrophage, 8,9 T and B cells,10 suggesting that beta-glucan exerts its effect via a signaling pathway leading to the production of a variety of cellular immune functions through the release of soluble mediators including cytokines and chemokines.

In terms of effector function, several studies reported that PSK has the capacity to stimulate neutrophils and macrophages for enhanced cytotoxicity against tumour cells and to suppress lung metastasis in tumor-bearing mice and rats, probably through a TNF-α− dependent mechanism. 11,12

PSK is also able to salvage and stimulate defective dendritic cells for enhanced T cell cytotoxicity against colon carcinoma cells in vitro13 and to induce NK cell cytotoxicity against NK-sensitive tumour cells via dependent and independent mechanisms involving IL-2 and PSK. 14

In addition, PSK can promote both phenotypicand functional maturation of dendritic cells derived from CD14+ human peripheral blood monocytes, 15 suggesting that it could be potentially useful in dendritic cell [[vaccine therapy]].

It has been reported that PSK increased the production of circulating CD4+ T cells relative to CD8+ cells in cancer patients16,17 and restored delayed-type hypersensitivity (DTH) in patients as well as in tumour- bearing mice 18 with defective cellular immunity. In addition, PSK has been reported to restore cellular immune function in older people without disease but who have depressed cellular immunity.19,20

However, the response declined to pre-treatment levels when PSK was discontinued after taking PSK for 6-10 months. 19,20 The reason for this is unclear but it does mean that the beneficial effect of PSK in individuals with depressed immunity is only sustainable when PSK is taken on a continual basis. Laboratory investigation showed no abnormalities in white blood cell count, ESR and liver function tests related to PSK.

Dendritic cells (DC) are potent antigen-presenting cells that induce anti-tumor immunity. However, a defective function of these cells can occur thus jeopardizing the efficacy of DC-based immunotherapy in cancer patients. In vitro studies showed that PSK was capable of driving the maturation of dendritic cells to induce potent T cell cytotoxicity against tumor cells.21

Cytotoxic T cells are activated by Th1 helper T cells associated with cellular immunity which is deficient in a cancer-bearing state due to a shift to a Th2 helper cell dominance associated with humoral immunity which is ineffective against tumor cells. 22

Dendritic cells can be divided into DC1 and DC2 subpopulations which drive the differentiation of Th1 and Th2 cells, respectively. Therefore, maintaining a correct balance between the cellular (Th1/DC1) and humoral (Th2/DC2) immune responses is critical to host defense and survival as determined by the Th1 and Th2 patterns of cytokines produced. In patients who underwent surgical resection for gastric or colorectal cancer, oral PSK therapy resulted in a shift from a Th1/Th2 balance towards Th1 and DC1 dominance associated with anti-tumor activity.22 Thus PSK treatment may suppress the induction of a Th2 shift associated with poor prognosis of cancer by promoting a Th1 dominance to enhance CTL cells induction, resulting in better outcome in patients with cancer.22

Orally administered PSK has been reported to stimulate immunomodulating cytokines such as IL-8 and TNF-α in peripheral blood mononuclear cells from normal healthy subjects as well as patients with gastric cancer. 23 Among cytokines produced in response to PSK in vitro, there are tumor-necrosis factors, TNF-α/β and IFN-γ which are known to kill tumour cells and activate NK cell14 and T-cell cytotoxicity24,25 against tumour cell target, respectively. IL-8, a chemokine involved in chemotaxis is produced by neutrophils which play a key role in acute inflammatory response to bacterial infection, a normal process known to be crucial to host protection and disease resolution.

PSK is not only capable of stimulating the immune system but also modulating tumor cell function and the tissue environment to facilitate the local destruction of tumour cells by activated immune effector cells. For example, PSK was reported to suppress tumor-induced angiogenesis, 26 extravasation and metastasis26,27 and tumor invasiveness by inhibiting cytoskeletal functions and by down regulating invasion-associated cytokines such as TGF-β, urokinase plasminogen activator (uPA), MMP-2 and MMP-9 and to augment infiltration of tumor-lymphokine activated killer cells (LAK). 28,29 In addition, PSK is reported to act directly on tumor cells to enhance the expression of HLA-Class I antigen and adhesion molecule (ICAM-1) for increased containment and killing of tumour cells by effectors cells. 30

A depressed immunity can be attributed to a number of causes including advanced age, stress, poor gut function due to disturbed microflora, infection, disease, exposure to carcinogens and treatment with immunosuppressive agents such as chemotherapy and radiation therapy commonly associated with immune suppression. For example, PSK may act as an anti-oxidant by enhancing superoxide dismutase (SOD)31 and glutathione peroxidase activities to protect tissue damage from harmful effects of free radicals, 32-33 chemotherapy and/or radiotherapy.34 PSK has been shown to delay or prevent cancer development in animals exposed to chemical carcinogens35.

PSK is known to enhance cellular immunity associated with surgical stress. 36,37 Pre-treatment with PSK inhibited the decline in the numbers of CD4+, cytotoxic T cells and NK cells and Con-A-induced T cell suppression caused by cyclophosphamide in patients undergoing radical surgery.37,38 In another study, PSK was shown to be effective in enhancing NK cell activity in subjects with chronic fatigue. 39

PSK may also have potential benefits for the treatment of infectious diseases. Several studies have shown that PSK protects normal and immunosuppressed mice from infection with virus, fungi or bacteria normally associated with the effects of chemotherapy or radiotherapy.7,40-41 PSK was found to interfere with the binding of HIV-1 virus to receptor on CD4+ T cells and to inhibit the activity of reverse transcriptase in culture. 42 Anti-viral activity was also demonstrated in type 1 and 2 strains of herpes simplex virus (HSV) by inhibiting protein synthesis. 43 The capacity of PSK to inhibit B cell growth infected with Epstein-Barr Virus (EBV) has recently being demonstrated.44 It occurred via the activation of T cell function by monocytes producing IL-15. 44 In tumor-bearing mice exposed to the effects of chemotherapy, PSK showed benefit by restoring normal intestinal microflora essential for healthy gut function. 45

PSK can act directly on tumor cells through its ability to inhibit cancer spread46 and growth induced by angiogenesis.26 Other direct anti-tumor effects of PSK included the ability to inhibit prostrate cancer cell sensitive to the hormone androgen, 47 indicating that PSK may be beneficial for treatment of patients with hormone-responsive prostrate cancer or as a maintenance therapy for patients with colorectal cancer following surgery.48

Therapeutic Use
PSK has shown to enhance cellular immune functions in healthy subjects. A recent randomized, double blind, placebo controlled crossover study in normal healthy subjects showed that consumption of PSK (50 mg/kg body wt) together with an herbal extract from Salvia miltiorrhiza (‘Danshen’) known to be beneficial for the circulatory system enhanced cell-mediated immunity. 49

Complementary Treatment
The findings suggest that regular consumption of PSK may be beneficial for immunological functions by enhancing key pathways of cell-mediated immunity in healthy subjects. However, evidence relating to therapeutic use of PSK comes mostly from studies in cancer patients showing significant benefits from PSK immunotherapy when used in conjunction with surgery and radiation and/or chemotherapy. Positive results from numerous randomized controlled trials have been published for a number of malignancies, including colorectal, esophageal, breast, and lung cancer. Some selected randomized controlled trials for each disease category published in peer-reviewed journals are shown in (Table 3 -colorectal cancer). The results showed that PSK alone or given together with chemotherapy and/or radiation therapy following surgery significantly improved survival rates.

Clinical Trials

 * Colorectal cancer

Positive results have been obtained from randomized controlled single or multi-center trials in patients with advanced colorectal cancer including those with stage II/III diseases. 48, 40-53 The results for both disease response and survival outcome in patients with colorectal or colon cancer receiving chemotherapy or radiation therapy with PSK are shown in Table 3.

''Table 3. Randomised Controlled Trials for Colorectal Cancer''

A recent meta-analysis of three centrally randomised controlled trials confirmed that adjuvant immunotherapy with PSK plus chemotherapy can improve both survival and disease-free survival of patients with curatively resected colorectal cancer compared with chemotherapy alone.54 The overall survival risk ratio was 0.71 (95% CI:0.55-0.90; p <0.006) and the disease-free survival risk ratio was 0.72 (95% CI:0.58-0.90); p <0.003).


 * Lung cancer

The benefits of PSK to lung cancer patients have been recently demonstrated in more advanced stage III disease where radiotherapy is only marginally effective.In a non-randomized controlled study of stage I/III non-small cell lung carcinoma, patients who responded well to radiotherapy were given PSK (3g/day) for two weeks followed by 2 weeks rest or placebo in 2-week repeated cycles. 55

The patients (n=62)being given PSK experienced a significant overall improvement in 2-year (58% vs 22%; p<0.0001) and 5-year (27% vs 7%;p<0.0001) survival rates compared to the placebo group (n=123). When stratified to disease stage and age, patients with stage I/II(n=22) and stage III (n=32) epidermoid carcinoma receiving PSK experienced significantly better survival rate (39% vs 16%;p<0.005 and 22% vs 5%; p<0.004) than in the placebo groups receiving radiotherapy alone (n=42 and n=46, respectively). Furthermore, patients greater than 70 years old who received PSK had better 2- year and 5-year survival rates than those not receiving PSK (p<007).


 * Breast cancer

PSK has also been shown to be effective in adjuvant therapy for breast cancer (Table 4). The trials showed a trend towards an improvement in patients treated with chemotherapy plus PSK than those treated with chemotherapy alone although the differences were short of significance(p=0.099).56,57 Overall disease survival was also better in the chemotherapy plus PSK group but it also did not reach significance (p=0.0739). However, when the patients were stratified according to HLA-B40 antigen, the results showed that patients positive for HLA-B40 had a better survival rate than patients who were HLA-B40 negative (100% (9/9) vs 55% (7/13), p <0.05) at 5 yrs. 58 It was concluded that HLA-B40-positive patients may benefit most from adjuvant immunotherapy with PSK.

''Table 4. Randomised controlled trials for breast cancer'' v+, vascular invasion; n+, lymph node involvement; ¶, 5-fluorouracil, cyclophosphamide, mitomycin;, prednisolone; LMS; levamisole, ER, estrogen receptor


 * Gastric cancer

A well-designed multi-center trial published in the Lancet reported that patients (n=129) with Stages I-IV gastric carcinoma receiving a standard dose of PSK (3g/day) for 4 weeks alternating with chemotherapy for 10 cycles following curative resection of cancer significantly improved both the 5- year survival (70.7% vs 59%, p=0.044) and the disease-free survival rates (73% vs 60%, p=0.047) compared with those receiving chemotherapy only (n=124).59 Based on the results, the investigators recommended the addition of PSK to standard chemotherapy for resected gastric cancer.

In a retrospective study of 872 patients with gastric cancer, abnormal levels of carcinoembryonic antigen (CEA) and acute phase reactants (APR) were associated with better survival with PSK than those without PSK (29.3% vs 6.9%: p <0.0015).60 CEApositive patients receiving PSK therapy showed a significantly better survival rate than those without PSK (38.1% vs 18.6%,p=0.0136). 60


 * Esophageal cancer

In esophageal cancer patients (n=158) treated with radiotherapy and PSK (3 g/day) for >3 months, raised serum �antichymotrypsin levels were associated with a higher survival rate at 5 years than in the control group (55% versus 26%, p < 0.008).61 Similarly, overall 5-year survival rate was also higher in patients with elevated serum sialic acid levels (58% vs 31%, p <0.07). 59 These findings are consistent with those reported for gastric cancer where patients with raised serum levels of tumor markers may benefit most from immunotherapy using PSK.60


 * Nasopharyngeal cancer

PSK was found to be effective in reducing the metastatic rate in a randomised study of 38 patients with stage I-IV nasopharyngeal carcinoma when used following radiotherapy with or without chemotherapy (14% vs 35%). 62 Median survival (35 months vs 25 months, p<0.043) and 5-year survival rate (28% vs. 15%, p<0.043) was significantly better in the PSK treatment group. The results suggest that PSK may be a useful therapeutic agent in the management of nasopharyngeal cancer.


 * Leukemia

The addition of PSK to maintenance chemotherapy was also found to improve the survival rate of patients with acute myelogenous leukemia (AML)63 but this was short of statistical significance (p =0.105). However, patients who remained in remission for 270 days benefited for a further 418 days on PSK. In another study, PSK was effective in preventing relapse in childhood acute lymphoblastic leukaemia following treatment with chemotherapy but the benefit was also not statistically significant.64 While showing no significant clinical benefit, no adverse side-effects were noted with PSK use in this paediatric population.

Side Effects
PSK has been shown to have minimal or no adverse effects although early studies have reported occasional effects including coughing, nail pigmentation, constipation and diarrhoea. 48,49 The side effects were significantly reduced when PSK was formulated in tablets or capsules instead of the medication taken in the powder form reconstituted in water.48 Low grade gastrointestinal and haematological toxicities have been reported, which may be due to chemotherapeutic agents and radiation themselves. 51,52 According to Drug Adverse Reaction Report of the Japanese Ministry of Health and Welfare, side effects caused by PSK were experienced in 114 of a total of 11,300 cancer patients (1.01%). 65 The main complaints were associated with diarrhoea and nausea.

Pharmacokinetics
PSK is present in the form of stable large molecules in blood, lymph and bile of tumor-bearing mice within 4 hrs after oral ingestion whereas smaller molecules are largely degraded in the digestive system.66 The intact stable molecules are detectable in the bone marrow, spleen, brain, liver, mucosal tissues, pancreas and tumour tissue.

About 70% is lost by expiration at 24 hrs and 30% in the urine after 72 hrs following ingestion.66 PSK does not interact with other drugs nor affect drugmetabolizing enzyme activities in the liver, 67 indicating that PSK has no effect on the efficacy of other drugs when taken in together with PSK.

Commercial Production
Mushrooms grown in the wild are non-commercially viable due to low volume and environmental contamination. Therefore, PSK is now produced commercially from cultured mushrooms or mycelia cultivated on solid substrate68 or mycelial biomass produced in submerged fermentation.68-70 The culture medium contains glucose or sucrose as the carbon source and peptone, yeast extract, yeast powder, peanut flour, soybean flour and soy sauce as a source of nitrogen, magnesium and phosphate. Fermentations are carried out for 7 days at 23-280C with stepwise feeding with fresh medium. The yield obtained as a biomass varies from 4 to 23 g/L depending on the size of the fermenter or the bioreactor. PSK is obtained by a multi-step hot water extraction of the Coriolus versicolor hyphae biomass. The extract is concentrated and the active substance is recovered by precipitation with ethanol.

Regulatory Status
In Japan, PSK is a prescriptive medication for use at a dosage of 3 g per day as an adjunct immunotherapeutic agent together with chemotherapy and/or radiotherapy and surgical treatments of colorectal and gastric cancers. Safety evaluations have reported that the product is extremely safe and complied with LD-50 test.

In other parts of Asia, PSK is sold as an OTC product in pharmacies to be taken in 500 mg capsules or as an extract or as a tea. PSK is also marketed in the US as a food supplement or a class of mushroom ‘immunoceuticals’ with known immunotherapeutic properties.

PSK is recorded as an anti-cancer fungal substance suited for treatment regimens used in cancer management by the American National Cancer Research Center 71,72 but has not been evaluated by the Food and Drug Administration.

PSK Coriolus versicolor is available worldwide from various sources on the internet.