臺灣博碩士論文加值系統

目前非小細胞肺癌患者對於藥物產生抗藥性是臨床癌症治療的主要瓶頸。當病人的表皮生長因子受體上具有exon 19 缺失或是exon 21的單點突變時會對於第一代與第二代的酪氨酸激酶抑制劑，如Gefitinib及Erlotinib反應良好，然而這類的藥物治療一段時間後表皮生長因子受體基因會發生突變，而產生抗藥性，其中T790M是最為常見的突變位點。此外，癌幹的特性也被認為是非小細胞肺癌產生抗藥性的重要因素。因此發展新的化合物來克服非小細胞肺癌的抗藥性是高度需要的。在這個研究中我們使用一種新穎由 5,8-quinolinedione衍生而來的化合物PT262，有潛力克服非小細胞肺癌的T790M及癌幹性的作用。在實驗中發現，PT262具有誘導抗藥性細胞株H1975 (含EGFR T790M突變) 死亡及凋亡的能力，且能抑制Survivin的蛋白表現並誘發caspase 3及PARP的活化導致細胞凋亡。除此之外，這個化合物也能抑制在肺癌細胞中癌幹性蛋白Oct4的表現。我們並發現PT262能有效抑制由臨床非小細胞肺癌病人之肺肋脊液中分離出的肺癌細胞之生存率。根據上述的結果，這個新穎的化合物有潛力進一步研究及探討在克服非小細胞肺癌之抗藥性作用。

Drug resistance has become bottleneck in clinical cancer therapy of non-small cell lung carcinoma (NSCLC) patients. The mutations of epidermal growth factor receptor (EGFR) on exon 19 deletion and exon 21 point mutation are respond well to the first and second generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as Gefitinib and Erlotinib for NSCLC therapy; however, patients acquired the T790M mutation of EGFR will induce drug resistance. In addition, cancer stemness properties are also a pivotal factor of drug resistance in NSCLC. Accordingly, development of novel compounds for overcoming drug resistance of NSCLC is highly desired. In this study, we show a novel synthetic compound PT262 that derived from 5,8-quinolinedione has potential in overcoming drug resistance of EGFR (T790M) and cancerous stemness in NSCLC. This new compound can induce cell death and apoptosis in the drug-resistant H1975 cells, which contained EGFR (T790M). This compound inhibited Survivin protein expression and conversely increased the active caspase 3 and cleaved PARP for apoptosis induction. In addition, this compound can inhibit the stemness protein expression of Oct4 in lung cancer cells. Moreover, it can also decrease the cell viability in drug resistance NSCLC cells, which were separated from pleural effusion of NSCLC. Taken together, we develop a novel compound, which has potential to further investigate for overcoming drug resistance in NSCLC.

Contents
中文摘要 i
Abstract ii
Abbreviations iii
1. Introduction 1
1.1. Lung cancer and EGFR 1
1.2. EGFR mutation and Tyrosine Kinase Inhibitors 1
1.3. Drug resistance of TKIs 2
1.4. Drug resistance of cancer stem cells 2
1.5. Derivatives of 5, 8-quinolinediones 3
1.6. Apoptosis and apoptosis-regulation proteins 3
1.7. Purpose of this study 4
2. Materials and Methods 5
2.1. Regents and Drugs 5
2.2. Antibodies 5
2.3. Cell lines and cell culture 6
2.4. Cell cytotoxicity MTT assay 6
2.5. Annexin V-PI analysis 6
2.6. Western blot 7
2.7. Immunofluorescence staining and confocal microscopy 8
2.8. Xenografted human lung tumors in nude mice 8
2.9. Transfection 8
2.10. Separation of lung cancer cells from the pleural effusion of NSCLC patients 9
2.11. Statistical analysis 9
3. Results and Discussion 10
3.1. PT262 inhibited cell viability in the EGFR T790M mutation NSCLC cells 10
3.2. PT262 and AZD9291 induced apoptosis in the H1975 NSCLC cells 10
3.3. PT262 inhibited Survivin protein levels but conversely increases the active caspase-3 and PARP protein expression in the H1975 cells 11
3.4. PT262 enhanced the inhibition of tumor growth in the xenografted human NSCLC model 11
3.5. PT262 inhibited cell vitality in the Oct4 ectopic expression of H1975 cells 12
3.6. PT262 inhibited Survivin for apoptosis in the Oct4-expressed H1975 cells 12
3.7. The morphology and stemness protein expression in the clinical NSCLC patients cells 13
3.8. PT262 reduced the cell viability in clinical patient NSCLC cells 13
4. Conclusions 15
5. References 16
6. Figures 24
Fig. 1. The effects of PT262 and AZD9291 in the reduction of cell viability of H1975 cells 24
Fig. 2. Comparison of PT262 and AZD9291 in the apoptosis induction of H1975 cells 25
Fig. 3. The expression of EGFR, p-EGFR, survivin, caspase 3 and PARP in H1975 cells after treatment with PT262 26
Fig. 4. The protein expression and survivin and active caspase 3 after treatment with PT262 in H1975 cells 27
Fig. 5. The effect of tumor growth inhibition of PT262 in the xenografted human H1975 lung tumor in animal model 28
Fig. 6. The effect of transfection of Oct4 expressed vector on the PT262-induced cell death in H1975 cells 29
Fig. 7. The expression and location of Oct4 proteins by transfection of Oct4 vector in H1975 30
Fig. 8. The effect of PT262 on the Oct4, survivin and PARP protein levels in the transfection of Oct4 vector in H1975 cells 31
Fig. 9. The cellular morphology and protein expression of clinical NSCLC patients in collagen coating dishes 32
Fig. 10. The cellular morphology and protein expression of clinical NSCLC patients in matrigel culture environment 33
Fig. 11. Comparison of PT262 and AZD9291 on cell viability assay in lung cancer cells which were separated from pleural effusion of clinical NSCLC patients. 34
Fig. 12. Comparison of PT262 and AZD9291 in the apoptosis induction of the human lung cancer patient PLC26 cells 35
Fig. 13. The model of PT262 in overcoming drug resistance 36
7. Appendixes 37
Appendix. 1. The major types of lung cancer. 37
Appendix. 2. The downstream signaling pathways of EGFR. 38
Appendix. 3. TKIs inhibited the phosphorylation of TK domain and cause cell death. 39
Appendix. 4. The mutation sites that sensitive or resistant to TKI drugs. 40

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