沉香萃取物之免疫調節功能及其對人類前列腺癌細胞和乳腺癌細胞的影響

Immunomodulatory effects of Agarwood extracts and their actions to human prostate cancer PC-3 cells and human breast cancer MCF-7 cells

10.6845/NCHU.2015.00508

劉雅惠

沉香 ； CDK 1基因 ； 細胞週期 ； Cyclin B1基因 ； 細胞激素 ； 人類乳腺癌MCF-7細胞 ； 人類前列腺癌PC-3細胞 ； 發炎 ； 癌症免疫療法 ； Agarwood ； CDK 1 gene ； cell cycle ； Cyclin B1 gene ； cytokine ； human breast adenocarcinoma MCF-7 cells ； human prostate carcinoma PC-3 cells ； inflammation ； tumor immunotherapy

中興大學食品暨應用生物科技學系所學位論文

2015年

碩士

林金源

繁體中文

沉香在神農本草經已經有所記載，為中國傳統作為鎮靜及鎮痛之用藥，但其在免疫調節功能仍不甚清楚，為釐清沉香之免疫調節功能，本實驗利用沉香葉片、沉香木片及沉香葉片與木片混合之熱水萃取物及其精油，於體外模式下利用小鼠初代脾臟細胞及腹腔巨噬細胞篩選最具抗發炎潛力活性物質，再以酒精區分及膠體過濾純化並篩選出最具抗發炎潛力之活性區分物，進一步以癌症免疫療法探討其對人類前列腺癌PC-3細胞株與乳腺癌MCF-7細胞株之影響。結果顯示，沉香熱水萃取物及其精油皆稍有抗發炎之潛力，其中以沉香木熱水萃取物最具促進促發炎與抗發炎細胞激素之分泌，但比較抗/促發炎細胞激素比值，具抗發炎潛力。為了解沉香木熱水萃取物中抗發炎之活性物質，因此將沉香木熱水萃取物以75%酒精沉澱，發現沉香木熱水萃取物之酒精沉澱區分物(多醣區分物)及其上清液(富含多酚區分物)皆具有抗發炎潛力。以膠體過濾純化多醣區分物，結果區分為F1及F2兩個區分物，F2可降低初代巨噬細胞促發炎/抗發炎細胞激素分泌之比值，推測F2為多醣中主要的活性區分物。 以單獨添加及癌症免疫療法方式，探討多醣區分物及富含多酚區分物對PC-3及MCF-7細胞之影響。結果顯示，單獨添加多醣區分物可降低PC-3細胞之生長，添加其條件培養液則可降低MCF-7細胞之生長，但無論單獨添加 F1、F2或其條件培養液，皆不會影響PC-3及MCF-7細胞之生長，將F1及F2混和後添加則可抑制PC-3細胞之生長，推測F1及F2對PC-3細胞生長之抑制具有協同作用，但進一步探討F1+F2對PC-3細胞細胞週期之影響，則對細胞週期無顯著影響。單獨添加富含多酚區分物及其與初代巨噬細胞共同培養之條件培養液，皆可降低PC-3及MCF-7細胞之生長，添加富含多酚區分物條件培養液可使PC-3及MCF-7細胞細胞週期停滯於G2/M期，並降低CDK 1 (cyclin dependent kinase 1) mRNA基因表現量。 綜合本實驗結果，沉香木熱水萃取物中富含多酚區分物可透過調節初代巨噬細胞之癌症免疫療法作用方式，降低CDK 1 mRNA表現量，並使人類前列腺癌細胞(PC-3)及人類乳腺癌細胞(MCF-7)細胞週期停滯於G2/M期，促使細胞走向凋亡。

Agarwood having sedative and analgesic functions among traditional Chinese herbal medicines has been recorded in Divine Husbandman's Herbal Foundation Canon. However, immunomodulatory effects of agarwood remain unclear. To clarify the puzzle, hot water extracts of agarwood leaves, agarwood lumber and agarwood leaf and lumber mixture, as well as agarwood essential oil were subjected to evaluate their anti-inflammatory activities using mouse primary splenocytes and peritoneal macrophages in vitro. The most potent extract was further purified with alcohol and gel filtration. Then, the potent fractions of the extract were selected to treat human prostate cancer PC-3 cells and human breast cancer MCF-7 cells using direct addition or immunotherapy of primary peritoneal macrophages. The results showed that agarwood hot water extracts and its essential oil had potential to inhibit inflammation. Agarwood’s lumber hot water extract increased pro- and anti-inflammatory cytokine secretions, but inhibited the secretion ratio of pro-/anti-inflammatory cytokines, suggesting it was the most potential to inhibit inflammation. To understand anti-inflammatory active components in agarwood’s lumber hot water extract, agarwood’s lumber hot water extract was selected to purify with 75% alcohol. Both ethanol precipitate (PALHWE, polysaccharide-rich fraction) and supernatant (SALHWE, poly phenol-rich fraction) of agarwood's lumber hot water extract were found to have potential to inhibit inflammation. PALHWE was purified using gel filtration, showing that there were two polysaccharide fractions F1 and F2 in PALHWE. F2 decreased pro-/anti- inflammatory cytokine secretion ratios by primary peritoneal macrophage, suggesting that F2 might be a major active component in PALHWE. To understand effects of PALHWE and SALHWE on PC-3 and MCF-7 cells, PC-3 and MCF-7 cells were treated with PALHWE and SALHWE using direct addition or immunotherapy. The results showed that addition with PALHWE alone inhibited the proliferation of PC-3 cells and its conditioned medium inhibited the proliferation of MCF-7 cells. Neither F1 nor F2 alone and its conditioned medium decreased the proliferation of PC-3 and MCF-7 cells. However, addition with the mixture of F1 and F2 inhibited the proliferation of PC-3 cells, suggesting that F1 and F2 might have synergistic reaction to inhibit the proliferation of PC-3 cells. Further exploring the effect of the mixture of F1 and F2 on the cell cycle of PC-3 cells showed that there was no significant effect on the cell cycle. Both SALHWE and its conditioned medium inhibited the proliferation of PC-3 and MCF-7 cells. Addition with SALHWE conditioned medium promoted the cell cycle of PC-3 and MCF-7 cells arresting in G2/M phase and decreasing the expression of CDK 1 (cyclin dependent kinase 1) mRNA. In conclusion, results from this study evidenced that SALHWE treatment might induce the death of PC-3 and MCF-7 cells through arresting the cell cycle in G2/M phase and decreasing CDK 1 mRNA expression using peritoneal macrophages' immunotherapy.

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