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School of Pharmacy, Nihon University, Funabashi, Chiba, Japan
*Address all correspondence to: yasukawa.ken@nihon-u.ac.jp, yasukawa.ken@nihon-.ne.jp
1. Introduction
Conquering cancer is one of the major challenges facing mankind in the 21st century. The advancement of diagnostic techniques has made discovering miniscule tumors feasible, and early treatment of many types of cancers has consequently become a reality. However, while the development of anticancer drugs progresses, the number of people diagnosed with cancer continues to rise. The drug, tamoxifen, has been approved in the US to prevent breast cancer relapse. In addition, cancer prevention has become an important part of conquering cancer, with both primary and secondary prevention strategies. The former entails the prevention of cancer itself, while the latter involves the prevention of death once an individual has already developed cancer.
Edible mushrooms such as Lentinula edodes (shiitake) and Grifola frondosa (maitake) have been known from ancient folklore to possess properties that enhance biological defense responses (immune functions), and have been used in people with decreased immune function such as those with cancer, allergies and other disorders, and in elderly people. Many of these mushrooms contain compounds called β-glucans, which are high molecular weight polysaccharides of glucose linked together by glycosidic bonds. β-glucans are contained in mushrooms, yeast, fungi, and higher plants. In Japan, several mushroom-derived pharmaceutical products have been developed, and include schizophyllan from Schizophyllum commune, krestin from Trametes versicolor, and lentinan from L. edodes an anticancer polysaccharide from shiitake. In South Korea, meshima, a mycelia culture of Phellinus linteus, was developed as an anticancer drug. Antitumor activities of polysaccharides and peptide polysaccharides in these mushrooms have been reported. In addition to polysaccharides, unique substances such as sterols and triterpenes are reportedly present in mushrooms. Some of these compounds are promising anticancer agents. Please refer to a review published elsewhere for a description on herbal medicine extracts that have been anticipated for their cancer prevention effects [1]. In this chapter, we will introduce the anticancer activities of polysaccharides as well as the cancer prevention activities of sterols and triterpenes.
Research on mushroom-derived β-glucans began when Chihara, Hamuro, and others at the National Cancer Center Research Institute in Japan isolated and purified lentinan, a β-1,3-glucan with branched chains formed by β-1,6-glycosidic bonds, from L. edodes in 1968 [2, 3]. Subsequently, many efficacy studies on lentinan, primarily concerning its antitumor activities, have been reported [4-6]. Ikekawa et al. intraperitoneally administered aqueous extracts of six types of edible mushrooms, and demonstrated their antitumor effects on cancer cell line sarcoma S-180 [7].
Upon such discoveries, polysaccharides lentinan and schizophyllan, glycoprotein krestin, and P. linteus mycelia extract meshima have been utilized as anticancer drugs.
Lentinan (Figure 1) demonstrated an effect to prolong the survival of patients with inoperable and relapsed stomach cancer in combination with a chemotherapeutic agent in a human double-blind controlled clinical trial. It has been revealed that its oral consumption, however, does not exhibit efficacy. In 1985, this compound was approved as an anti-malignant tumor agent (injectable solution), and has been prescribed to cancer patients as a pharmaceutical product. Subsequently, the antitumor effects of various mushroom extracts that contain β-glucan were reported in animal experiments [8]. However, most of these studies administered mushroom extracts that contain β-glucan to animals via injection, and there are very few reports that showed its effect via oral consumption. There is, however, one such rare report; an epidemiological study that suggests mushroom intake via oral consumption may be effective [9]. Intraperitoneal administration of lentinan suppressed 3-methylcolanthrene-induced tumor expression [5]. In Lentinula edodes, α-(1,4)-glucan binds with TLR-4, thereby inducing monocyte differentiation and exhibiting cytotoxic effects in A549 human lung carcinoma cells [10].
Figure 1.
Structure of lentinan
Schizophyllan derived from Schizophyllum commune (Figure 2) is typically structured with β1 → 3 linkage and on rare occasions with β1 → 6 linkage between D-glucose monomers [11]. Due to such structure, a rigid triple-helical structure is formed. In addition, this compound is used in anticancer drugs since it possesses antitumor activities [12]. However, it is administered via intramuscular injection, and its effects via oral route in the manner of food consumption have not been elucidated. Although the mechanism of the antitumor activities of β-glucans including schizophyllan is not completely understood, it is thought that they activate macrophages and natural killer (NK) cells through respective β-glucan receptors, induce a helper T1 cell-dominant immune response state, and consequently exhibit antitumor activities [13, 14].
Figure 2.
Structure of schizophyllan
Krestin, an anti-malignant tumor agent, is a protein-bound polysaccharide derived from the mycelia of Trametes versicolor CM-101 strain. Since this drug does not cause serious side effects with oral administration, there was a period of time in which it was used alone after its release in 1977. However, it is now evident that it has no effect by itself, and is now used in conjunction with other drugs. Krestin is thought to exhibit its antitumor actions by acting on the immune response mechanism that has decreased due to a cancer-bearing state. Krestin has a mean molecular weight of 9.4 × 104, and its sugar chain moiety consists of glucose (74.6%), galactose (2.7%), mannose (15.5%), xylose (4.8%), and fucose (2.4%), but mostly glucose in the form of β-glucans. The glucans have main chain β1 → 4 bond, and side chain β1 → 3 and 1 → 6 bond structures, and it has been suggested that branching occurs per number of sugar residues. Proteins and sugar chain moeities in Krestin are linked with each other by either O- or N-glycosidic bond [15]. In addition, coriolan, another antitumor polysaccharide derived from Trametes versicolor, was reported in 1971 [16].
P. linteus belongs to Hymenochaetaceae family, and is called souou in traditional Japanese medicine, and has been highly valued since ancient times. It has been referred to as the "mythical" mushroom since it grows extremely slowly in nature and artificial cultivation is also difficult. Research in South Korea succeeded in the mass cultivation of P. linteus Yoo (HKSY-PL2) strain, which has been shown to be more effective than most other strains. P. linteus has properties to enhance the natural healing capability of the body, and was developed as a pharmaceutical product called meshima. Mycelia culture of P. linteus activated dendritic cells and macrophages through increased secretions of interleukin 12 (IL-12), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) by T-cells, and enhanced the antitumor effects of NK cells [17]. A proteoglycan generated by P. linteus acted as an immunostimulant and disrupted the Reg IV/EGFR/Akt signaling pathway, thereby exhibiting tumor-inhibitory effects [18]. In addition, polysaccharides from P. linteus activated the P27kip1-cyclinD1/E-CDK2 pathway and induced S-phase cell cycle arrest in HT-29 cells, resulting in cellular damage [19].
Through their immunostimulatory properties, mushroom-derived polysaccharides and glycoproteins augment anticancer drugs, alleviate side effects, and contribute greatly to quality of life (QOL) improvement.
3. Chemical carcinogenesis and two-stage carcinogenesis theory
It has been acknowledged that many types of cancers are caused by environmental carcinogenic agents. In 1915, Yamagiwa and Ichikawa succeeded in inducing cancer by rubbing coal tar on rabbit ears [20]. The significance from this study was the skin cancer had metastasized to the rabbit lung. In 1941, Berenblum et al. applied carcinogenic agent benz[a]pyrene (B[a]A) and croton oil (seed oil of Croton tiglium) on mouse skin, and proposed a two-stage carcinogenesis theory that tumorigenesis occurs similarly to when B[a]A is applied continually [21, 22]. Specifically, changes due to a carcinogenic agent were termed initiation, and changes due to croton oil were termed promotion. Later, Hecker reported the cancer-promoting ingredient of croton oil as 12-O-tetradecanoylphorbol-13-acetate (TPA). Many of these experiments are conducted using initiators 7,12-dimethylbenz[a]anthracene (DMBA) and TPA [23,24]. Fujiki et al. later reported on many mouse skin tumor promoters such as teleocidin [25]. Cancer begins when cells transform into latent cancer cells after undergoing initiation by receiving initiators or radiation. Subsequently, these cells become cancer cells after a long period of promotion process by promoters. Finally, after modifications through a process termed progression, the cells acquire the ability to divide infinitely, thereby clinically morphing to cancer. These steps occur in a continuous manner, and cannot be strictly distinguished from each other. When considering primary prevention, it is realistic to suppress the promotion process, which requires a long period of time and is known to be reversible to some degree. In addition, it has also become evident that cancer develops via similar mechanisms in many organs. Furthermore, TPA is known to activate Epstein-Barr virus (EBV). Although the prevalence of EBV is extremely high in Africa, the incidence of Burkitt's lymphoma greatly differs depending on the village [26]. It has been revealed that villages with greater incidence regularly utilized Euphorbia tirucalli and phorbol-esters, which are constituents of Euphorbia tirucalli and closely related to TPA. It is suggested these phorbol-esters are involved in the onset of Burkitt's lymphoma [27, 28].
We are conducting a screening for an antitumor substance using a method in which the suppressive effect against tumor promoter-induced inflammation is examined as a positive outcome index [29]. This method was utilized by Hecker et al. when they isolated and identified TPA and this method has been confirmed to be advantageous with high correlation as it employs a carcinogenesis experiment and skin from inbred (syngeneic) mice. Specifically, when TPA is applied on the auricle of female ICR mice, maximum swelling was observed 6-10 hours later. The mushroom extracts suppressed the TPA effects, as seen by swelling inhibition, and were confirmed by two-stage carcinogenesis experiments on mouse skin. We induced inflammation with TPA in mice and investigated methanol extracts of 27 edible mushrooms, 8 mushroom supplements, and 3 medicinal mushrooms, discovering the presence of promising mushrooms as shown in Table 1. Specifically, inhibitory effects were observed in: Russula delica, Lactarius deliciosus, Hypsizigus marmoreus (H. marmoreus), Mycoleptodonoides aitchisonii (M. aitchisonii), Naematoloma sublateritium for edible mushroom; Inonotus obliquus (chaga), meshima, Ganoderma lucidum (reishi), deer horn shape Ganoderma amboinense (rokkaku reishi), Pleurotus cornucopiae (golden oyster mushroom) for mushroom supplements; and Poria cocos (poria) and polyporus as medicinal mushrooms [30]. Of these mushrooms, the application of methanol extracts of H. marmoreus [31], M. aitchisonii [30], poria [32], chaga [33], and meshima [34] suppressed the promotion process. These results indicated that edible and medicinal mushrooms are effective cancer preventing foods. In addition, there is a method in which the suppressive effect against the EBV activation that is involved in the onset of Burkitt's lymphoma is examined as a positive outcome index [35]. Substances that were confirmed to have inhibitory effects through this method are thought to contribute to cancer prevention in those infected with EBV.
Scientific name
IR (%)
Polyporus confluens
35**
Russula delica
65**
R. cyanoxantha
38**
R. pseudodelica
41**
R. sanguinea
41**
Lactarius deliciosus
61**
L. volemus
17
Armillariella mellea
12
Flammulina velutipes
30**
Hypsizigus marmoreus
58**
Lyophyllum decastes
54**
L. connatum
53**
L. shimeji
40**
Pleurocybella porrigens
50**
Tricholoma japonicum
49**
T. matsutake
39**
T. portentosum
41**
Lycoperdon perlatum
20*
Agaricus bisporus
36**
Macrolepiota procera
11
Phaeolepiota aurea
15
Sarcodon aspratus
22*
Mycoleptodonoides aitchisonii
62**
Rhodophyllus crassipes
23*
Naematoloma sublateritium
55**
Pholiota squarrosa
33**
Hygrophorus russula
36*
Ganoderma lucidum
82**
Ganoderma amboinense
79**
Polyporus mylittae
33**
Phellinus linteus
73**
Inonotus obliquus
84**
Pleurotus cornucopiae var. citrinopileatus
52**
Hericium erinaceum
19
Sparassis crispa
49**
Table 1.
Inhibitory effect of edible and medicinal mushrooms on TPA-induced inflammation in mice.
IR: Inhibitory ratio at 1 mg/ear. * p < 0.05, p < 0.01 vs control group by Student’s t test.
Figure 3 illustrates the inhibitory effects of M. aitchisonii in mouse skin, two-stage carcinogenesis experiments. Specifically, Figure 3-A indicates the tumor incidence, where the vehicle control group showed the first tumor appearance in week 5 and tumor development in 93% of the mice in week 20. In contrast, mice that were given M. aitchisonii (M. aitchisonii group) showed the first tumor appearance in week 5 and tumor development in 53% of the mice in week 20. Figure 3-B shows the mean number of tumors at 20 weeks, where M. aitchisonii group presented 1.6 tumors in contrast to the vehicle control group that exhibited 11.2 tumors, confirming a 63% inhibitory effect [30]. Methanol extracts of H. marmoreus similarly suppressed the tumor promotion process [31].
Figure 3.
Inhibitory effect of the methanol extract from Mycoleptodonoides aitchisonii on the promotion of skin papillomas by TPA in DMBA-initiated mice [30].
A screening for suppressive ingredients was, therefore, conducted; using inhibitory effects against TPA-induced inflammation as an index, active ingredients were isolated and their chemical structures were elucidated. The active ingredients were ergosterol (1) and ergosterol peroxide (2) (Figure 4), which are normal ingredients of mushrooms, and these were stronger than non-steroidal anti-inflammatory drug indomethacin as shown by their 50% inhibitory effects (ID50: 756 and 467 nM/ear, respectively vs. 908 nM/ear). These two sterols have been demonstrated to suppress the promotion process in mouse skin two-stage carcinogenesis experiments [31, 36]. Other sterols (6-10) have been reported to inhibit the TPA-induced EBV activation (Table 2.) [37].
6. Cancer preventative effects of mushroom supplements
Mushroom supplements, such as meshima, chaga, and almond mushroom, are all believed to be beneficial for cancer, and utilized based on the wishes of cancer patients and their families. As shown in Table 1, supplements including reishi, rokkaku reishi, meshima, and chaga strongly suppressed TPA-induced inflammation [30]. Methanol extracts of Meshima and chaga strongly suppressed the promotion process in experiments involving DMBA and TPA carcinogens [33, 34]. Furthermore, chaga and meshima suppressed the promotion process through oral administration [38, 39].
Lanostane-type triterpenes depicted in Figure 5 were isolated and identified from chaga, and these triterpenes are known to show inhibitory effects in TPA-induced EBV activation (Table 3) [40, 41]. Eight types of lanostane-type triterpenes were isolated as active ingredients, and using the inhibitory effects against TPA-induced inflammation as an index, their 50% inhibitory effects (ID50: 125-458 nM/ear) indicated that they are stronger than non-steroidal anti-inflammatory drug indomethacin (908 nM/ear) (Tasble 4) [33]. Of these triterpenes, inotodiol (13) and 3β-Hydroxylanosta-8,24-dien-24-al (15) suppressed the tumor promotion process [40, 41].
Compound
IC50
Uvariol (10)
392
3β-Hydroxylanosta-8,24-dien-21-al (12)
232
Lanosta-8,23E-diene-3β,22R,25-triol (14)
231
Lanosta-7:9(11),23E-triene-3β,22R,25-triol (15)
228
Oleanolic acid
389
Table 3.
Inhibitory effects of lanostane-type triterpenes from Inonotus obliquus on induction of the Epstein-Barr virus early antigen.
IC50: Mol ratio/32 pmol/TPA.
Figure 5.
Structures of lanostane-type triterpenes from Inonotus obliquus.
Compound
ID50 (nM/ear)
Lanosterol (8)
458
Inotodiol (9)
125
Uvariol (10)
134
3β-Hydroxylanosta-8,24-dien-21-al (12)
389
Methoxyinonotsutriol (14)
272
3β,22-Dihydroxylanosta-7,9(11),24-triene (16)
335
Inotolacton B (19)
265
Indomethacin
908
Table 4.
Inhibitory effects of lanostane-type triterpenes from Inonotus obliquus on TPA-induced inflammation in mice.
ID50: 50% Inhibitory dose.
Reishi belongs to the Ganodermataceae family, and is cut into appropriate sizes to be brewed in hot water and consumed as an extract since the fruiting body is woody and not suitable for direct consumption, or is consumed as medicinal alcohol. It has been described in Shennong Ben Cao Jing (or The Classic of Herbal Medicine) compiled in the Eastern Han Dynasty (25-220), as a life-prolonging miracle drug that nourishes life, and since then, it has been used for various medicinal purposes in China. Akihisa et al. isolated multiple lanostane-type triterpene acids from its fruiting body, and reported that they suppress EBV activation as shown in Table 5 [42-44]. Of these compounds 20-Hydroxylucidenic acid N (21) suppressed the promotion process in mouse skin two-stage carcinogenesis [42]. With regards to triterpenes from reishi, ganoderic acid T (49) exhibited anticancer activities by inducing apoptosis in metastatic lung cancer cells mediated through mitochondria dysfunction and p53 expression [45]. In addition, ganoderic acid T (49) suppressed the nuclear translocation of NF-κB and expression of MMP-9 and iNOS, thereby inhibiting invasion by cancer cells [46]. Ganoderic acid DM (46) displayed anticancer activities by inducing G1-phase cell cycle arrest and apoptosis in MCF-7 cancer cells [47]. Ganoderic acid A (44) and ganoderic acid H (42) suppressed breast cancer cell invasion by inhibiting AP-1 and NF-κB and consequently down-regulating Cdk4 expression [48]. Ganoderic acid Me (48) inhibited tumor invasion by suppressing MMP2/9 expressions [49]. Lucidenic acid B (26) exhibited anti-invasive activity through suppressing TPA-induced NF-κB and AP-1 DNA-binding activities thereby downregulating MMP-9 expression in HepG(2) cells [50]. Lucidenic acid B (26) induced apoptosis through mitochondrial cytochrome release and the activations of caspase-9 and caspase-3 [51].
Compound
IC50
Lucidenic acid F (20)
352
Methyl lucidenate F (21)
285
Lucidenic acid D2 (22)
287
Methyl l ucidenic acid D2 (23)
290
Lucidenic acid A (24)
280
Methyl l ucidenate A (25)
287
Lucidenic acid B (26)
354
Methyl lucidenate Q (27)
283
Methyl lucidenate L (28)
275
Lucidenic acid E2 (29)
280
Methyl l ucidenate E2 (30)
288
Lucidenic acid N (31)
332
Methyl l ucidenate C (32)
331
Lucidenic acid P (33)
286
Methyl l ucidenate P (34)
293
20-Hydroxy lucidenic acid F (35)
339
20-Hydroxy lucidenic acid D2 (36)
350
20-Hydroxy lucidenic acid E2 (37)
290
20-Hydroxy lucidenic acid N (38)
288
20-Hydroxy lucidenic acid P (39)
288
20(21)-Dehydrolucidenic acid A (40)
350
Methyl 20(21)-dehydrolucidenate A (41)
357
Ganoderic acid F (42)
293
Ganoderic acid C1 (43)
336
Ganoderic acid A (44)
291
Ganoderic acid C2 (45)
290
Ganoderic acid DM (46)
352
Ganoderic acid T-Q (47)
281
Ganodermanondiol (50)
348
Ganolactone (51)
415
Ganoderic acid E (52)
281
Methyl ganoderate F (53)
289
Table 5.
Inhibitory effects of lanostane-type triterpene acids from Ganoderma lucidum on induction of the Epstein-Barr virus early antigen.
IC50: Mol ratio/32 pmol TPA.
Figure 6.
Structures of lanostane-type triterpene acids from Ganoderma lucidum.
Piptoporus betulinus is a fungus in the Polyporaceae family and the surface of its fruiting body had been used as a strop for razor blades. It is known that the Iceman, as evidenced by a mummy from 5,000 years ago found in the Tyrol region glacier, carried around this mushroom to prevent wound suppuration [52, 53]. Lanostane-type triterpenes (Figure 7) isolated from this mushroom suppressed TPA-induced inflammation [54].
Figure 7.
Structures of lanostane-type triterpenes from Piptoporus betulinus.
7. Cancer preventative effects and active ingredients of medicinal mushrooms
Of the medicinal mushrooms, polyporus (Polyporus umbellatus; Polyporaceae family) is an herbal medicine that possesses diuretic effects, but is also known to suppress TPA-induced inflammation. Screening for the active ingredients of this mushroom resulted in the isolation of insect metamorphosis hormone sterols, and the structures of eight compounds including new compounds polyporoid A (58), polyporoid B (59), and polyporoid C (60) were elucidated (Figure 8.) As shown in Table 6, the effects of these compounds in inhibiting TPA-induced inflammation (ID50) were 117-682 nM/ear, which were greater than that of indomethacin [55].
Figure 8.
Structures of ecdysteroids from Polyporus umbellatus.
Compound
ID50 (nM/ear)
Polyporoid A (58)
531
Polyporoid B (59)
682
Polyporoid C (60)
184
Polyporusterone A (61)
141
Polyporusterone C (62)
289
Polyporusterone B (63)
117
Polyporusterone G (64)
207
Ergosta-7,22-diene-3β,5α,6β-triol (65)
666
Indomethacin
838
Table 6.
Inhibitory effect of ecdysterolids from Polyporus umbellatus on TPA-induced inflammation in mice.
ID50: 50% Inhibitory dose.
The sclerotia of Poria cocos (Polyporaceae family) are referred to as poria, and due to their diuretic properties, and they are formulated in traditional Japanese medicine prescriptions. Additionally, they are also commonly formulated in traditional Japanese medicine prescriptions that are used as adjuvants. The oral administration of Juzentaiho-to and Rikkunshi-to, Japanese Kampo medicines, suppressed cancer promotion in mouse skin two-stage carcinogenesis experiments [56, 57]. It has been shown that, for an effect to appear, the immune response that is decreased during carcinogenic process be activated [57]. Of the formulated ingredients in these prescriptions, hoelen showed the strongest effect in suppressing TPA-induced inflammation [58]. A screening for the active ingredients of hoelen was therefore conducted, and multiple lanostane-type triterpene acids were isolated and identified (Figure 9) [32]. Of the poria-derived triterpenes, pachymic acid (71), 3-O-acetyl-16α-hydroxytrametenolic acid (70), dehydropachymic acid (79), 3β-hydroxylanosta-7,9(11),24-trien-21-oic acid (75), dehydroebuliconic acid (81), and poricoic acids A (97) and B (94) had inhibitory effects against TPA-induced inflammation (ID50: 31-83 nM/ear), that were greater than that of indomethacin but similar to that of hydrocortisone (ID50: 69 nM/ear). With regards to pachymic acid (71), 3-O-acetyl-16α-hydroxytrametenolic acid (70), and poricoic acid B (94), all of which showed strong inhibitory effects, a mouse skin two-stage carcinogenesis experiment using DMBA and TPA demonstrated that they exhibited suppressive effects that were similar to that of the aforementioned ergosterol (1), ergosterol peroxide (2) and other triterpenes, even when 10% of the dosage of the latter compounds were administered [59]. These compounds have a carboxyl group (COOH) at the carbon 21 position (on side chain), and their suppressive effects decreased 90% when the COOH-group was methylated. It was discovered that COOH at the carbon 21 position plays an important role for activation [32]. Akihisa et al. isolated many new lanostane-type triterpene acids from poria, and reported their suppressive effects in TPA-induced EBV activation (Table 8) [60-62]. Moreover, they confirmed that 16-deoxyporicoic acid B (93), poricoic acid C (95), and 25-methoxyporicoic acid A (102) suppress the promotion process [60, 61]. Of these compounds, poricotriol A was revealed to induce apoptosis and possess antitumor effects [63]. Pachymic acid and dehydrotumulosic acid strongly suppress PL-A2, which is related to inflammation [64].
Mushroom polysaccharides and glycoproteins have antitumor mechanisms such as activating various immunocompetent cells and reinforcing the tumor aggressiveness of the host. Many mushroom-derived polysaccharides have very weak effects when administered orally. However, with the advancement in food technology, the development of these polysaccharides as food products is progressing and their development as oral pharmaceutical products is also anticipated.
Poria and reishi are listed in the first treatise of Shennong Ben Cao Jing, and viewed as herbal medicines that help maintain health. Although some mushroom triterpenoids show strong suppressive effects similar to that of hydrocortisone, most result in a moderate antitumour promotor effect. It is expected that these triterpenoids, such as pachymic acid, may inhibit phospholipase A2. Nonetheless, since these mushrooms are edible and are used as supplements and herbal medicines, they are considered to have extremely low or no toxicity. Therefore, these triterpenoids from poria and reishi are a promising group of compounds. In particular, pachymic acid, ganoderic acid T, and lucidenic acid B, are leads in the search for cancer prevention drugs; the development of cancer prevention drugs with properties akin to tamoxifen is desired. When developing a preventative drug, the safety of the substance must first and foremost be considered.
There are many other challenges, such as further elucidating the mechanism, ascertaining the appropriate intake level, and supplying large amounts of the compound. The cooperation and collaboration of researchers from various fields will be necessary to address these issues.
Dr. Michio Takido, my mentor and professor emeritus at School of Pharmacy, Nihon University, passed away on August 25, 2014. My research and attitude towards this research were greatly influenced by his guidance. This article is dedicated to Dr Takido with profound gratitude.
References
1.Yasukawa K. Medicinal and edible plants as cancer preventive agents. In: Vallisuta O, Olimat SM (eds) Drug Discovery Research in Pharmacognosy. Rijeka: InTech; 2012. p181‒208.
2.Chihara G, Maeda Y, Hamuro J, Sasaki T, Fukuoka F. Inhibition of mouse sarcoma 180 by polysaccharides from Lentinus edodes (Berk.) sing. Nature 1969;222(5194) 687–688.
3.Chihara G, Hamuro J, Maeda Y, Arai Y, Fukuoka F. Fractionation and purification of the polysaccharides with marked antitumor activity, especially lentinan, from Lentinus edodes (Berk.) Sing. (an edible mushroom). Cancer Research 1970;30(11) 2776‒2781.
4.Zákány J, Chihara G, Fachet J. Effect of lentinan on tumor growth in murine allogeneic and syngeneic hosts. International Journal of Cancer 1980;25(3) 371‒376.
5.Suga T, Shiio T, Maeda YY, Chihara G. Antitumor activity of lentinan in murine syngeneic and autochthonous hosts and its suppressive effect on 3-methylcholanthrene-induced carcinogenesis. Cancer Research 1984;44(11) 5132‒5137.
6.Hamuro J, Chihara G. Immunopotentiation by the antitumor polysaccharide lentinan, its immunopharmacology and physiology. In: The reticuloendoyhelial system. Vol. 8 (Hadden JW, Szentivanyl A, eds) Plenum Publ., New York, 1985, pp. 285‒307.
7.Ikekawa T, Uehara N, Maeda Y, Nakanishi M, Fukuoka F. Antitumor activity of aqueous extracts of edible mushrooms. Cancer Research 1969;29(3) 734‒735.
8.Ikekawa T. Beneficial effects of edible and medicinal mushrooms on health care. International Journal of Medicinal Mushroom 2001;3(4); 291‒298.
9.Hamuro J, Chihara G. Effect of antitumor polysaccharides on the higher structure of serum protein. Nature 1973;245(5419) 40‒41.
10.Lo TC-T, Hsu F-M, Chang CA, Cheng JC-H. Branched α-(1,4) glucans from Lentinula edodes (L10) in combination with radiation enhance cytotoxic effect on human lung adenocarcinoma through the Toll-like receptor 4 mediated induction of THP-1 differentiation/activation. Journal of Agricultural and Food Chemistry 2011;59(22) 11997‒12005.
11.Komatsu N, Okubo S, Kikumoto S, Kimura K, Saito G, Sakai S. Host-mediated antitumor action of Schizophyllan, a glucan produced by Schizophyllum commune. Japanese Journal of Cancer Research (Gann) 1969;60(2) 137‒144.
12.Okamura K, Suzuki M, Chihara T, Fujiwara A, Fukuda T, Goto S, Ichinohe K, Jimi S, Kasamatsu T, Kawai N, Mizuguchi K, Mori S, Nakano H, Noda K, Sekiba K, Suzuki K, Suzuki T, Takahashi K, Takeuchi K, Takeuchi S, Yajima A, Ogawa N. Clinical evaluation of Schizophyllan combined with irradiation in patients with cervical cancer. Cancer 1986;58(4), 865‒872.
13.Ross GD, Vetvicka V. CR3 (CD11b, CD18): a phagocyte and NK cell membrane receptor with multiple ligand specificities and functions. Clinical and Experimental Immunology 1993;92(2) 181‒184.
14.Di Renzo L, Yefenof E, Klein E. The function of human NK cells is enhanced by β-glucan, a ligand of CR 3 (CD11b/CD18). European Journal of Immunology 1991;21(7) 1755‒1758.
15.Kobayashi H, Matsunaga K, Oguchi Y. Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiol, Biomarkers & Prevention 1995;4(3) 275‒281.
16.Ito H, Hidaka H, Suigura M. Effects of coriolane, an antitumor polysaccharide, produced by Coriolus versicolor Iwade. Japanese Journal of Pharmacology 1979;29(6) 953‒957.
17.Huang H-Y, Chieh S-Y, Tso TK, Chien T-Y, Lin H-T, Tsai Y-C. Orally administered mycelia culture of Phellinus linteus exhibits antitumor effects in hepatoma cell-bearing mice. Journal of Ethnopharmacology 2011;133(2) 460‒466.
18.Li Y-G, Ji D-F, Zhong S, Zhu J-X, Chen S, Hu G-Y. Anti-tumor effects of proteoglycan from Phellinus linteus by immunomodulating and inhibiting Reg IV/EGFR/Akt signaling pathway in colorectal carcinoma. International Journal of Biological Macromolecules 2011;48(8) 511‒517.
19.Zhong S, Ji D-F, Li Y-G, Lin T-B, Lv Z-Q, Chen H-P. Activation of P27kip1-cyclin D1/E-CDK2 pathway by polysaccharide from Phellinus linteus leads to S-phase arrest in HT-29 cells. Chemico-Biological Interactions 2013;206(2) 222‒229.
20.Yamagiwa K, Ichikawa K. Experimental study of the pathogenesis of carcinoma. The Journal of Cancer Research 1918;3 (1) 1–29.
21.Berenblum I. The cocarcinogenic action of croton resin. Cancer Research 1941;1(1) 44–48.
22.Berenblum I. The mechanism of carcinogenesis. A study of the significance of cocarcinogenic action and related phenomena. Cancer Research 1941;1(10) 807–814.
23.Hecker E. Phorbol esters from crotn oil, chemical nature and biological activities. Naturwissenschaften 1967;54(11) 282–284.
24.van Duuren BL. Tumor-promoting agents in two-stage carcinogenesis. Progress in Expremental Tumor Research 1969;11(1) 31–68.
25.Fujiki H, Suganuma M. Naturally-derived tumor promoters and inhibitors of carcinogenesis. Toxin Reviews 1996;15(2) 129–156.
26.van den Bosch CA. Is endemic Burkitt’s lymphoma an alliance between three infections and a tumour promoter? Lancet Oncology 2004;5(12) 738–746.
27.Aya T, Kinoshita T, Imai S, Koizumi S, Mizuno F, Osato T, Satoh C, Oikawa T, Kuzumaki N, Ohigashi H, Koshimizu K. Chromosome translocation and c-myc activation by Epstein-Barr virus and Euphorbia tirucalli in B lymphocytes. Lancet 1991;337(8751) 1190.
28.Imai S, Sugiura M, Mizuno F, Ohigashi H, Koshimizu K, Chiba S, Osato T. African Burkitt’s lymphoma: A plant, Euphorbia tirucalli, reduces Epstein-Barr virus-specific cellular immunity. Anticancer Research 1994, 14(3A) 933–936.
29.Yasukawa K, Takido M, Takeuchi M, Nakagawa S. Effect of chemical constituents from plants on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice. Chemical & Pharmaceutical Bulletin 1989;37(4) 1071–1073.
30.Yasukawa K, Kanno H, Kaminaga T, Takido M, Kasahara Y, Kumaki K. Inhibitory effect of methanol extracts from edible mushroom on TPA-induced ear oedema and tumour promotion in mouse skin. Phytotherapy Research 1996;10(4) 367–369
31.Yasukawa K, Aoki T, Takido M, Ikekawa T, Saito H, Matsuzawa T. Inhibitory effects of ergosterol isolated from the edible mushroom Hypsizigus marmoreus on TPA-induced inflammatory ear oedema and tumour promotion in mice. Phytotherapy Research 1994;8(1) 10–13.
32.Kaminaga T, Yasukawa K, Takido M, Tai T, Nunoura Y. Inhibitory effect of Poria cocos on 12-O-tetradecanoylphorbol-13-acetate-induced ear oedema and tumour promotion in mouse skin. Phytotherapy Research 1996;10(7) 581–584.
33.Akita A, Sun Y, Yasukawa K. Inhibitory effects of chaga (Inonotus obliquus) on tumor promotion in two-stage mouse skin carcinogenesis. Journal of Pharmacy and Nutrition Science 2015;5(1), 71-76.
34.Yasukawa K, Kitanaka S, Takahashi H, Hirayama H, Shigemoto K. Inhibitory effect of natural fruit body of Phellinus linteus on tumor promotion in mice skin. The Japanese Journal of Pharmacognosy 2007;61(1), 14–17.
35.Ohigashi H, Takamura H, Koshimizu K, Tokuda H, Ito Y. Search for possible antitumor promoters by inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation; ursolic acid and oleanolic acid from anti-inflammatory Chinese medicinal plant, Glechoma hederaceae L. Cancer Letters 1986;30(2) 143‒151.
36.Yasukawa K, Akihisa T, Kanno H, Kaminaga T, Izumida M, Sakoh T, Tamura T, Takido M. Inhibitory effects of sterols isolated from Chlorella vulgaris on 12-O-tetradecanoyl- phorbol-13-acetate-induced inflammation and tumor promotion in mouse skin. Biological & Pharmaceutical Bulletin (Tokyo) 1996;19(4), 573–576.
37.Akihisa T, Franzblau SG, Tokuda H, Tagata M, Ukiya M, Matsuzawa T, Metori K, Kimura Y, Suzuki T, Yasukawa K. Antitubercular activity and inhibitory effect on Epstein-Barr virus activation of sterols and polyisoprenepolyols from an edible mushroom, Hypsizigus marmoreus. Biological & Pharmaceutical Bulletin 2005;28(6) 1117–1119.
38.Akita A, Yasukawa K. Inhibitory effect of chaga (Inonotus obliquus) on tumor promotion in two-stage mouse skin carcinogenesis, Japanese Journal of Complementary and Alternative Medicine 2011;8(1) 29‒32.
39.Yasukawa K, Takahashi H, Kitanaka S, Hirayama H, Shigemoto K. Inhibitory effect of an aqueous extract of Phellinus linteus on tumor promotion in mouse skin. Mushroom Science and Biotechnology 2007;15(2) 97–101.
40.Nakata T, Yamada T, Taji S, Ohishi H, Wada S, Tokuda H, Sakuma K, Tanaka R. Structure determination of inonotsuoxides A and B in vivo anti-tumor promoting activity of inotodiol from the sclerotia of Inonotus obliquus. Bioorganic & Medicinal Chemistry 2007;15(1) 257‒264.
41.Taji S, Yamada T, Wada S, Tokuda H, Sakuma K, Tanaka R. Lanostane-type triterpenoids from the sclerotia of Inonotus obliquus possessing anti-tumor promoting activity. European Journal of Medicinal Chemistry 2008;43(11) 2373‒2379.
42.Akihisa T, Nakamura Y, Tagata M, Tokuda H, Yasukawa K, Uchiyama E, Suzuki T, Kimura Y. Anti-inflammatory and anti-tumor-promoting effects of triterpene acids and sterols from the fungus Ganoderma lucidum. Chemistry & Biodiversity 2007;4(2) 224–231.
43.Akihisa T, Tagata M, Ukiya M, Tokuda H, Suzuki T, Kimura Y. Oxygenated lanostane-type triterpenoids from the fungus Ganoderma lucidum. Journal of Natural Products. 2005;68(4) 559‒563.
44.Iwatsuki K, Akihisa T, Tokuda H, Ukiya M, Oshikubo M, Kimura Y, Asano T, Nomura A, Nishino H. Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barr virus activation. Journal of Natural Products 2003;66(12) 1582‒1585.
45.Tang W, Liu J-W, Zhao W-M, Wei D-Z, Zhong J-J. Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. Life Sciences 2006;80(3) 205‒211.
46.Chen N-H, Liu J-W, Zhong J-J. Ganoderic acid T inhibits tumor invasion in vitro and in vivo through inhibition of MMP expression. Pharmacological Reports 2010;62(1) 150‒163.
47.Wu GS, Lu JJ, Guo JJ, Li YB, Tan W, Dang YY, Zhong ZF, Xu ZT, Chen XP, Wang YT. Ganoderic acid DM, a natural triterpenoid, induces DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells. Fitoterapia 2012;83(2) 408‒414.
48.Jiang J, Grieb B, Thyagarajan A, Sliva D. Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-κB signaling. International Journal of Molecular Medicine 2008;21(5) 577‒584.
49.Chen N-H, Liu J-W, Zhong J-J. Ganoderic acid Me inhibits tumor invasion through down-regulating matrix metalloproteinases 2/9 gene expression. Journal of Pharmacological Sciences 2008;108(2) 212‒216.
50.Wang C-J, Chau C-F, Hsich Y-S, Yang S-F, Yen G-C. Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-κB and AP-1. Carcinogenesis 2008;29(1) 147‒156.
51.Hsu C-L, Yu Y-S, Yen G-C. Lucidenic acid B induces apoptosis in human leukemia cells via a mitochondria-mediated pathway. Journal of Agricultural Chemistry 2008;56(11) 3973‒3980.
52.Capasso L. 5300 years ago, the Ice Man used natural laxatives and antibiotics. The Lancet 1998;352(9143) 1864.
53.Schlegel B, Luhmann U, Härtl A, Gräfe U. Piptamine, a new antibiotic produced by Piptoporus betulinus Lu 9-1. The Journal of Antibiotics 2000;53(9) 973–974.
54.Kamo T, Asanoma M, Shibata H, Hirota M. Anti-inflammatory lanostane-type triterpene acids from Piptoporus betulinus. Journal of Natural Products 2003;66(8) 1104‒1106.
55.Sun Y, Yasukawa K. New anti-inflammatory ergostane-type ecdysteroids from the sclerotium of Polyporus umbellatus. Bioorganic & Medicinal Chemistry Letters 2008;18(9) 3417–3420.
56.Haranaka R, Kosoto H, Hirama N, Hanawa T, Hasegawa R, Hyun SJ, Nakagawa S, Haranaka K, Satomi N, Sakurai A, Yasukawa K, Takido M. Antitumor activities of Zyuzen-taiho-to and Cinnamomi Cortex. Journal Medical and Pharmaceutical Society for Wakan-Yaku 1987;4(1) 49–58.
57.Yasukawa K, Yu S-Y, Takido M. Inhibitory effect of oral administration of Rikkunshi-to on tumor promotion in two-stage carcinogenesis in mouse skin. Journal of Traditional Medicines 1996;13(2) 180–184.
58.Yasukawa K, Yu S-Y, Kakinuma S, Takido M. Inhibitory effect of of Rikkunshi-to, a traditional Chinese herbal prescription, on tumor promotion in two-stage carcinogenesis in mouse skin. Biological & Pharmaceutical Bulletin 1995;18(5) 730–733.
59.Kaminaga T, Yasukawa K, Kanno H, Tai T, Nunoura Y, Takido M. Inhibitory effect of lanostane-type triterpene acids, the components of Poria cocos, on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Oncology 1996;53(5) 382–385.
60.Akihisa T, Nakamura Y, Tokuda H, Uchiyama E, Suzuki T, Kimura Y, Uchikura K, Nishino H. Triterpene acids from Poria cocos and their anti-tumor-promoting effects. Journal of Natural Products 2007;70(6) 948‒953.
61.Akihisa T, Uchiyama E, Kikuchi T, Tokuda H, Suzuki T, Kimura Y. Anti-tumor-promoting effects of 25-methoxyporicoic acid A and other triterpene acids from Poria cocos. Journal of Natural Products 2009;72(10) 1786–1792.
62.Ukiya M, Akihisa T, Tokuda H, Hirano M, Oshikubo M, Nobukuni Y, Kimura Y, Tai T, Kondo S, Nishino H..Inhibition of tumor-promoting effects by poricoic acids G and H and other lanostane-type triterpenes and cytotoxic activity of poricoic acids A and G from Poria cocos. Journal of Natural Products 2002;65(4) 462‒465.
63.Kikuchi T, Uchiyama E, Ukiya M, Tabata K, Kimura Y, Suzuki T, Akihisa T. Cytotoxic and apoptosis-inducing activities of triterpene acids from Poria cocos. Journal of Natural Products 2011;74(2) 137–144.
64.Cuéllar MJ, Giner RM, Recio MC, Just MJ, Máñez S, Ríos JL. Two fungal lanostane derivatives as phospholipase A2 inhibitors. Journal of Natural Products 1996;59(10) 977‒979.
Written By
Ken Yasukawa
Submitted: May 29th, 2014Published: June 3rd, 2015
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