Introduction
Health benefits from consumption of mushrooms have been known for thousands of years. Mushrooms products have been used as dietary supplements or as medicines for over 2000 years in Far East countries (China, Japan, Korea, the Asian part of Russia) [1]. In contrast, in the Western world, mushrooms have been consumed primarily because of their taste and smell. In recent years, however, mushrooms have been in the center of attention for scientists worldwide as a source of biologically active compounds with a favorable impact on functioning of the human body. As a result of these studies the so-called “mycopharmaceuticals” or “fungal supplements” were introduced to the global markets. The scale and importance of this phenomenon emphasizes the fact that edible mushrooms have been included in the product group defined as “functional food”, i.e. food whose health benefit was documented by scientific research and whose favorable impact could not to attributed solely to the presence of nutrients traditionally deemed necessary [2–5].
It has been known for centuries that some representatives of Basidiomycetes have anticancer properties. One of the first studies pertaining to the anticancer properties of this class of mushrooms was carried out by Lucas and coworkers, who successfully applied an extract obtained from Boletus edulis fruiting bodies in the treatment of Sarcoma 180 in mice (1957) [6]. Lucas’s team also isolated calvacin from Calvatia gigantea. In the 1960s, it was the most popular natural product with anticancer properties isolated from mushrooms [7]. Its effect was confirmed against many experimental tumors, including Sarcoma 180, mammary adenocarcinoma 755, leukemia L-1210 and HeLa cell lines [4].
Numerous studies have shown that the anticancer properties of biologically active compounds isolated from mushrooms are mostly attributed to polysaccharides [4, 8–12]. Their main source appears to be fungal cell walls. However, as shown in the study, chitin and chitosan have no anticancer activity [13]. Considering their chemical nature most mushroom polysaccharides with anticancer properties can be included in derivatives of (13), (16) -glucans or (13) -glucans [14]. These compounds are composed of a linear or branched chain made up of glucose molecules, and a side chain containing a different combination of other simple sugars, mainly glucuronic acid, xylose, galactose, mannose, arabinose, or ribose. Protein complexes are also very common. Glycans represents an equally large group of anticancer polysaccharides. Their molecules are created by monosaccharides other than glucose. In mushrooms most often there occur glycans containing arabinose, mannose, fucose, galactose, xylose, glucuronic acid and also glucose [12].Chemical structure and antitumor properties
Depending on the source (each species and even strain has a slightly different set of polysaccharides), polysaccharides differ in chemical structure, molecular weight, branching rate and form, which affect their biological activity [5–18].
Anticancer properties of polysaccharides depend on:
• sugar composition – anticancer properties of polysaccharides have been described in the case of hetero--glucans [19],
heteroglycans [20], complexes of -glucan-protein [21],
-manno--glucans, complexes of -glucan-protein [19] and complexes of heteroglycan-protein [22, 23];
• molecular weight – high molecular weight glucans appear to be more effective than those of low molecular weight [8–10, 13];
• water solubility – water-soluble glucans are characterized by greater activity [24];
• glucose linkage – it is obvious that structural features such as -(13) linkages in the main chain of the glucan and additional -(16) branch points are needed for anticancer activity; -glucans containing mainly -(16) linkages have lesser activity [8–10];
• tertiary structure – it has been shown that the destruction of the tertiary structure of polysaccharides by denaturation substantially reduces or completely abolishes their biological activity [25–27];
• branching rate and form – it was shown that the highest activity characterized glucans where the value of branching degree in relation to the molecular weight is 0.20–0.33 [16, 17, 28, 29];
• presence of other ligands – e.g. galactose, mannose, fructose, xylose and arabinose, profitably affected anticancer properties of polysaccharides; in addition, protein ligands increase the anticancer potential [13];
• chemical modification – it is often carried out to improve the anticancer activity of polysaccharides and their clinical qualities by increasing their water solubility and ability to penetrate the intestinal wall after oral administration; the main procedures used for chemical improvement are Smith degradation (oxydo-reducto-hydrolysis), activation by formolysis, and carboxymethylation [8, 9, 23, 30–33].The most popular anticancer agents derived from Basidiomycetes
Major and still largely untapped source of potent new anticancer polysaccharides are higher Basidiomycetes. This was confirmed by extensive research done by Chinese and Japanese scientists, who have shown that most if not all Basidiomycetes contain biologically active polysaccharides. Studies were performed on animals with Sarcoma 180 and Ehrlich cancer [11]. So far, the best characterized were three polysaccharides, which for nearly 50 years have been commercially available: lentinan, PSK (Krestin) and schizophyllan [8, 34].
Lentinan is a highly purified polysaccharide fraction isolated from Lentinus edodes (Shiitake). Considering its chemical nature it is classified as a -glucan. Its main chain is formed of glucose units linked by -(13) glycosidic bonds, while side chains are connected with the main chain by -(16) glycosidic bonds [9]. It is an approved, commonly used, anticancer drug in Japan. It is generally administered in conjunction with other conventional pharmaceutical drugs in cancer therapy, e.g. against bowel, liver, stomach, ovarian and lung cancer. It increases the effectiveness of therapy and thus patients’ survival [35]. Experimental studies have shown that administration of lentinan prevents oncogenesis induced chemically or by viruses, as well as preventing metastasis [25, 36–38].
Krestin (PSK) is a polysaccharide isolated from Trametes versicolor. Apart from the sugar which is -glucan, PSK also consists of peptide. The sugar part is composed of the main chain created by glucose units linked by -(13) glycosidic bonds, while in the side branches occur -(16) glycosidic bonds [9]. Like lentinan it is a very popular drug in Japan. Numerous clinical studies have shown that its administration increases the effectiveness of chemotherapy in patients suffering from breast, liver, prostate, stomach, lung, and colon cancer. Alone, as an anticancer drug, it is used in veterinary medicine against adenosarcoma, fibrosarcoma, mastocytoma, plasmacytoma, melanoma, sarcoma, carcinoma, mammary cancer, colon cancer, and lung cancer [35].
Schizophyllan is obtained from Schizophyllum commune. In terms of chemical structure, i.e. the composition of sugars and their manner of linking, it is similar to lentinan. The commercial name of this -glucan is Sonifilan [9]. This product is used in the treatment of stomach and neck cancer [2]. Additionally, it is administered during radiotherapy due to its radioprotective properties. Schizophyllan restores mitosis of bone marrow cells previously suppressed by gamma radiation [39–41].
Polysaccharides derived from other Basidiomycetes also exhibit pro-healthy properties. Lot of scientific reports have confirmed their ability to prevent carcinogenesis and metastasis, and inhibit the development of existing tumor lesions [25, 36–38].Mechanisms of action
The diversity of the polysaccharides and their derivatives is reflected in the diversity of their mechanisms of action. Generally there are two basic mechanisms of polysaccharide action against tumor cells: indirect action (immunostimulation) and direct action (inhibition of tumor cell growth and apoptosis induction).
Indirect action
Indirect action is based on stimulation of host defense mechanisms, primarily on activation of T and B lymphocytes, macrophages and natural killer (NK) cells [15, 16, 18, 28]. Many mushroom -glucans have been shown to stimulate production of interferons (IFNs), interleukins (ILs), and others cytokines. These are regarded as the first line in the host defense system, and may themselves successfully transform cells prior to the establishment of fully fledged humoral and cell-mediated immune responses [42].
Studies have shown that -glucans induce the body’s response by binding to membrane receptors on immunologically competent cells [43]. One of the most important -glucan receptors is CR3 receptor (syn. Mac-1, CD11b/CD18) [44, 45]. This receptor occurs commonly on the surface of immune effector cells, such as macrophages, neutrophils, NK cells and K cells. CR3 is able to recognize opsonin iC3b, which often presents on the cancer cells’ surface. Simultaneous connection to the CR3 complement component iC3b and -glucan induces stimulation of phagocyte activity, while the lack of any of these components prevents cytotoxicity induction [44, 46, 47]. Numerous reports have suggested that polysaccharides enhance the ability of immune cells to recognize tumor cells as foreign and thereby enhance the effectiveness of host defense mechanisms [48]. The best documented immune stimulating properties have been described in the case of lentinan, PSK and schizophyllan.
Lentinan
Studies have shown that lentinan stimulates the proliferation of blood mononuclear cells such as lymphocytes, monocytes and macrophages [49, 50]. Furthermore, it also stimulates the maturation and differentiation of cells involved in host defense mechanisms. Lentinan is also able to increase the reactivity of immune cells and stimulate them to secrete cytokines, hormones and/or other biologically active substances. As a result of such properties, lentinan increases the body's resistance to malignant transformation [51, 52]. Lentinan has been described as an adjuvant focused on T cells [53]. It shifts the balance of Th1/2 towards Th1 by a significant increase of IL-12 production [54]. It intensifies macrophage phagocytosis and increases the secretion of cytokines, particularly tumor necrosis factor (TNF-) by the activation of NF-2 [55, 56]. Its stimulating effect on the population of NK cells was also observed [57]. Plentiful evidence suggests that lentinan stimulates dendritic cells, which is essential for immunomodulation and antitumor activity of this agent. Dendritic cells in collaboration with K cells play a key role in the elimination of tumor cells [52]. Additionally, it was observed that lentinan treatment in patients suffering from stomach cancer inhibits prostaglandin synthesis, which compounds in many cases leading to a slowdown of T lymphocyte differentiation, as well as inhibition of Treg cell activity [49]. At the same time, increased levels of activated and cytotoxic T lymphocytes were observed in the spleen [50] as well as stimulation of peripheral blood mononuclear cells to produce interleukin 1 (IL-1), IL-1
and TNF- [52]. Lentinan ability to stimulate IL-1 release has been demonstrated in other tumor types [51]. Additionally, many other interesting biological activities of lentinan have been described, including increased non-specific inflammatory response evidenced by stimulated production of acute phase proteins [58] and inhibition of the complement system [54].
Krestin
It has been demonstrated that (krestin PSK) stimulates components of both cellular and humoral immunity [59]. After injection of PSK at the tumor site, its direct interaction with tumor cells and induction of an inflammatory response leading to elimination of transformed cells have been observed [60]. Increased numbers of immunologically competent cells and a rise in dendritic and Tc cells capacity of tumor infiltrate were noted in patients who received PSK. Krestin affects the phenotypic and functional maturation of dendritic cells from human CD14+ cells [61], and stimulates the phagocytic activity of macrophages [41]. In addition, it stimulates expression of TNF-, IL-1, IL-6, and IL-8 [62–65]. These cytokines induce reactions leading to the stimulation of T cell cytotoxicity against tumor cells, intensification of antibody production by B cells, or induction of receptor expression for IL-2 on T cells [63]. The study indicated that antitumor activity of PSK relies on its ability to stimulate T cells and antigen-presenting cells, which allows efficient recognition and destruction of tumor cells [59, 66].
Schizophyllan
Schizophyllan’s chemical structure and mechanism of action are very similar to lentinan. Its antitumor action is based on the modulation of the immune response [66]. Like lentinan, antitumor properties of schizophyllan appear only in the presence of T cells, which has been proven in studies performed on mice with sarcoma 180. Administration of cyclosporine A (T cell suppressor) to mice resulted in the abolition of anticancer properties of both agents [67, 68]. Schizophyllan stimulates production of acute phase proteins and CSF, resulting in incitement of macrophage, peripheral blood mononuclear cell and lymphocyte proliferation as well as stimulation of the complement system [69]. Moreover, this formulation increases the production of Th lymphocytes and macrophages [69]. It is characterized by strong activation of phagocytes, increases the production of reactive oxygen species, proinflammatory cytokines IL-6, IL-8 and TNF-, and also increases the expression of CD11b and CD69L markers on leukocytes’ surface [70, 71].
Direct action
Besides the indirect action, several polysaccharides have shown direct effects on cancer cells. Many in vitro and in vivo studies have suggested that polysaccharides inhibit tumor cell proliferation and/or induce their death by apoptosis
[16, 17, 28, 29, 72].
One of the best described mechanisms of direct anticancer action of polysaccharides extracted from Basidiomycetes is modulation of NF- activity. Excessive activation of NF- is observed in many types of cancer. Active NF- promotes tumor growth by increasing the transcription of genes that induce cell proliferation, inhibit apoptosis, or promote angiogenesis and metastasis [73]. It was proven that polysaccharides inhibit phosphorylation of and/or degradation of the inhibitor of NF- (I) [4, 19, 28, 74–77], which prevents activation of the transcription factor and consequently the expression of its subordinate genes [78, 79]. In addition to NF- pathway modulation, polysaccharides may also affect cancer cells in other ways. An excellent example of that is the protein complex of polysaccharide extracted from Trametes versicolor known as PSP. It was demonstrated that PSP induced cell cycle arrest at restrictive points G1/S and G2/M in leukemia cells U-937 and breast cancer cells MDA-MB-231, and also inhibited antiapoptotic proteins, resulting in repression of cell division and increase of apoptosis [80, 81]. However, in leukemia cells HL-60, PSP elicited a similar effect through decrease of NF- level and expression of ERK kinase [81].Summary
For centuries, mushrooms in the Western world have been treated only as a tasty supplement to the daily diet. Far Eastern medicine has created a foundation for their therapeutic use. The last half-century is a period of a flourishing new field of medicine – mycopharmacology. The scientific approach to compounds contained in mushrooms allowed the isolation of many valuable active substances which are used in the prevention and treatment of lifestyle diseases, including cancer. References
1. Chang ST, Buswell JA. Mushroom nutriceuticals. World J Microb Biotech 1996; 12: 473-6.
2. Hobbs ChL. Medicinal Mushrooms: An Exploration of Tradition, Healing and Culture. Botanica Press, Williams, OR 1995.
3. Rajewska J, Bałasińska B. Związki biologicznie aktywne zawarte w grzybach jadalnych i ich korzystny wpływ na zdrowie. Postępy Hig Med Dosw 2004; 58: 352-7.
4. Wasser SP, Weis AL. Medicinal properties of substances occurring in higher Basidiomycetes. Int J Med Mushr 1999; 1: 31-62.
5. Wasser SP, Weis AL. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective. Critical Rev Immunol 1999; 19: 65-96.
6. Lucas EH, Montesano R, Pepper MS, Hafner M, Sablon E. Tumor inhibitors in Boletus edulis and other holobasidiomycetes. Antibiot Chemother 1957; 7: 1-4.
7. Lucas EH, Byerrum M, Clarke DA, Reilly HC, Stevens JA, Stock CC. Production of oncostatic principles in vivo and in vitro by species of the genus Calvatia. Antibiot Annu 1958; 6: 493-6.
8. Mizuno T. Development of antitumor polysaccharides from mushroom fungi. Foods Food Ingred J Jpn 1996; 167: 69-85.
9. Mizuno T. The extraction and development of antitumoractive polysaccharides from medicinal mushrooms in Japan. Int J Med Mushrooms 1999; 1: 9-29
10. Mizuno T. Bioactive substances in Hericium erinaceus (Bull. Fr.) Pers. (Yamabushitake), and its medicinal utilization. Int J Med Mushrooms 1999; 1: 105-19.
11. Reshetnikov SV, Wasser SP, Tan KK. Higher Basidiomycota as a source of antitumor and immunostimulating polysaccharides. Int J Med Mushrooms 2001; 3: 361-94.
12. Wasser SP. Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. Appl Microbiol Biotechnol 2002; 60: 258-74.
13. Mizuno T. Yamabushitake, Hericium erinaceum: bioactive substances and medicinal utilization. Food Rev Intern 1995; 11: 173-8.
14. Gorin PAJ, Barreto-Berger E. The chemistry of polysaccharides of fungi and lichens. W: The polysaccharides. Aspinall GO (ed.). Academic Press, Orlando 1983; 365-409.
15. Augustin J. Glucans as modulating polysaccharides:thei characteristics and isolation from microbiological sources. Biologia 1998; 53: 277-82.
16. Bao X, Duan J, Fang X, Fang J. Chemical modifications of the (13)--D-glucan from spores of Ganoderma lucidum and investigation of their physicochemical properties and immunological activity. Carbohydrate Res 2001; 336: 127-40.
17. Tao Y, Zhang L, Cheung PCK. Physicochemical properties and antitumor activities of watersoluble native and sulfated hyperbranched mushroom polysaccharides. Carbohydrate Res 2006; 341: 2261-9.
18. Zhang P, Cheung PCK. Evaluation of sulfated Lentinus edodes -(1,3)-D-glukan as a potential antitumor agent. Biosci Biotechnol. Biochem 2002; 66: 1052-6.
19. Mizuno T, Saito H, Nishitoba T, Kawagishi H. Anti-tumoractive substances from mushrooms. Food Rev Int 1995; 11: 23-61.
20. Gao QP, Seljelid R, Chen HQ, Jiang R. Characterization of acidic heteroglycans from Tremella fuciformis Berk. with cytokine stimulating activity. Carbohydr Res 1996; 288: 135-42.
21. Kawagishi H, Kanao T, Inagaki R, Mizuno T, Shimura K, Ito H, Hagiwara T, Hakamura T. Formulation of a potent antitumor (16)-beta-D-glucan-protein complex from Agaricus blazei fruiting bodies and antitumor activity of the resulting products. Carbohydr Polym 1990; 12: 393-404.
22. Zhuang C, Mizuno T, Shimada A, et al. Antitumor protein-containing polysaccharides from a Chinese mushroom Fengweigu or Houbitake, Pleurotus sajor-caju (Fr.) Sing. Biosci Biotechnol Biochem 1993; 57: 901-6.
23. Mizuno T, Yeohlui P, Kinoshita T, Zhuang C, Ito H, Mayuzumi Y. Antitumor activity and chemical modification of polysaccharides from Niohshimeji mushroom, Tricholoma giganteum. Biosci Biotechnol Biochem 1996; 60: 30-3.
24. Manzi P, Pizzoferrato L. Beta-glucans in edible mushrooms. Food Chem 2000; 68: 315-8.
25. Maeda YY, Watanabe ST, Chihara C, Rokutanda M. Denaturation and renaturation of a -1,6; 1,3-glucan, lentinan, associated with expression of T-cell-mediated responses. Cancer Res 1988; 48: 671-5.
26. Yanaki T, Ito W, Tabata K, Kojima T, Norizuye T, Takano N, Fujita H. Correlation between the antitumor activity of a polysaccharide schizophyllan and its triple-helical conformation in dilute aqueous solution. Biophys Chem 1983; 17: 337-42.
27. Yanaki T, Ito W, Tabata K. Correlation between antitumor activity of schizophyllan and its triple helix. Agric Biol Chem 1986; 509: 2415-6.
28. Ooi VEC, Liu F. Immunomodulation and anti-cancer activity of polysaccharide-protein complexes. Curr Med Chem 2000; 7: 715-729
29. Zhang M, Cui SW, Cheung PCK, Wang Q. Antitumor polysaccharides from mushrooms: a review on their isolation process, structural characteristics and antitumor activity. Trends in Food Sci Technol 2007; 18: 4-19.
30. Karácsonyi S, Kuniak L. Polysaccharides of Pleurotus ostreatus: isolation and structure of pleuran, an alkali-insoluble -D-glucan. Carbohydr Polym 1994; 24: 107-11.
31. Kuniak L, Karácsonyi S, Augusti J, Ginterová A, Széchényl S, Kravarik D, Dubaj J, Varjú J. A new fungal glucan and its preparation. World Patent 9312243, Date of Patent 24.06.1993.
32. Paulik S, Svrcec, Mojisová J, Durove A, Benisek Z, Húska M. The immunomodulatory effect of the soluble fungal glucan (Pleurotus ostreatus) on delayed hypersensitivity and phagocytic ability of blood leucocytes in mice. J Vet Med B 1996; 43: 129-35.
33. Zhuang C, Mizuno T, Ito H, Shimura K, Sumiya T. Chemical modification and antitumor activity of polysaccharides from the mycelium of liquid-cultured Grifola frondosa. Nippon Shokuhin Kogyo Gakkaishi 1994; 41: 733-40.
34. Miles PG, Chang ST. Mushroom biology. Concise basics and current developments. World Scientific, Singapore, New Jersey, London, Hong Kong 1997; 194.
35. Mahajna JA, Yassin M, Wasser SP. Mushrooms extracts having anticancer activity. USA Patent US 7,258,862 B2, Date of Patent 21.08.2007.
36. Chihara G, Maeda Y, Hamuro J, Sasaki T, Fumiko F. Inhibition of mouse Sarcoma 180 by polysaccharides from Lentinus edodes (Berk.)Sing. Nature 1969; 222: 687-8.
37. Chihara G, Hamuro J, Maeda YY, Arai Y, Fukuoka F. Fractionation and purification of the polysaccharides with marked antitumor activity, especially lentinan, from Lentinus edodes. Cancer Res 1970; 30: 2776-81.
38. Ikekawa T, Uehara N, Maeda Y, Nakanishi M, Fukuoka F. Antitumor activity of aqueous extracts of edible mushrooms. Cancer Res 1969; 29: 734-5.
39. Brown G, Siamon G. Immune recognition: A new receptor for -glucans. Nature 2001; 413: 36-7.
40. Herre J, Gordon S, Brown GD. Dectin-1 and its role in the recognition of -glucans by macrophages. Mol Immunol 2004; 40: 869-76.
41. Zhu D. Recent advances on the active components in Chinese medicines. Abstr Chin Med 1987; 1: 251-86.
42. Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin ME. Mushrooms, tumors, and immunity. Proc Soc Exp Biol Med 1999; 221: 281-93.
43. Czop JK, Austen KF. Properties of glycans that activate the human alternative complement pathway and interact with the human monocyte beta-glucan receptor. J Immunol 1985; 135: 3388-93.
44. Ross GD, Vetvicka V, Yan J, Xia Y, Vetvickova J. Therapeutic intervention with complement and beta-glucan in cancer. Immunopharmacology 1999; 42: 61-74.
45. Xia Y, Vetvicka V, Yan J, Hanikyrova M, Mayadas T, Ross GD. The beta-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells. J Immunol 1999; 162: 2281-90.
46. Vetvicka V, Thornton BP, Wieman TJ, Ross GD. Targeting of NK cells to mammary carcinoma via naturally occurring tumor cellbound iC3b and beta-glucan-primed CR3 (CD11b/CD18). J Immunol 1997; 159: 599-605.
47. Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, Ross GD. Beta-glucan, a “specific” biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18). J Immunol 1999; 163: 3045-52.
48. Hamuro J, Chihara G. Lentinan, a T-cell oriented immunopotentiator: its experimental and clinical applications and possibile mechanism of immune modulation. W: Immunomodulation agents and their mechanisms. Fenichel RL, Chirigos MA (eds.). Dekker, New York 1985; 409-36.
49. Aoki T. Lentinan. In: Immunology Studies: Immune modulation agents and their mechanisms. Vol. 25. Femchel RL, Chirgis MA (eds.). 1984; 62-77.
50. Hobbs C. Medicinal value of Lentinus edodes (Berk.) Sing. (Agaricomycetideae). A literature review. International Journal of Medicinal Mushrooms 2000; 2: 287-302.
51. Chihara G, Maeda YY, Taguchi T, Hamuro J. Lentinan as a host defence potentiator (HDP). International Journal of Immunotherapy 1989; 5: 145.
52. Chihara G. Immunopharmacology of Lentinan, a polysaccharide isolated from Lentinus edodes: its application as a host defense potentiator. International Journal Oriental Medicine 1992; 17: 57-77.
53. Wang GL, Lin ZB. The immunomodulatory effect of lentinan. Yao Xue Xue Bao 1996; 31: 86-90.
54. Lull C, Wichers HJ, Savelkoul HFJ. Antiinflamatory and immunomodulating properties of fungal metabolites. Mediators of inflammation 2005; 2: 63-80.
55. Hamuro J. Anticancer immunotherapy with perorally effective lentinan. Gan To Kagaku Ryoho 2005; 32: 1209-15.
56. Kerekgyarto C, Virag L, Tanko L, Chihara G, Fachet J. Strain differences in the cytotoxic activity and TNF production of murine macrophages stimulated by lentinan. Int J Immunopharmacol 1996; 18: 347-53.
57. Takada K, Okumara K. CAM and NK cells. eCAM 2004; 1: 17-27.
58. Suga T, Maeda YY, Uchida H, Rokutanda M, Chihara G. Macrophage-mediated acute-phase transport protein production induced by Lentinan. International Journal of Immunopharmacology 1986; 8: 691.
59. Tzianabos A. Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function. Clinical Microbiology Reviews 2000; 13: 523-33.
60. Mizutani Y, Yoshida O. Activation by the protein-bound polysaccharide PSK (krestin) of cytotoxic lymphocytes that act on fresh autologous tumor cells and T24 human urinary bladder transitional carcinoma cell line in patients with urinary bladder cancer. J Urol 1991; 145: 1082-7.
61. Nio Y, Shiraishi T, Tsubono M, Morimoto H, Tseng CC, Imai S, Tobe T. In vitro immunomodulating effect of protein-bound polysaccharide PSK on peripheral blood, regional nodes, and spleen lymphocytes in patients with gastric cancer. Cancer Imunol Immunother 1991; 32: 335-41.
62. Hsieh TC, Wu JM. Cell growth and gene modulatory activities of Yunzhi (Windsor Wunxi) from mushroom Trametes versicolor in androgen-dependent and androgen-insensitive human prostate cancer cells. Int J Oncol 2001; 18: 81-8.
63. Kato M, Hirose K, Hakozak M et al. Induction of gene expression for immunomodulating cytokines in peripheral blood mononuclear cells in response to orally administered PSK, an immunomodulating protein-bound polysaccharide. Cancer Immunol Immunother 1995; 40: 152-6.
64. Liu F, Fang MC, Ooi VEC, Chang ST. Induction in the mouse of gene expression of immunomodulating cytokines by mushroom polysaccharide-protein complexes. Life Science 1996; 58: 1795-803.
65. Sakagami H, Sugaya K, Utsumi A, Fujinaga S, Sato T, Takeda M. Stimulation by PSK of interleukin-1 production by human peripheral blood mononuclear cells. Anticancer Res 1993; 13: 671-5.
66. Okazaki M, Adach Y, Ohno N, Yadomae T. Structure-activity relationship of (1-3)--Dglucan in the induction of cytokine production from macrophages in vitro. Biological Pharmacological Bulletin 1995; 18: 1320-7.
67. Kraus J, Franz G. (1-3) Glucans: anti-tumour activity and immunostimulation. W: Fungal Wall and Immune Response. Latge JP, Boucias D (eds.). NATO ASI Series H53, Springer, Berlin 1991; 39-42.
68. Kraus J, Franz G. Immunomodulating effects of polysaccharides from medicinal plants. W: Microbial Infections. Friedman H, Klein TW, Yamaguchi H (red.). Plenum Press, NewYork 1992; 299-308.
69. Bohn JA, BeMiller JN. (1-3)--D-Glucans as biological response modifiers: a review of structure-functional activity relationships. Carbohydrate Polymers 1995; 28: 3-14.
70. Falch BH, Espevik T, Ryan L, Stokke BT. The cytokine stimulating activity of (13)-beta-Dglucans is dependent on the triple helix formation. Carbohydr Res 2000; 329: 587-96.
71. Kubala J, Ruzickova J, Nickova K, Sandula J, Ciz M, Lojek A. The effect of (13)-beta-D-glucans, carboxymethyloglucan and schizophyllan on human leukocytes in vitro. Carbohydr Res 2003; 338: 2835-40.
72. Smith JE, Rowan NJ, Sullivan R. Medicinal mushrooms: a rapidly developing area of biotechnology for cancer therapy and other bioactivities. Biotech Letters 2002; 24: 1839-45.
73. Ravi R, Bedi A. NF-kappa B in cancer-a friend turned foe. Drug Resist Update 2004; 7: 53-67.
74. Ohno N, Miura NN, Nakajima M, Yadomae T. Anti-tumor 1,3--glucan from cultured fruit body of Sparassis crispa. Biol Pharm Bull 2000; 23: 866-872.
75. Ohno N, Nameda S, Harada T et al. Immunomodulating activity of a ß-glucan preparation, SCG, extracted from a culinary-medicinal mushroom, Sparassis crispa Wulf. : Fr. (Aphyllophoromycetidae), and application to cancer patients. Int J Med Mushr 2003; 5: 359-68.
76. Yoshida I, Kiho T, Usui S, Sakushima M, Ukai S. Polysaccharides in fungi. XXXVII. Immunomodulating activities of carboxymethylated derivatives of linear (1-3)-alpha-d-glucans extracted from the fruiting bodies of Agrocybe cylindracea and Amanita muscaria. Biol Pharm Bull 1996; 19: 114-21.
77. Yoshioka Y, Ikekawa T, Noda M, Fukuoka F. Studies on anti-tumor activity of some fractions from Basidiomycetes. I. An anti-tumor acidic polysaccharide fraction of P. ostreatus (Fr.) Quél. Chem Pharm Bull 1972; 20: 1175-80.
78. Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A, Zamora A. The transcription factor nuclear factor-B and cancer. Clin Oncol (R Coll Radiol) 2007; 19: 154-61.
79. Sheikh MS, Huang Y. Death receptor activation complexes: it takes two to activate TNF receptor 1. Cell Cycle 2003; 2: 550-2.
80. Chow LW, Lo CS, Loo WT, Hu XC, Sham JS. Polysaccharide peptide mediates apoptosis by up-regulating p21 gene and downregulating cyclin D1 gene. Am J Chin Med 2003; 31: 1-9.
81. Hsieh T, Wu P, Park S, Wu JM. Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signaling regulatory protein expression by water extracts of I'm-YunityTM (PSP). BMC Complement Altern Med 2006; 6: 30.
Address for correspondence
Marta Lemieszek
Department of Medical Biology
Institute of Agricultural Medicine
Jaczewskiego 2
20-090 Lublin
e-mail: martalemieszek@gmail.com
Submitted: 24.03.2011
Accepted: 18.01.2012
