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研究生:翁顥誠
研究生(外文):Hao-Cheng Weng
論文名稱:具潛力之第一型葡萄糖轉運蛋白抑制劑與順鉑合併使用於乳癌細胞協同機轉之研究
論文名稱(外文):Study on the synergistic mechanism of a potential GLUT1 inhibitor and cisplatin against breast cancer cells
指導教授:許麗卿許麗卿引用關係
指導教授(外文):Lih-Ching Hsu
口試委員:顧記華孔繁璐
口試委員(外文):Jih-Hwa GuhFan-Lu Kung
口試日期:2019-07-01
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:74
中文關鍵詞:順鉑第一型葡萄糖轉運蛋白抑制劑乳癌MAPK 訊息傳遞路徑PI3K/Akt/mTOR 訊息傳遞路徑DNA 損傷氧化壓力
DOI:10.6342/NTU201901193
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乳癌在全世界無論是癌症發生率或致死率都居高不下。順鉑為乳癌化療之常見用藥。然而,因順鉑產生之眾多嚴重副作用,併用療法可能為可同時減少副作用並增強抗癌活性之策略。日前研究中發現由於 Warburg effect ,第一型葡萄糖轉運蛋白可能為癌症治療之新標靶。此研究目的為探討順鉑與由高通量篩選出具潛力之葡萄糖轉運蛋白抑制劑, #43合併使用於 MCF-7 乳癌細胞株之協同作用及其機轉。研究過程中發現順鉑與 #43併用會藉由細胞凋亡路徑增加細胞毒性,且順鉑與 #43 會分別造成細胞週期停滯於 S 、 G2/M 及 G0/G1。此外,藥物合併使用也觀察到細胞中活性含氧物之提升及粒線體膜電位之損失。因順鉑對於 DNA 的破壞性,實驗結果顯示合併處理藥物使 Chk1、Chk2 磷酸化及 -H2AX 上升且增加 p53 表現及活化,顯示出 #43 可增強順鉑之 DNA 破壞性。MAPK 訊息傳導調控細胞增殖、細胞分化及細胞凋亡。特別的是 #43 單獨使用使促進對於細胞存活重要之 MEK1/2 及 ERK1/2 磷酸化上升。但當與順鉑合併使用時此效果會被消去且磷酸化之 MEK1/2 及 ERK1/2 甚至與控制組相比更加減少。另一方面,p38 磷酸化於順鉑及 #43 合併使用時增加。Akt/mTOR 訊息傳遞路徑與細胞生長、細胞增殖及細胞代謝皆有相關性。此路徑之下游蛋白 p70S6K 及 4EBP1 之磷酸化於合併使用順鉑與 #43 之情形下被抑制,顯示其細胞生長抑制作用之效果。總結來說, MAPK 訊息傳遞路徑、Akt/mTOR 訊息傳遞路徑、氧化壓力及細胞凋亡皆可能於順鉑及 #43 在 MCF-7 細胞株之協同作用扮演重要的角色。
Breast cancer remains within the top position when it comes to the cancer incidence and mortality rate worldwide. Cisplatin is a commonly used chemotherapeutic drug for breast cancer. However, owing to the serious side effects of cisplatin, drug combination may be an effective strategy to reduce side effects and increase the anticancer activities simultaneously. In recent studies, it was found that GLUT1 may be a target for cancer treatment because of the Warburg effect. The purpose of this study was to determine whether the combination of a potential GLUT1 inhibitor #43 (obtained from a high throughput screening) and cisplatin exerted a synergistic anticancer effect in MCF 7 breast cancer cells and to investigate the underlying mechanisms. In the present study, we found that #43 could enhance the cytotoxicity of cisplatin via induction of apoptosis, and that cisplatin and #43 cause S, G2/M and G0/G1 arrest, respectively. Moreover, an increase in intracellular ROS and the loss of mitochondrial membrane potential were also observed. Cisplatin is a DNA damaging agent. We found that phosphorylation of DNA damage checkpoint kinases Chk1 and Chk2, and DNA damage marker, -H2AX were increased and p53 was also induced and activated by the combination treatment, suggesting that #43 may enhance the DNA damaging effect of cisplatin. The MAPK pathway regulates cell proliferation, differentiation and apoptosis. Interestingly, #43 alone induced phosphorylation of MEK1/2 and ERK1/2, which may be involved in cell survival. When combined with cisplatin, the effects were reversed and both p-MEK1/2 and p-ERK1/2 were even downregulated compared to the untreated controls. On the other hand, p38 phosphorylation was increased by the combination of cisplatin and #43. The Akt/mTOR signaling pathway is involved in cell growth, proliferation and metabolism. Phosphorylation of p70S6K and 4EBP1, downstream effectors of this pathway, was inhibited by the combination treatment, indicating a growth inhibitory effect. In conclusion, our data indicate that the MAPK pathway, Akt/mTOR pathway, oxidative stress and apoptosis may be involved in the synergism of cisplatin and #43 in MCF-7 breast cancer cells.
國立臺灣大學(碩)博士學位論文口試委員會審定書 i
誌謝 ii
List of abbreviations iii
中文摘要 vi
Abstract vii
Contents ix
Aim of the study 1
Chapter 1: Introduction 3
1.1. Breast cancer 3
1.2. Human breast cancer cell lines 7
1.3. The Warburg effect and glucose transporters 7
1.4. Cisplatin 8
1.5. DNA damage signaling and DNA double strand breaks repair 9
1.6. Programmed cell death 10
1.7. Oxidative stress 12
1.8. The PI3K/Akt/mTOR pathway 13
1.9. The MAPK pathway 14
Chapter 2: Materials and Methods 16
2.1. Materials 16
2.2. Methods 17
2.2.1. Cell culture 17
2.2.2. Cell viability assay and combination index analysis 17
2.2.3. Colony formation assay 17
2.2.4. 2-NBDG uptake assay 18
2.2.5 Small interfering RNA (siRNA) transfection and cell viability assay 18
2.2.6. Propidium Iodide (PI) staining (cell cycle analysis) 19
2.2.7. Annexin V-FITC/PI double staining 19
2.2.8. DCFH-DA assay (measurement of reactive oxygen species) 19
2.2.9. JC-1 assay 20
2.2.10. Western blotting 20
2.2.11. Immunofluorescence staining 22
2.2.12. Data analysis 22
Chapter 3: Results 23
3.1. Effects of cisplatin and #43 on cell viability and clonogenic growth 23
3.2. Effect of #43 on glucose uptake 23
3.3. Effects of cisplatin and #43 on cell cycle progression 24
3.4. Enhancement of apoptosis by #43 in combination with cisplatin 25
3.5. Elevation of cellular ROS production induced by cisplatin and #43 25
3.6. Induction of mitochondrial membrane potential loss by cisplatin combined with #43 26
3.7. Enhancement of DNA damage response by #43 in combination with cisplatin 27
3.8. Effects of cisplatin and #43 on the Akt/mTOR signaling pathway 28
3.9. Effects of cisplatin and #43 on the MAPK signaling pathway 29
3.10. Effects of Akt and the ERK signaling pathway on #43-induced cytotoxicity 30
Chapter 4: Discussion 31
4.1. Effects of cisplatin and #43 on cell cycle progression 31
4.2. Effects of cisplatin and #43 on apoptosis 32
4.3. Effects of cisplatin and #43 on ROS and mitochondrial membrane potential 33
4.4. The DNA damage response induced by cisplatin and #43 and their effects on the DNA repair system 34
4.5. Effects of cisplatin and #43 on the Akt/mTOR signaling pathway 35
4.6. Effects of cisplatin and #43 on the MAPK pathway 36
4.7. The role of Akt and the ERK signaling pathway in #43-induced cytotoxicity 37
Chapter 5: Conclusion 38
Figures
Figure 1. Effects of cisplatin and #43 on the growth inhibition and clonogenicity of MCF-7 cells. 40
Figure 2. Glucose uptake was inhibited by #43 in MCF-7 cells. 42
Figure 3. Effects of cisplatin and #43 on cell cycle progression in MCF-7 cells. 44
Figure 4. The combination of cisplatin and #43 significantly induced apoptosis in MCF-7 cells. 46
Figure 5. Effects of cisplatin and #43 on proteins involved in apoptosis in MCF-7 cells. 48
Figure 6. Cisplatin and #43 combination induced ROS generation in MCF-7 cells. 50
Figure 7. The combination of cisplatin and #43 induced mitochondrial membrane potential loss in MCF-7 cells. 52
Figure 8. Effects of cisplatin and #43 on proteins involved in DNA damage response and DNA repair in MCF-7 cells. 54
Figure 9. The combination of cisplatin and #43 increased r-H2AX positive MCF-7 cells. 56
Figure 10. Effects of cisplatin and #43 on proteins involved in the Akt/mTOR signaling pathway in MCF-7 cells. 58
Figure 11. Effects of cisplatin and #43 on proteins involved in the MAPK signaling pathway in MCF-7 cells. 60
Figure 12. MK-2206 and U0126 potentiated #43-induced cytotoxicity in MCF-7 cells. 61
Tables
Table 1. Staging system and estimated 5-year survival rate for breast cancer. 4
Table 2. The status of commonly used breast cancer cell lines. 7
Appendixes 62
Appendix 1. The Warburg effect. 62
Appendix 2. The DNA damage response. 63
Appendix 3. The extrinsic and intrinsic apoptosis pathways. 64
Appendix 4. The PI3K/Akt/mTOR signaling pathway. 65
Appendix 5. The MAPK signaling pathway. 66
References 67
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