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研究生:呂美津
研究生(外文):Mei-Chin Lu
論文名稱:臺灣特有牛樟芝及番荔枝科乙醯生合成物-squamocin之抗癌相關機轉
論文名稱(外文):Mechanisms of Anticancer-Related Activities of Formosan Antrodia cinnamomea and Annonaceous Acetogenins - Squamocin
指導教授:吳永昌
指導教授(外文):Yang-Chang Wu
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
畢業學年度:96
語文別:英文
論文頁數:101
中文關鍵詞:Antrodia cinnamomeaSquamocinAnticancerDendritic Cells (DCs)Zhankuic acid A
外文關鍵詞:Antrodia cinnamomeaSquamocinAnticancerDendritic Cells (DCs)Zhankuic acid A
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關於天然物抗癌的研究是最近的新潮流, 因為傳統化療的副作用太大, 所以癌症病患往往不能真正受益,因此開發天然物之活性分性析為目前研究之標的。就目前而言,有愈有愈多的證據指出,從天然物中所萃取出來的化合物可用於治療人類的各種疾病。在本研究計畫的主體為臺灣特有牛樟芝 (Antrodia cinnamomea Chang & Chou) 野生子實體之萃取物及臺灣產番荔枝科乙醯生合成物 (Formosan Annonaceous Acetogenins) 之squamocin來研究抗癌相關作用機制之探討。本研究論文總共分為三個部份如下:

研究論文的第一部份,我們將著重於研究臺灣特有牛樟芝的抗癌活性。牛樟芝是台灣特有珍貴藥用真菌類,屬於多孔菌科(Polyporeceae),越來越多的研究證實具有相當大的潛力開發成為癌症治療的新藥物。在我們的研究結果發現,利用酒精萃取野生樟芝子實體之萃取物(EEAC),可誘使HL 60血癌細胞經由降低組織蛋白的乙醯化進而造成細胞凋亡,其機制為增加癌細胞之組織蛋白去乙醯化轉移酶1 (histone deacetyltransferase, HDAC)的表現,並且降低了組織蛋白乙醯化轉移酶 (histone acetyltransferase)的活性,乙醯化轉移酶包括了GCN 5、CBP及PCAF。我們合併使用組織蛋白去乙醯化抑制劑trichostain A (TSA)來處理癌細胞,發現TSA並不能抑制EEAC所誘發的細胞凋亡。有趣的是,TSA及EEAC的合併使用對於抑制癌細胞的生長及誘發細胞凋亡具有協同作用的效果。且由我們結果顯示出EEAC可藉由增加死亡接受器(DR5)的表現及NF kappa B的活化來增加TSA細胞毒殺作用。接著,我們利用NMR來偵測牛樟芝子實體萃取物的成份組成, NMR及細胞毒殺分析的結果得知EA萃取物中最主要的活性成份為triterpenoids及steroids,且從活性導引分離(bioassay-guided fractionation)的結果得到zhankuic acid A為主要的活性成份,因此我們認為EEAC具有發展成為癌症化學療法佐劑之潛力。

研究論文的第二部份,我們將著重於研究於牛樟芝對於樹突細胞(Dendritic cells, DCs) 的免疫調控活性。目前認為調控免疫反應的樹突細胞是最具有潛力的抗原呈現細胞(Antigen Presenting Cells, APCs)。而菇類所產生的多醣體,在現今研究中發現其可成為一種誘使樹突細胞成熟及功能活化的新藥劑。且藥用菇類中,牛樟芝在台灣是屬於較常用於化學預防之藥用菇類,因此,在本計劃最主要的研究目標為探討牛樟芝萃取物(ACW)在活化樹突細胞功能性成熟過程中,所扮演免疫調節之角色。從實驗結果得知,相較lipopolysaccharides (LPS)促進樹突細胞功能成熟的作用,我們發現ACW也可提升樹突細胞的表面抗原表現及IL-12之生成。我們更進一步地發現,ACW可誘發樹突細胞表現Akt 、 p38 、及JNK/MAPKs的磷酸化之增加,且在利用p38抑制劑(SB 203580)及Akt抑制劑(LY94002)前處理後,可顯著地阻斷ACW所誘發的共同刺激因子(costimulatory factor)表現及IL-12的生成。因此我們認為ACW將具有成為癌細胞免疫療法之佐劑且可促進Th1之免疫反應。

研究論文的第三部份,我們將著重於研究squamocin之生物活性,squamocin是屬於臺灣產番荔枝科乙醯生合成物的一種,由現今研究結果證實具有抗癌活性,因此探討其對血癌細胞K562細胞生長抑制之影響。從實驗結果顯示squamocin的細胞毒殺作用都是隨著處理時間或是劑量的增加明顯地抑制K562細胞之增生,並且可發現K562增生之抑制是因細胞週期停滯於G2/M所致。在探討調控細胞週期蛋白質的表現方面,發現cyclin-dependent kinase inhibitors (CDKIs), p21及p27 隨著squamocin處理劑量的增加,其表現量也隨之增加;而Cdk2,Cdk4, cyclin A,cyclin B1,cyclin D3及cyclin E則是維持不變;但在Cdk1及Cdc25C表現是隨之減少的。由以上結果得知,我們得知squamocin藉由增加p21及p27及減少Cdk1及Cdc25C的表現使得K562停滯於G2/M期而抑制細胞生長。

總結來說,我們將更進一步的研究這些天然物,使之能應用於臨床的癌症治療上。因此,之後我們將更精確的鑑定出AC子實體粗萃取物中的有效活性成份,並且用於的動物體內模式,使之具有潛力發展成為新的癌症免疫療法輔助性疫苗。另一目標,我們將探討臺灣產番荔枝科乙醯生合成物中的squamocin其對於被接種腫瘤細胞老鼠的抗癌機制及對於樹突細胞免疫方面的調控。
Accumulating evidence indicates that the importance of compounds derived from natural products to treat human diseases. Main investigations of this proposal are to study the mechanisms of these anticancer-related activities from natural extracts of Taiwanofungus cinnamomea and squamocin of Formosan Annonaceous Acetogenins. This proposal is divided to three parts that included:
In the first part, we focused on the anticancer activity of Tiwanofungus cinnamomea. The endemic species of Antrodia camphorate (AC) is a promising chemotherapeutic drug for cancer. We found that the ethanol extract from wild fruiting bodies of Antrodia cinnamomea (EEAC) could induce HL 60 cells apoptosis via histone hypoacetylation, up-regulation of histone deacetyltransferase 1 (HDAC 1), and down-regulation of histone acetyltransferase activities including GCN 5, CBP and PCAF in dose-dependent manner. Combination with histone deacetylase inhibitor, trichostatin A (TSA), did not block EEAC-induced apoptosis. Interestingly, combined treatment (100 nM of TSA and 100 μg/ml EEAC) caused synergistic inhibition of cell growth and increase of apoptotic induction. EEAC could effectively increase the cytotoxic sensitivity of TSA through the up-regulation of DR5 and NFκB activation. In this present study, bioassay-guided fractionation of EEAC led to the major active compound, zhankuic acid A, as the bioactive marker. Moreover, our findings may represent an experimental basis for developing EEAC as a potential chemotherapeutic adjuvant.
In the second part, we focused the immunomodulatory activity of Tiwanofungus cinnamomea on dendritic cells (DCs). Dendritic cells (DCs) are now recognized as the most potent professional antigen presenting cells (APCs) involved in initiating primary immune responses. The medicinal mushroom Antrodia cinnamomea (AC), is one of the most popular chemopreventive mushroom in Taiwan. Polysaccharides of mushroom products are among emerging new agents that activate maturation and functions of dendritic cells. The aim of this study is to investigate immunomodulating activity of Antrodia cinnamomea extract (ACW) on functional maturation of DCs. Compared with lipopolysaccharides (LPS), ACW effectively promoted the functional maturation of DCs in expression of phenotypic characteristics and IL-12 production as well as chemotaxic activity. Moreover, ACW increased phosphorylstion of Akt, p-38, and JNK/MAPKs in DCs. Specific inhibitors, SB 203580 and LY94002, significantly block ACW-induced up-regulation of costimulatory factor expression and IL-12 production. These findings suggest that ACW plays a potent adjuvant for cancer immunotherapy and promotes Th1 immune responses.
In the final part, we focused the antiproliferation activity of squamocin in Leukemia K562 cells. Squamocin is one of the annonaceous acetogenins and has been reported to have anticancer activity. Squamocin was found to inhibit the growth of K562 cells in a time-and dose-dependent manner. Cell cycle analysis showed G2/M phase arrest in K562 cells following 24 h exposure to squamocin. During the G2/M arrest, cyclin-dependent kinase inhibitors (CDKIs), p21 and p27 were increased in a dose-dependent manner. Analysis of the cell cycle regulatory proteins demonstrated that squamocin did not change the steady-state levels of Cdk2, Cdk4, cyclin A, cyclin B1, cyclin D3 and cyclin E, but decreased the protein levels of Cdk1and Cdc25C. These results suggest that squamocin inhibits the proliferation of K562 cells via G2/M arrest in association with the induction of p21, p27 and the reduction of Cdk1and Cdc25C kinase activities.
Taken together, these results warrant further investigation of these natural products toward the development of clinical applications in cancer therapy. Thus, the study will be to precisely identify the active components of crude extract from fruiting bodies of AC and examine the potential to develop a new immunotherapeutic adjuvant of cancer vaccine in in vivo animal model. The other study will be further to investigate anticancer mechanisms of squamocin of Formosan Annonaceous Acetogenins in tumor-bearing mice as well as immunomodulatory effect on DCs.
Table of contents
中文摘要 …………………………………………………………… 2-3
Abstract …………………………………………………………… 4-5
Background and Significance ……………………………………………… 6-17
PartⅠ. Active Extracts of Wild Fruiting Bodies of Antrodia cinnamomea (EEAC) Induce Leukemia HL 60 Cells Apoptosis Partially through Histone Hypoacetylation and Synergistically Promote Anticancer Effect of Trichostatin A
1.1 Introduction and background …………………………………..…………… 19-20
1.2. Material and methods ……………………………………………… 21-26
1.3. Results …………………………………………………………………… 27-31
1.4. Discussions ………………………………………………………………… 32-33
Part Ⅱ. Immunostimulatory Effect of Antrodia cinnamomea Extract on Functional Maturation of
Dendritic Cells
2.1. Introduction and background ………………………………………………………….. 45-46
2.2. Material and methods ……………………………………………………………….. 47-51
2.3. Result and Discussion ……………………………………………………………….. 52-57
2.4. Conclusion ………………………………………………………………………….. 58
Part Ⅲ. Induction of G2/M Phase Arrest by Squamocin in Chronic Myeloid Leukemia ( K562 ) Cells
3.1. Introduction and background ………………………………………………………….. 68-69
3.2. Material and methods ……………………………………………………….. 70-72
3.3. Result and Discussion ………………………………………….. 73-74
3.4. Discussions …………………………………………….. 75-76
References …………………………………………….. 80-93
Major publication and submissions ……………………………………………….. 94
Referable publications …………………………………………….. 95-96
Participative proposal and supported grants ……………………………………………… 97



List of Figures
Figure 1. Chemical structures of ergostane-typy triterpenoids from wild fruiting bodies of AC …… 8
Figure 2. Chemical structures of steroid acids from fruiting bodies of AC …… 8
Figure 3. Chemical structures of steroids and triterpenoids from fruiting bodies of AC …… 9
Figure 4. Chemical structures of neuroprotective diterpenes from fruiting bodies of AC …… 10
Figure 5. Chemical structures of ergostanes and lanostanes from fruiting bodies of AC …… 11
Figure 6. Chemical structures of anti-inflammatory benzenoids from fruiting bodies of AC …… 12
Figure 1.1. Morphology of wild fruiting bodies of Antrodia camphorata (AC). …… 34
Figure 1.2. Effects of EEAC on DNA fragmentation and histone acetylation in HL 60 cells. …… 35
Figure 1.3. Combination effects of TSA (100 nM) and EEAC (100 μg/ml) on cell viability and NF-kB activity in HL 60 cells. …… 36-37
Figure 1.4. Effects of three subfractions from EEAC on cell growth and apoptotic induction in HL 60 cells. …… 38
Figure 1.5. 1H NMR of EEAC (3.0 mg/mL in CD3OD). …… 39
Figure 1.6. 1H NMR of FA (EA fraction) (3.0 mg/mL in CD3OD). …… 39
Figure 1.7. 1H NMR of FB (EtOH fraction) (3.0 mg/mL in CD3OD). …… 40
Figure 1.8. 1H NMR of FC (n-hexane fraction) (3.0 mg/mL in CD3OD). …… 40
Figure 1.9. 1H NMR of zhankuic acid A (3.0 mg/mL in CD3OD). …… 41
Figure 1.10. Scheme of bioassay-guided fractionation from wild fruiting bodies of Antrodia cinnamomea. …… 42
Figure 2.1. Confocal microscopic observation of ACW-induced DC maturation. …… 59
Figure 2.2. Effect of ACW on phenotypic maturation of DCs compared with effects of GLW and ABW. …… 60
Figure 2.3. NMR chemical profiles and carbohydrate content of ACW and its subfractions. …… 61
Figure 2.4. Effect of ACW and its subfractions on phenotypic maturation of DCs. …… 62
Figure 2.5. Effect of ACW on functional maturation of DCs. …… 63
Figure 2.6. Effect of ACW on functional activation of DCs. …… 64


Figure 2.7. Effect of ACW on cell survival as well as apoptosis-related proteins of DCs. …… 65
Figure 2.8. Effect of ACW involved signal transduction pathways in maturation process of DCs. …… 66
Figure 3.1. Chemical structure of squamocin. …… 77
Figure 3.2. Effect of squamocin on proliferation of K562 cells determined by (A) MTT and (B) trypan blue dye exclusion assay. …… 77
Figure 3.3. Accumulation of G2/M phase of cell cycle in squamocin treated K562 cells. …… 78
Figure 3.4. Immunoblot analysis for the levels of cell cycle regulatory proteins. …… 79
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