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研究生:洪韋莉
研究生(外文):Wei-Li Hung
論文名稱:探討三氧化二砷促進ABT-737或環孢素A引發子宮頸癌細胞死亡之機制
論文名稱(外文):The mechanisms of Arsenic trioxide potentiated ABT-737/Cyclosporine A-induced cell death in cervical cancer cells
指導教授:柯俊良柯俊良引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:90
中文關鍵詞:子宮頸癌三氧化二砷ABT-737環孢素A細胞凋亡細胞壞死內質網壓力粒線體膜電位氧化壓力
外文關鍵詞:Cervical cancerArsenic trioxideABT-737Cyclosporine AApoptosisNecrosisER stressMitochondrial membrane potentialReactive oxygen species
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晚期子宮頸癌預後不佳,目前臨床療效有限,透過轉譯醫學開發不同藥物組合應用於臨床治療。本研究探討已被臨床用於治療骨髓性細胞白血病 (Acute promyelocytic leukemia, APL)的三氧化二砷 (As2O3合併抗細胞凋亡B cell lymphoma 2 (Bcl-2) 蛋白抑制劑ABT-737或抗發炎的免疫抑制劑環孢素A (Cyclosporine A, CsA) 來治療子宮頸癌。首先本實驗使用細胞存活試驗來分析兩株子宮頸癌細胞Caski、SiHa在經過As2O3合併ABT-737、CsA處理後存活率之變化,接下來利用西方墨點法分析細胞凋亡、細胞自噬、內質網壓力與細胞週期之相關蛋白表現量,發現經過As2O3合併ABT-737、CsA處理後,增加Cleavage Caspase 7、Cleavage PARP、LC3BII、GRP78之表現量,另一方面Survivin、Mcl-1、ANT1/2/3、CDK6、TS表現量減少。此外,透過Annexin V/PI Staining螢光染色發現了As2O3合併使用ABT-737會出現細胞凋亡情形,而As2O3合併CsA則出現了細胞壞死,並且利用JC-1和H2DCFDA等螢光染色證實了As2O3合併ABT-737、CsA處理後會造成粒線體膜電位下降及氧化壓力的上升。伴隨蛋白GRP78表現量增加,同時代表著內質網壓力的上升,故用shRNA抑制子宮頸癌細胞內GRP78基因表現後,發現Caski經過加藥處理後不會誘發Cleavage Caspase 7、Cleavage PARP、LC3BII等表現量,證實內質網壓力的增加會促使Caski走向細胞死亡,而SiHa無明顯改變。綜合上述實驗結果證明了As2O3合併ABT-737、CsA可造成子宮頸癌細胞粒線體膜電位下降、內質網壓力及氧化壓力的增加,最後使癌細胞走向死亡,未來期待透過As2O3加上ABT-737、CsA的合併治療成為子宮頸癌嶄新的治療方針。
It is a poor prognosis for late stage cervical cancer patients. Till now, the improvements of clinical therapeutic efficacy are little benefit for patients. To investigate the therapeutic effects, combinations of arsenic trioxide against acute promyelocytic leukemia (APL) and ABT-737, the B cell lymphoma 2 (Bcl-2) inhibitor, or Cyclosporine A (CsA), immune inhibitor, were examined in cervical cancers. First, we used the MTT assay to anylyze the survival of cervical cancer cells (Caski and SiHa) following treatment of As2O3 and ABT-737/CsA. In addition, we investigated the expression of apoptosis, autophagy, endoplasmic reticulum stress and cell cycle related proteins by Western blot. The expressions of cleavage Caspase 7, Cleavage PARP, LC3BII and GRP78 were increased. Survivin, Mcl-1, ANT1/2/3, CDK6 and TS were decreased after combined treatment. On Annexin V/PI staining, we found that apoptosis and necrosis were presented in As2O3/ABT-737 group and As2O3/CsA group, respectively. It was reduced mitochondrial membrane potential and induced ROS by JC-1 and H2DCFDA staining. Co-treatment was upregulated ER stress such as GRP78. GRP78 silencing mitigated cleavage Caspase 7, Cleavage PARP and LC3BII in the Caski cells not in Siha cells. In conclusion, As2O3 combined with ABT-737/CsA induced ER stress, reduced mitochondrial membrane potential and ROS generation resulting in cell death. As2O3 combine with ABT-737/CsA may be a potential chemotherapeutic agent againt cervical cancer.
第一章、緒論 (Introduction) 1
第一節 子宮頸癌 (Cervical cancer) 1
第二節 細胞死亡 (Cell death) 3
第三節 Bcl-2蛋白家族 (B cell lymphoma 2 protein family) 9
第四節 三氧化二砷 (Arsenic trioxide, As2O3) 之分子機制與臨床應用 10
第五節 ABT-737之分子機制與臨床應用 12
第六節 環孢素A (Cyclosporine A, CsA) 之分子機制與臨床應用 13
第二章 縮寫表 (Abbreviation) 14
第三章 研究動機 (Motivation) 17
第四章 實驗材料與研究方法 (Material and methods) 18
第一節 藥品與試劑 18
第二節 實驗儀器設備 20
第三節 抗體資料 21
第四節 實驗方法 23
一、細胞培養 (Cell culture) 23
二、繼代培養 (Passage) 23
三、細胞存活試驗 (MTT assay) 24
四、西方墨點法 (Western blot) 25
五、Annexin V/ Propidium iodide 之細胞凋亡試驗 28
六、活性氧化物質 (Reactive oxygen species, ROS) 之測定 29
七、粒線體膜電位 (Mitochondrial membrane potential, MMP) 之測定 29
八、質體抽取 30
九、RNA干擾 (RNA interference;RNAi) 31
十、細胞RNA萃取、反轉錄酶聚合酶連鎖反應 (Reverse transcription-polymerase chain reaction, RT-PCR) 33
十一、藥物合併作用分析 36
第五章 實驗結果 (Results) 37
一、As2O3單獨處理48小時後改變子宮頸癌細胞存活率 37
二、As2O3合併ABT-737/CsA處理後降低子宮頸癌細胞存活率 37
三、As2O3合併ABT-737或CsA處理後在子宮頸癌細胞內出現藥物協同作用 39
四、As2O3合併ABT-737或CsA處理促進Annexin V/ Propidium iodide (PI) 訊號的產生 40
五、As2O3合併ABT-737或CsA處理後,促進細胞凋亡相關蛋白之表現量 41
六、As2O3合併ABT-737或CsA處理下減少抗凋亡蛋白Survivin與Mcl-1之表現量 41
七、As2O3合併ABT-737或CsA共同處理後改變SiHa內Survivin的mRNA表現量 42
八、As2O3合併ABT-737或CsA處理後對細胞週期調控蛋白與DNA合成之影響 43
九、As2O3合併ABT-737或CsA共同處理會增加LC3B II之表現量 44
十、As2O3合併ABT-737或CsA處理造成子宮頸癌細胞粒線體膜電位下降 44
十一、As2O3合併ABT-737或CsA處理會降低粒線體內膜上腺嘌呤核苷酸轉運體 (Adenine nucleotide translocator, ANT) 之蛋白質表現量 45
十二、單獨使用CsA及使用As2O3合併ABT-737或CsA會增加活性氧化物質 (Reactive oxygen species, ROS) 45
十三、As2O3合併ABT-737或CsA處理後使子宮頸癌細胞內內質網壓力上升 46
十四、以VSV-G pseudotyped lentivirus-shRNA系統降低子宮頸癌細胞內GRP78表現量,可減緩Caski經As2O3合併ABT-737或CsA處理後的細胞毒殺能力 47
十五、As2O3合併ABT-737處理後使子宮頸癌細胞走向細胞凋亡 48
十六、As2O3合併CsA處理後使子宮頸癌細胞壞死及凋亡 48
第六章 討論 (Discussion) 49
第七章 圖表 62
第八章 參考文獻 (References) 81
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