Antitumor and Immunomodulatory Activities of Medicinal Mushroom Polysaccharides and Polysaccharide-Protein Complexes in Animals and Humans (Review)
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MYCOLOGIA BALCANICA 2: 221–250 (2005) 221 Antitumor and immunomodulatory activities of medicinal mushroom polysaccharides and polysaccharide-protein complexes in animals and humans (Review) Solomon P. Wasser *, Maryna Ya. Didukh & Eviatar Nevo Institute of Evolution, University of Haifa, Mt Carmel, 31905 Haifa, Israel M.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine, 2 Tereshchenkovskaya St., 01001 Kiev, Ukraine Received 24 September 2004 / Accepted 9 June 2005 Abstract. Th e number of mushrooms on Earth is estimated at 140 000, yet perhaps only 10 % (approximately 14 000 named species) are known. Th ey make up a vast and yet largely untapped source of powerful new pharmaceutical products. Particularly, and most important for modern medicine, they present an unlimited source for polysaccharides with anticancer and immunostimulating properties. Many, if not all Basidiomycetes mushrooms contain biologically active polysaccharides in fruit bodies, cultured mycelia, and culture broth. Th e data about mushroom polysaccharides are summarized for 651 species and seven intraspecifi c taxa from 182 genera of higher Hetero- and Homobasidiomycetes. Th ese polysaccharides are of diff erent chemical composition; the main ones comprise the group of β-glucans. β-(1→3) linkages in the main chain of the glucan and further β-(1→ 6) branch points are needed for their antitumor action. Numerous bioactive polysaccharides or polysaccharide- protein complexes from medicinal mushrooms are described that appear to enhance innate and cell-mediated immune responses, and exhibit antitumour activities in animals and humans. Stimulation of host immune defense systems by bioactive polymers from medicinal mushrooms has signifi cant eff ects on the maturation, diff erentiation, and proliferation of many kinds of immune cells in the host. Many of these mushroom polymers were reported previously to have immunotherapeutic properties by facilitating growth inhibition and destruction of tumour cells. Whilst the mechanism of their antitumor actions is still not completely understood, stimulation and modulation of key host immune responses by these mushroom polymers appears central. Recent evidence suggests that mushroom polymers (β-glucans) may trigger the stimulation of many kinds of immune cells in animals and humans. Several of the mushroom polysaccharide compounds have proceeded through Phases I, II, and III clinical trials, and are used extensively and successfully in Asia to treat various cancers and other diseases. Th e present review analyzes the pecularities of polysaccharides derived from fruit bodies and cultured mycelia (two main ways of biotechnological production today) in selected examples of medicinal mushrooms. Key words: active hexose correlated compound (AHCC), beta-glucans, Ehrlich carcinoma, immunomodulator activity, macrophages, polysaccharides, polysaccharide-protein complexes, Sarcoma 180 *Corresponding author: e-mail: [email protected] 222 wasser, s.p. et al. — antitumor and immunomodulatory activities of medicinal mushrooms Introduction developed in submerged culture of the strain Cov-1 of the same species. Both proteoglucans have the same polysaccharide For millennia, mushrooms have been valued as edible and component but with diff erent protein molecules bound to the medical provisions for humankind. A number of bioactive polysaccharide (Hiroshi & Takeda 1993). molecules, including antitumor substances, have been In the present review, antitumor and immunomodulating identifi ed in many mushroom species. Polysaccharides are the polysaccharides from higher Basidiomycetes mushrooms are best known and most potent mushroom-derived substances analyzed. More attention is given to their common features with antitumor and immunomodulating properties (Mizuno than to specifi c peculiarities. Th e review summarizes a general 1996, 1999a, b, 2002; Lorenzen & Anke 1998; Borchers et state of knowledge in the area of biodiversity of mushrooms and al. 1999; Ooi & Liu 1999; Wasser & Weis 1999; Tzianabos their polysaccharides; the chemical structure of polysaccharides 2000; Reshetnikov et al. 2001; Wasser 2002; Didukh et al. and its connection with their antitumor activity, including 2003; Rowan et al. 2003; Smith et al. 2003). Historically, possible ways of chemical modifi cation; results of experimental hot-water-soluble fractions (decoctions and essences) from testing and clinical use of antitumor or immunostimulating medicinal mushrooms, i.e., mostly polysaccharides, were polysaccharides; possible mechanisms of their biological used as medicine in the Far East, where knowledge and action; and, fi nally, the diff erence in polysaccharide fraction practice of mushroom use primarily originated (Hobbs composition in fruit bodies and pure culture mycelia in selected 1995, 2000). Such mushrooms as Ganoderma lucidum examples of the studied medicinal mushrooms. (W. Curt. : Fr.) P. Karst. (Reishi), Lentinus edodes (Berk.) Singer (Shiitake), Inonotus obliquus (Ach. ex Pers.) Pilát (Chaga) and many others have been collected and used for Th e diversity of mushrooms with antitumor and centuries in Korea, China, Japan, and eastern Russia. Th ose immunomodulatory polysaccharides practices still form the basis of modern scientifi c studies of fungal medical activities, especially in the fi eld of stomach, Recent estimates of the number of fungi on Earth range from prostate, and lung cancers. It is notable and remarkable how 500 000 to 9.9 million species, and the generally accepted reliable the facts collected by traditional eastern medicine working fi gure is 1.5 million (Hawksworth 2001). Meanwhile, are in the area of medicinal mushrooms (Ying et al. 1987; the total number of described fungi of all kinds is currently Hobbs 1995, 2000; Wasser & Weis 1997a, b, 1999; Stamets 80 060 species. Th e fi gure is based on the total reached by 2000; Wasser 2002). summing the numbers of species in each genus given in the Chihara et al. (1969, 1970) published the fi rst scientifi c last edition of the Dictionary of the Fungi (Kirk et al. 2001) and report on antitumor activity of polysaccharides from includes all organisms traditionally studied by mycologists: Lentinus edodes on mouse Sarcoma 180. Ikekawa et al. slime molds, chromistan fungi, chytridiaceous fungi, lichen- (1969, 1982) published reports on antitumor activities forming fungi, fi lamentous fungi, molds, and yeasts. Out of of essences obtained from fruit bodies of Polyporaceae these, mushrooms constitute 14 000 species, calculated from species (Aphyllophoromycetideae) and a few other families the Dictionary of the Fungi (Kirk et al. 2001) or go as high as manifested as host-mediated activity against grafted cancer 22 000 (Hawksworth 2001). However, the actual number of – such as Sarcoma 180 – in animals (Ikekawa et al. 1982, such species on Earth is undoubtedly much higher. 1992; Ikekawa 2001). Soon thereafter, the fi rst three major By the term ‘mushroom’ we generally take the defi nition drugs were developed from medicinal mushrooms. All three by Chang & Miles (1992): “a macrofungus with a distinctive were polysaccharides, specifi cally β-glucans: Krestin from fruit body which can be hypogeous or epigeous, large enough cultured mycelial biomass of Trametes versicolor (L. : Fr.) to be seen with the naked eye and to be picked by hand”. Lloyd (Turkey Tail), Lentinan from fruit bodies of Lentinus Two main reasons for the actual number being higher are edodes, and Schizophyllan from liquid medium broth product (1) the great number of as yet undescribed species and (2) of Schizophyllum commune Fr. : Fr. In the 40 years since then the fact that many morphologically defi ned mushroom medicinal mushrooms have been intensively investigated for ‘species’ prove to be assemblages of several biological medicinal eff ects in in vivo and in vitro model systems, and (Anderson & Stasovski 1992; Hawksworth 2001) or many new antitumor and immunomodulating polysaccharides phylogenetic (Kasuga et al. 1999; Taylor et al. 1999) species. have been identifi ed and put to practical use (Mizuno 1996, Studies of compatibility and molecular sequences between 1999a; Wasser & Weis 1999; Ikekawa 2001; Wasser 2002; mushrooms previously considered to be the same species Didukh et al. 2003; Rowan et al. 2003; Smith et al. 2003). on morphological grounds revealed ‘cryptic species’, i.e., Biologically active polysaccharides are widespread among populations functioning as separate biological species but higher Basidiomycetes mushrooms, and most of them have covered by a single scientifi c name. A single morphologically unique structures in diff erent species. Moreover, diff erent strains defi ned species may consist of 20 or more biological species of one Basidiomycetes species can produce polysaccharides (Hawksworth 2001) and a varying number of phylogenetic with diff erent properties. For example, proteoglucan Krestin species (Taylor et al. 2000). was developed in Japan from the strain of Trametes versicolor An analysis of the localities from which fungi new to science CM-101, whereas polysaccharide-peptide (PSP) in China was have been described and catalogued in the Index of Fungi in mycologia balcanica () 223 the 10 years from 1990 to 1999 revealed that about 60 % of properties (Chang 1999; Wasser & Weis 1999; Reshetnikov all newly described fungi are from the tropics (Hawksworth et al. 2001; Wasser 2002). Clearly, mushrooms represent a 1993, 2001). Th is is also the case for mushrooms, especially major and yet largely untapped