Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor – PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide – have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens.
Department of Biochemistry, Kitasato University School of Medicine, Kanagawa, Japan.
Abstract
Natural killer (NK) cells are susceptible to reactive oxygen species (ROS), and lose the activity by the effects of ROS. Cancer bearing hosts usually suffer from oxidative stress (OS), and the NK-activity decreases to a significantly lower level than normal controls. Superoxide dismutase (SOD)-mimicking substances, such as protein-bound polysaccharide of Coriolus versicolor (Fr) QUEL (PSK) and iron-chelating chlorine e6-Na (FeCNa), can restore the NK-activity of cancer bearing hosts, when collaborating with catalase. Incorporation of 3H-thymidine by ROS-treated NK-cells is not affected, indicating that these cells are still active in the nucleic acid metabolism. Intraperitoneal administration of anti-Asialo GM1 antibody extinguished the NK-activity. NK-cells affected by ROS lost the adherence to target cancer cells in both in vitro and in vivo. ROS may change the surface charge of NK-cells to anionic, resulting in an inability of adhesion to target cancer cells which usually show the negative surface charge.
Radiobiology Laboratory, St. Mary’s Medical Center, California Pacific Medical Center Research Institute, San Francisco 94118, USA.
Abstract
Polysaccharide-K (polysaccharide-Kureha; PSK), also known as krestin, is a unique protein-bound polysaccharide, which has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. PSK and Polysaccharopeptide (PSP) are both protein-bound polysaccharides which are derived from the CM-101 and COV-1 strains of the fungus Coriolus versicolor by Japanese and Chinese researchers, respectively. Both polysaccharide preparations have documented anticancer activity in vitro, in vivo and in human clinical trials, though PSK has been researched longer and has therefore undergone more thorough laboratory, animal and clinical testing. Several randomized clinical trials have demonstrated that PSK has great potential as an adjuvant cancer therapy agent, with positive results seen in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunotherapy or biological response modifier (BRM). BRMs potentially have the ability to improve the “host versus tumor response,” thereby increasing the ability of the host to defend itself from tumor progression. The mechanisms of biological response modification by PSK have yet to be clearly and completely elucidated. Some studies suggest that PSK may act to increase leukocyte activation and response through up-regulation of key cytokines. Indeed, natural killer (NK) and lymphocyte-activated killer (LAK) cell activation has been demonstrated in vivo and in vitro, and recent genetic studies reveal increased expression of key immune cytokines in response to treatment with PSK. An antimetastatic action of PSK has also been demonstrated and is perhaps attributed to its potential to inhibit metalloproteinases and other enzymes involved in metastatic activity. PSK has also been shown to cause differentiation of leukemic cells in vitro, and this effect has been attributed to induction of differentiation cytokines. PSK has further been shown to have antioxidant capacity which may allow it to play a role as a normal tissue chemo- and radio-protector when used in combination with adjuvant or definitive chemotherapy and/or radiotherapy in the treatment of cancer, while it may also enable it to defend the host from oxidative stress. Interestingly, studies have also shown that PSK may actually inhibit carcinogenesis by inhibiting the action of various carcinogens on vulnerable cell lines. This action of PSK may play a role in preventing second primary tumors when an inducing agent, such as tobacco or asbestos, is suspected and may also prevent second malignancies due to the carcinogenic effects of radiotherapy and cytotoxic chemotherapy. Another very important aspect of chemoimmunotherapy, in general is that it may be used on debilitated patients such as those with AIDS and the elderly who might otherwise be denied potentially helpful adjuvant cytotoxic chemotherapy. Further determination of the mechanisms of these anti-cancer, immunostimulating and biological response modifying effects of PSK as well as of other protein-bound polysaccharides is certainly warranted. Indeed, with modern cellular and molecular biology techniques, a better understanding of the specific molecular effects of PSK on tumor cells as well as leukocytes may be determined. Much of the research that has been done on PSK is outlined in this paper and may serve as a foundation toward determining the mechanisms of action of this and other protein-bound polysaccharides in the treatment of cancer. This information may open new doors in the development of novel strategies for the treatment of malignancies using adjuvant immunotherapy in combination with surgery, chemotherapy and/or radiotherapy.
Osaka Organic Chemical Industry, Ltd, Kashiwara, Japan.
Abstract
4-Acetyltropolone, a minor component of Thujopsis dolabrata SIEB. et Zucc. hondai MAKINO, showed antimicrobial activity against various microorganisms including wood-rotting fungi, a phytogrowth-inhibitory effect with chlorophyll biosynthesis inhibition, cytotoxic effect and inhibitory activity on metalloproteases. This compound had strong antifungal activity on Daedalea dickinsii IFO-4979 [minimum inhibitory concentration (MIC): 0.2 microg/ml] and Coriolus versicolor IFO-4940 (MIC: 0.39 microg/ml). Its cytotoxic effect at 20.0/microg/ml on human stomach cancer KATO-III and Ehrich’s ascites carcinoma was stronger than those of podophyllotoxin, vincristine and vinblastine, the anticancer agents isolated from higher plants and used clinically. This compound also had potent antibacterial activity against Staphylococcus epidermidis IFO-12993, its MIC being 1.56 microg/ml. However, other biological activities of 4-acetyltropolone were lower than those of hinokitiol which is the main component of this plant, suggesting that the contribution of the acetyl group at C-4 to biological activity is smaller than that of the isopropyl group at that position. The acute toxicity of 4-acetyltropolone (LD50: 335.2 mg/kg) to mice was much lower than that of hinokitiol (LD50: 191 mg/kg).
PMID: 12186430 [PubMed – indexed for MEDLINE]Free Article
Institute of Technology and Engineering PN456, Massey University, Private Bag 11 222, 5320, Palmerston North, New Zealand.
Abstract
The protein-bound polysaccharides or polysaccharopeptides produced by Coriolus versicolor are effective immunopotentiators, which are used to supplement the chemotherapy and radiotherapy of cancers and various infectious diseases. Antitumor activity of polysaccharopeptides has been documented. Several kinds of protein-bound polysaccharides have been shown to be produced by the white rot fungus, C. versicolor. Although some of these polymers are structurally distinct, they are not distinguishable in terms of their physiological activity. This review focuses on the physiologically active polysaccharopeptides of C. versicolor. In nature, C. versicolor occurs as a mushroom body, but the fungus can be grown as mycelial biomass in submerged culture in bioreactors. Mushrooms gathered in the wild, cultivated mushrooms, and the mycelial biomass of submerged culture are used to produce the polysaccharopeptides. Submerged cultures are typically carried out in batches lasting 5-7 days and at 25-27 degrees C. Hot water extraction of the biomass is used to recover the thermostable polysaccharopeptides that are concentrated, purified, and dried into a powder for medicinal use. In view of the documented physiological benefits of these compounds, extensive research is underway on the structure, composition, production methods, and use of new C. versicolor strains for producing the therapeutic biopolymers. Properties, physiological activity, recovery, and purification of the bioactive polysaccharopeptides are discussed.
Breakspear Hospital, Hemel Hempstead, Herts, United Kingdom. jmonro@breakspearmedical.com
Abstract
Cancer has been attributed to 3 causes: pollution, infection, and poor nutrition. Conventional treatments include surgery, chemotherapy, and radiotherapy. The author proposes that immunotherapy also be considered. Among other environmental influences, dietary deficiencies and carcinogenic viral infections must be investigated and treated wherever possible. It has been suggested that mushrooms, in particular, have a structure that is immunomodulatory because it resembles the proteoglycan structure in the human extracellular matrix, and both are metabolically active. Inasmuch as mitochondria have a bacterial origin, proteoglycans may have a mushroom origin. The author describes a study which shows that natural killer cells can double in number with 8 wk of treatment with Coriolus versicolor. Also described is an epidemiological survey of cancer deaths among Flammulina velutipes farmers in Japan, which found that the mushroom farmers had lower rates of cancer deaths than controls who were not involved in mushroom farming.
Department of Zoology, The University of Hong Kong, Pokfalum Road, Hong Kong, SAR, P.R. China.
Abstract
The polysaccharide peptide (PSP) isolated from the mycelia of Chinese Medicinal fungus Coriolus versicolor has proven benefits in clinical trials in China but the mechanism of action has not been elucidated. In this study, HL-60 cell line was used to investigate the anti-proliferation and cell death process of PSP. The cytotoxicity of PSP on normal human T-lymphocytes was also evaluated. We show that PSP induced apoptosis of human promyelocytic leukemia HL-60 cells but not of normal human T-lymphocytes. The apoptotic machinery induced by PSP was associated with a decrease in Bcl-2/Bax ratio, drop in mitochondrial transmembrane potential, cytochrome c release, and activation of caspase-3, -8 and -9. Activation of the cellular apoptotic program is a current strategy for the treatment of human cancer, and the selectivity of PSP to induce apoptosis in cancerous and not on normal cells supports its development as a novel anticancer agent.
School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Abstract
Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells, but the underlying mechanism has not been fully elucidated. The present study aimed to evaluate the in vitro anti-tumor activity of a standardized aqueous ethanol extract prepared from CV on four breast cancer cell lines using MTT assay, and test whether the mechanism involves apoptosis induction and modulation of p53 and Bcl-2 protein expressions using cell death detection ELISA, p53 and Bcl-2 ELISAs respectively. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of three breast tumor cell lines, with ascending order of IC50 values: T-47D, MCF-7, MDA-MB-231, while BT-20 cells were not significantly affected. Tumoricidal activity of the CV extract was found to be comparable to a chemotherapeutic anti-cancer drug, mitomycin C. Nucleosome productions in apoptotic MDA-MB-231, MCF-7 and T-47D cells were significantly augmented in a time-dependent manner and paralleled the anti-proliferative activity of CV extract. Expression of p53 protein was significantly upregulated only in T-47D cells treated with the CV extract in a dose- and time-dependent fashion, but not in MCF-7 (except at 400 mug/ml after 16 h) and MDA-MB-231 cells. The CV extract significantly induced a dose-dependent downregulation of Bcl-2 protein expression in MCF-7 and T-47D cells, but not in MDA-MB-231 cells. These results suggested that apoptosis induction, differentially dependent of p53 and Bcl-2 expressions, might be the possible mechanism of CV extract-mediated cytotoxicity in human breast cancer cells in vitro.
PMID: 15908782 [PubMed – indexed for MEDLINE]Free Article
Department of Zoology, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, P.R. China.
Abstract
Activation of the cell death program (apoptosis) is a strategy for the treatment of human cancer, and unfortunately a large number of drugs identified as cell cycle-specific agents for killing cancer cells are also toxic to normal cells. The present study demonstrates that the polysaccharide peptide (PSP) extracted from the Chinese medicinal mushroom, Coriolus versicolor, used in combination therapy in China, has the ability to lower the cytotoxicity of certain anti-leukemic drugs via their interaction with cell cycle-dependent and apoptotic pathways. Flow cytometry analysis demonstrated that pre-treatment of PSP (25-100 microg/ml) dose-dependently enhanced the cell cycle perturbation and apoptotic activity of doxorubicin (Doxo) and etoposide (VP-16), but not cytarabine (Ara-C) in human promyelocytic leukemia HL-60 cells. The antagonistic result from combined treatment with Ara-C and PSP may be caused by the removal of HL-60 cells in the G1-S boundary by PSP before exposure to Ara-C. A negative correlation between the increase in apoptotic cell population (pre-G1 peak) with the S-phase cell population expression (R2=0.998), the expression of cyclin E expression (R2=0.872) and caspase 3 activity (R2=0.997) suggests that PSP enhanced the apoptotic machinery of Doxo and VP-16 in a cell cycle-dependent manner and is mediated, at least in part, by the PSP-mediated modulation of the regulatory checkpoint cyclin E and caspase 3. This study is the first to describe the cell cycle mechanistic action of PSP and its interaction with other anticancer agents. Our data support the potential development of PSP as an adjuvant for leukemia treatment, but also imply the importance of understanding its interaction with individual anticancer agents.
Department of Zoology, The University of Hong Kong, Hong Kong, SAR, P.R. China.
Abstract
Proteins and peptide bound polysaccharides (PSP) extracted from Basidiomycetous fungi are widely used in cancer immunotherapy and recently demonstrated to induce apoptosis in cancer cells in vitro. In order to provide the molecular pharmacological mechanisms of PSP on human cancer cells, we investigated the gene expression profiles of PSP-treated apoptotic human promyelotic leukemic HL-60 cells using ResGen 40k IMAGE printed cDNA microarray. In total 378 and 111 transcripts were identified as differentially expressed in the apoptotic cells by at least a factor of 2 or 3, respectively. Our data show that PSP-induced apoptosis in HL-60 cells might be mediated by up-regulation of early transcription factors such as AP-1, EGR1, IER2 and IER5, and down-regulation of NF-kappaB transcription pathways. Other gene expression changes, including the increase of several apoptotic or anti-proliferation genes, such as GADD45A/B and TUSC2, and the decrease of a batch of phosphatase and kinase genes, may also provide further evidences in supporting the process of PSP induced apoptosis in cancer cells. Some of the well-characterized carcinogenesis-related gene transcripts such as SAT, DCT, Melan-A, uPA and cyclin E1 were also alternated by PSP in the HL-60 cells. These transcripts can be employed as markers for quality control of PSP products on functional levels. The present study provides new insight into the molecular mechanisms involved in PSP-induced apoptosis in leukemic HL-60 cells analyzed by cDNA microarray.