高分子量化合物

高分子量成分以多醣體或是多醣結合物為主，多醣體以不同形式的糖苷鍵結 或是多醣與蛋白質或胜肽殘基結合為多醣體-蛋白質和多醣體-胜肽（表1-7）。已 有眾多證據顯示菇類多醣體透過增強巨噬細胞、NK細胞和T細胞的數量或功能 (Zhuang, 2009; Chen et al., 2010; Ferreira et al., 2010; Rubel et al., 2010; Xu et al., 2011) ，調控先天性和後天性免疫反應，活化免疫系統達到抗腫瘤的效果。

以GLPS為例，分子量約584.9 KDa，屬於多醣體-胜肽，是由靈芝子實體熱 水萃取而來(Cao and Lin, 2002; Cao and Lin, 2004)。GLPS（100、200和400 mg/kg）

管餵接種S180腫瘤小鼠，發現GLPS能有效抑制腫瘤生長，具有劑量的關係(Xu et al., 2011)，增強TNF-α和IFN-γ的表現及毒殺型T細胞和NK細胞的活性(Gao et al., 2005a)；結合cyclophospamide化療藥物處理腫瘤小鼠，可以降低化療藥物的毒性 與副作用(Ning et al., 2003)；GLPS作為佐劑時，患者血液IL-2、IL-6和顯著增加，

而IL-1和TNF-α下降，CD3、CD4和CD8細胞顯著性增加(Gao et al., 2003)，其活 化機制及免疫調節活性如圖1-9(Xu et al., 2011)，刺激B細胞增生與活化、促進T 細胞釋出TNF-α和INF-γ、增強並刺激未成熟樹突細胞成熟。對高分子量的多醣體 抗腫瘤效果而言，一般認為與高分子量、低分支度和高水溶性有相關性(Ferreira et al., 2010)。

目前很多學者都聚焦在靈芝抗腫瘤的效果，在體內和體外試驗累積了許多 成果，靈芝也已經使用在預防或治療人類許多疾病，像是支氣管炎、過敏、肝炎、

高血壓、免疫失調和腫瘤等(Yuen and Gohel, 2005; Boh et al., 2007; Jeong et al., 2008; Zhuang, 2009; Li et al., 2010c; Xu et al., 2011)，很多研究也顯示靈芝抽出物 在體外具有抑制很多腫瘤細胞株的增生作用，如直腸前列腺癌細胞(Berovic et al., 2003)、肺癌細胞(Jiang et al., 2005; Chen, 2006)、急性骨髓白血球癌細胞(Cheng et

al., 2007)、乳癌細胞(Thyagarajan et al., 2006)、子宮頸癌細胞、肝癌細胞(Chen, 2006)和膀胱癌細胞(Paterson, 2006)等。

圖1-8. 食用菇菌中具有抗腫瘤功能之有效成分

Figure 1-8. Low-molecular-weight (LMW) and high-molecular-weight (HMW) compounds with antitumor potential found in mushrooms (Ferreira et al., 2010).

表1-6 食用菇菌中小分子之抗腫瘤有效成分

Table 1-6. Low-molecular-weight compounds with antitumor potential in mushrooms (Ferreira et al., 2010)

Class Antitumor Agents Mushroom Species Molecular Targets

Panepoxydone Panus conchatus, P.

rudis, Lentinus crinitus NF-κB inhibitor

Cycloepoxydon Xylaria strain 45-93 NF-κB inhibitor

Clavilactones Clitocybe clavipes Tyrosine kinase

inhibitors 490 Quinone

(γ-L-glutaminyl-4-hydroxy-2,5-benzoquinone) Agaricus bisporus DNA polymerase α inhibitor Quinones

(E)-2-(4-hydroxy-3-methyl-2-butenyl)-hydroquinone Piptoporus betulinus MMPs inhibitor

Cerebrosides

(4E,8E)-N-D-2’-hydroxypalmitoyl-1-O-β-D-glucopyranos yl-9-methyl-4,8-sphingadienine

(4E,8E)-N-D-2’-hydroxystearoyl-1-O-β-D-glucopyranosyl -9-methyl-4,8-sphingadienine

Ganoderma lucidum DNA polymerase
inhibitors

Isoflavones ^Genistein Flammulina velupites Cdc2 kinase modulator

6-(3,4-dihydroxystyryl)-4-hydroxy-2-pyrone (Hispidin)

P. linteus, Gymnopilus marginatus, G. patriae, G. parvisporus, Ionotus

hispidus

PKCβ inhibitor Catechols

Gerronemins A-F (9a-f) Gerronema COX-2 inhibitors

2-aminophenoxazin-3-one Lepiota americana Aromatase inhibitor Amines

and amides Putrescine-1,4-dicinnamide Pholiota spumosa inducer of apoptosis and necrosis

Triacylglycerols 1-Oleoyl-2-linoleoyl-3-palmitoylglycerol (12) Grifola frondosa Cyclooxygenase

inhibitor

Sesquiterpenes Iludin S and M and derivatives Omphalotus illudens,

Lampteromyces japonicus

DNA-alkylating agents

5,8-Epidioxy-24(R)-methylcholesta-6,22-dien-3β-ol Lepiota americana,

Cordyceps sinensis Sulfatase inhibitor 5,8-Epidioxy-24(R)-methylcholesta-6,22-dien-3β-D-gluco

pyranoside,

5,6-Epoxy-24(R)-methylcholesta-7,22-dien-3β-ol Cordyceps sinensis Not known

Ergosterol Grifola frondosa,

Agaricus blazei Cyclooxygenase inhibitor

Lucidenic acid O, Lucidenic lactone, Cerevisterol, Lucidumol A and B, Ganoderiol F, Ganodermanondiol, Ganodermanontriol, Ganoderic acids A, F, H, W, X, Y, T

Ganoderma lucidum

DNA polymerase α and β, RT inhibitors, NF-κB and AP-1 inhibitors, DNA topoisomerase

inhibitor Polyporenic acid C Piptoporus betulinus,

Daedalea dickinsii MMPs inhibitor

Dehydroebriconic acid Poria cocos DNA topoisomerase II

inhibitor Steroids

Fomitellic acids A and B Fomitella fraxinea DNA polymerase α and β inhibitors Organic

germanium Bis-β-carboxyethylgermanium sesquioxide:

O3(GeCH2CH2COOH)2 Ganoderma lucidum Not known

Trace

elements ^Selenium

Agaricus bisporus,

表1-7 菇類中具抗腫瘤活性之高分子化合物

Table 1-7. High-molecular-weight compounds with antitumor potential in higher Basidiomycetes mushrooms (Wasser, 2002; Ferreira et al., 2010).

Class Antitumor Agents

Mushroom Species Functions

ATOM Agaricus blazei Immunomodulatory; pre-clinical animal models

AB-FP Agaricus blazei Immunomodulatory; clinical trials

PSPC Tricholoma lobayense Immunomodulatory; pre-clinical animal models

Galactoxylogluc an-protein complex

Hericium erinaceus Immunomodulatory; in vitro cell lines

Glucoxylan-prot ein complex

Hericium caput-medusae Immunomodulatory; in vitro cell lines

Glycoproteins(P olysaccharide-pr otein complexs)

Ganoderans Ganoderma lucidum Immunomodulatory; in vitro cell lines

PSP Trametes versicolor Immuno-enhancing activity;

clinical trials

PSK or krestin Trametes versicolor Immuno-enhancing activity;

clinical trials

KS-2 Lentinus edodes Immunomodulatory; in vitro cell lines

Ganoderma lucidum Immunomodulatory; pre-clinical animal models

GLIS Ganoderma lucidum Immunomodulatory; pre-clinical

animal models Proteoplycans

PL Phellinus edodes Immunomodulatory; pre-clinical animal models

Mixture of polysaccharides and lignin

LEM Lentinus edodes Immunomodulatory; pre-clinical animal models

Flammulin Flammulina velutipes Immunomodulatory; in vitro cell lines

LZ-8 Ganoderma lucidum Immunomodulatory; pre-clinical

animal models

Clitocypin Clitocybe nebularis Cysteine proteinase inhibitor; in vitro enzyme inhibition assays Proteins

Lectins Agaricus bisporus, Boletus satans, Grifola frondosa, Tricholoma mongolicum, Volvariella volvacea

Immunomodulatory and antiproliferative; in vitro cell lines

RNA-protein complex

FA-2-b-Md Agaricus blazei Immunomodulatory; in vitro cell lines

圖1-9 . 靈芝多醣體 GLPS 對免疫細胞之免疫調節機制

Fig. 1-9. The immunomodulatory of GLPS on immune cells (Xu et al., 2011).

六、研究架構