氧化石墨烯(GO)為當前具有生物應用潛力的奈米材料，本實驗室先前研究發現GO可以藉由活化類鐸受體(Toll-like receptor，TLR)中之TLR-4及TLR-9引起細胞自噬反應，並達到抑制CT26腸癌之腫瘤生長。順鉑(Cisplatin ，CDDP)是目前廣泛運用於癌症治療之化療藥物，然而腸癌及許多癌症目前對於CDDP具有抗藥性，造成癌症治療上阻礙。因此，我們希望可以藉由GO結合CDDP引發CT26小鼠腸癌細胞自噬並造成細胞壞死以發展出新式化療策略。我們在體外細胞實驗發現以GO結合CDDP加入培養基中可以使CT26細胞存活率降至約40%，同時，我們發現細胞壞死相關蛋白RIP1、HMGB1有切割降解或活化的情形，而在動物實驗中我們也同樣觀察到腫瘤組織中細胞壞死的情形。此外，我們在免疫螢光染色實驗中發現以GO結合CDDP處理細胞後，在CT26細胞中引發細胞自噬並伴隨著大量LC3 puncta於細胞核中，同樣地，ICP-MS的結果顯示CDDP進入CT26細胞也顯著增加。相反地，當我們以核傳輸抑制劑(ivermectin)及細胞壞死抑制劑(necrostatin-1)處理細胞，LC3點狀聚集進核及細胞壞死的情形會被抑制，表示GO結合CDDP對於細胞核傳輸及細胞壞死有莫大的影響。動物實驗結果顯示GO結合CDDP進行原位注射會增加腫瘤部位免疫細胞浸潤的情形並達到抑制腫瘤生長的效果。我們的研究結果顯示以GO結合CDDP共同處理細胞，可以刺激細胞自噬、造成細胞壞死並達到抑制腫瘤生長的效果，有效降低癌細胞對CDDP的抗藥性。因此，本研究顯示GO是一極具潛力的奈米材料，可作為CDDP的化療增敏劑(chemosensitizer)，GO/CDDP是一值得開發的新式治療方式。

Graphene oxide (GO) is a derivative of graphene and we recently uncovered that GO itself is sufficient to provoke both autophagy and toll-like receptor (TLR) responses in CT26 colon cancer cells and confer antitumor effects in immunocompetent mice bearing CT26 colon tumor. Cisplatin (CDDP) is an anticancer drug for the treatment of solid tumors by inducing cell death, but colon cancer cells have evolved chemoresistance to CDDP, hence compromising the therapeutic efficacy. Here we examined whether GO can act as a chemosensitizer to potentiate the efficacy of chemotherapy drugs. We found that combination of GO with irinotecan, doxorubicin and oxaliplatin failed to potentiate the killing of CT26 cells, but GO in combination with CDDP (GO/CDDP) significantly potentiated the CT26 cell killing mainly via necrosis and elicited CT26 autophagy. In addition to regular autophagic flux, GO/CDDP co-treatment also strikingly induced nuclear transport of autophagy marker LC3 and CDDP (but not GO), which was concomitant with the enhanced necrosis. Prior treatment of cells with nuclear import inhibitor (ivermectin) or cell necrosis inhibitor (necrostatin-1) hindered the import of LC3 puncta and CDDP into the nucleus and impaired the cell necrosis. Intratumoral injection of GO/CDDP into colon cancer in mice augmented the antitumor effects, enhanced the intratumoral autophagy, necrosis and immune cell infiltration. These data collectively demonstrated that combination of GO and CDDP synergistically triggers autophagy, necrosis and suppresses tumor growth, thus implicating the potentials of GO as a chemosensitizer of CDDP in colon cancer chemotherapy.

目錄
摘要 I
Abstract II
圖表目錄 VI
第一章 文獻回顧 1
1.1 氧化石墨烯(Graphene oxide, GO) 1
1.1.1 GO與傳統奈米材料之比較 1
1.1.2 GO的生物相容性探討 2
1.2 細胞自噬(Autophagy) 2
1.2.1 細胞自噬介紹 2
1.2.2 細胞自噬於癌症中之應用 4
1.3 結腸癌與治療方式(Colon cancer and Chemotherapy) 5
1.3.1 結腸癌介紹 5
1.3.2 治療方式 5
1.4 研究動機 7
第二章 實驗材料與方法 13
2.1 細胞培養 13
2.2 實驗材料及化療藥物 13
2.2.1氧化石墨烯(Graphene Oxide, GO) 13
2.2.2化療藥物 14
2.2.3化療藥物結合GO處理細胞 14
2.2.4抑制劑及前處理 15
2.3 細胞毒性測試 (MTT assay) 16
2.4 細胞壞死(necrosis)及細胞凋亡(apoptosis)試驗 16
2.4.1細胞凋亡 16
2.4.2 細胞壞死 17
2.5 流式細胞儀分析(Flow cytometry) 17
2.6 免疫螢光染色 (Immunofluorescence staining) 18
2.7 螢光顯微鏡分析(Fluorescence microscopy analysis) 19
2.8 核質分離(Subcellular fractionation of cytoplasmic and Nuclear Protein) 20
2.9 感應耦合電漿質譜分析(ICP-MS) 21
2.10 動物實驗及腫瘤生長體積測量 22
2.11 腫瘤組織冷凍切片 22
2.12 免疫組織染色及定量分析 22
第三章 實驗結果 24
3.1 GO結合不同化療藥物對CT26細胞存活率之影響 24
3.2 GO/CDDP對CT26產生細胞凋亡及壞死之現象 25
3.3 GO/CDDP對CT26產生細胞自噬及細胞自噬流之現象 26
3.4 GO及CDDP在細胞內之分佈 27
3.5 利用抑制劑觀察LC3進核機制 27
3.6 探討LC3進核現象與細胞壞死之關係 29
3.7 小鼠動物模型中利用GO結合CDDP抑制腫瘤生長 30
3.7.1 腫瘤生長曲線 30
3.7.2 體重測量(Body weight measurement) 31
3.8 觀察GO/CDDP對腫瘤組織的影響 31
3.8.1 組織細胞死亡 31
3.8.2 免疫細胞浸潤 32
3.9 結論 32
第四章 討論 43
第五章 未來展望 48
5.1 GO/CDDP治療對不同癌細胞株存活率之影響 48
5.2 探討在GO/CDDP治療下CT26細胞核內所產生的LC3 puncta之形態及效用 48
5.3 探討LC3 puncta在細胞核內的傳輸途徑 49
5.4 探討在不同癌細胞株中， HMGB1、p53的表現量及對細胞死亡的引響 49
第六章 參考文獻 50

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