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

The mechanisms of Arsenic trioxide potentiated ABT-737/Cyclosporine A-induced cell death in cervical cancer cells

洪韋莉

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 ； Cervical cancer ； Arsenic trioxide ； ABT-737 ； Cyclosporine A ； Apoptosis ； Necrosis ； ER stress ； Mitochondrial membrane potential ； Reactive oxygen species

中山醫學大學醫學研究所學位論文

2017年

碩士

柯俊良

繁體中文

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.

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