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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄭穹翔(Chiung-Hsiang Cheng) | |
| dc.contributor.author | Wei-An Chen | en |
| dc.contributor.author | 陳薇安 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:47:15Z | - |
| dc.date.available | 2020-02-21 | |
| dc.date.copyright | 2017-02-21 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-01-23 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59957 | - |
| dc.description.abstract | 犬淋巴癌為犬隻中最常發生的惡性腫瘤之一。除了提早檢查預防之外，腫瘤治療的進步及改善也是相當重要的，有些癌細胞在一開始使用化學治療時即對化療藥物具有抗性，另一部分的抗藥性則是在療程時逐漸產生。這些具有抗藥性的癌細胞，通常會高度表現和藥物排出有關的運輸蛋白，這樣的機制在多重抗藥性的細胞中是相當常見的。這些運輸蛋白中，ABC transporters 尤其是P-glycoprotein (P-gp, ABCB1)，breast cancer resistant protein (BCRP, ABCG2)，以及 multidrug resistant protein (MRP1, ABCC1)在對艾黴素(doxorubicin)具有抗藥性的細胞當中常常有高度表現的現象，因此使得化療藥物的效果降低，因此這些蛋白在抗藥性中扮演了重要的角色。在我們的研究中，酪胺酸激酶抑制劑基利克(imatinib)能夠有效的藉由促使細胞進行凋亡，以提升具有過度表現P-glycoprotein的doxorubicin抗藥性犬淋巴癌細胞對於doxorubicin的敏感度。並且當同時使用imatinib以及doxorubicin時，可以藉由減少doxorubicin的排出以提高其在抗藥性細胞內的累積量，而非藉由改變比起母細胞還要過度表現的P-glycoprotein之表現量。然而，Akt在同時給予兩種藥物後的24小時有被活化的現象，這可能是在癌細胞中特有的性質以避免細胞死亡的機制之一。但經過48小時後，活化的Akt表現量則降低，這樣的結果可與先前實驗互相對照，此時細胞已經經由細胞凋亡的機制而死亡，因此調控細胞存活的磷酸化蛋白激酶B (Protein kinase B/Akt) 表現量因此降低。總結來說，在過度表現P-glycoprotein的doxorubicin抗藥性犬淋巴癌細胞當中，使用imatinib可以藉由抑制藥物的排出以反轉doxorubicin的抗藥性。而此結果顯示未來在臨床上imatinib 或許可以用來反轉抗藥性，並提高doxorubicin的抗癌效果。 | zh_TW |
| dc.description.abstract | Canine lymphoma is one of most common malignant tumors to occur in dogs with high incidence around the world. Despite advances in the cancer prevention, the treatment of tumor diseases also has to be improved. Some cancer cells may resist the effect of chemotherapeutic agents by upregulating drug transporters which efflux the drugs intrinsically or develop during treatments, this kind of mechanism is commonly seen in doxorubicin resistant tumor cells. ABC transporters, especially P-glycoprotein (P-gp, ABCB1), breast cancer resistant protein (BCRP, ABCG2), and multidrug resistant protein (MRP1, ABCC1) are mostly involved in doxorubicin resistant cancer cells. In our studies, CLBL1-8.0, a doxorubicin resistant B type lymphoma cell line was created from CLBL-1 by increasing doxorubicin concentration during culturing, it shows highly expressed of P-glycoprotein (P-gp, ABCB1), the protein which are mostly involved in doxorubicin resistant cancer cells. Also, we demonstrated that imatinib, a tyrosine kinase inhibitor, significantly potentiated the sensitivity of doxorubicin in P-gp overexpressing resistant cells by promoting cells into apoptosis. And also combination of these two drugs may increase the accumulation of doxorubicin by decreasing the efflux of doxorubicin, but not by altering the protein expression of P-glycoprotein, which was highly expressed than its parental cells. While the Akt was activated after 24 hours treatment of imatinib and doxorubicin to suppress apoptosis, it may be one of a mechanism reflects a cellular defense of cancer cells in order to prevent doxorubicin-induced cytotoxicity effects. While after 48 hour treatment, activated Akt was decreased, it corresponds to the results of cell viability assay that imatinib may induce cell death after 48 hour of treatment combined with doxorubicin. In conclusion, imatinib can reverse doxorubicin resistant by decreasing the drug efflux in ABCB1 overexpressed canine lymphoma doxorubicin resistant cells. These results suggest an optimal to use this strategy of combining doxorubicin, one of the mostly used chemotherapeutic drugs in the treatment of canine lymphoma, with imatinib in clinic to overcome its resistance. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:47:15Z (GMT). No. of bitstreams: 1 ntu-106-R03644003-1.pdf: 1828914 bytes, checksum: 86579867e4aff0453b0773c8aefa58b3 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
致謝 II 中文摘要 III Abstract IV Chapter 1 Introduction 1 Chapter 2 Background and Literature Review 3 2.1 Canine lymphoma 3 2.1.1 Prevalence of canine lymphoma 3 2.1.2 Classification, staging of canine lymphoma 4 2.1.3 Treatment and prognosis of canine lymphoma 6 2.2 Multidrug resistance (MDR) 9 2.2.1 Classification of multidrug resistance 9 2.2.2 Mechanisms of multidrug resistance 10 2.3 Reverse of multidrug resistance 16 2.3.1 ABC transporters inhibitor 16 2.3.2 Tyrosine kinase 18 2.3.3 Tyrosine kinase inhibitors (TKIs) 19 3.1 Cell lines and reagents 22 3.2 Development and maintenance of doxorubicin resistance canine lymphoma cell line 23 3.3 Cell viability assay 24 3.4 Cell cycle analysis 25 3.5 Western blot 25 3.6 Passive uptake, accumulation and efflux of doxorubicin 27 3.7 Statistical analysis 28 Chapter 4 Results 30 4.1 Doxorubicin inhibited proliferation of CLBL-1, CLBL1-8.0, UL1 and CLC 30 4.3 Imatinib inhibited proliferation of CLBL-1, CLBL1-8.0, UL1 and CLC 31 4.4 The protein expression were altered in DOX-resistant cell lines 32 4.4 The transport functions were altered in DOX-resistant cell lines 33 4.5 Imatinib potentiates the sensitivity of doxorubicin in doxorubicin resistant cell lines 33 4.6 The effect of imatinib on the reversing of doxorubicin is not shown in MDCK 35 4.7 Imatinib enhanced the accumulation of doxorubicin in CLBL1-8.0 35 4.8 Imatinib only slightly decreased the expression of ABCC1, while the protein levels of ABCB1 and ABCG2 did not change in the presence of imatinib 36 4.9 Imatinib decreased the efflux of doxorubicin in ABCB1 overexpressed canine lymphoma cells 37 4.10 Imatinib prevented doxorubicin-induced cytotoxicity effects after 24 hours, while potentiated the cell death effect of doxorubicin after 48 hours 38 Chapter 5 Discussion 40 Tables 47 Table 1. World Health Organization’s clinical staging system for lymphoma in domestic animals 49 Tables 2. Tyrosine kinase inhibitors used in human cancer types 50 Table 3. Tyrosine kinase inhibitors used in veterinary cancer types and species 51 Table 4. Sources and dilutions of the antibodies used in this study for Western blot 52 Table 5. Effect of DOX and Imatinib on canine lymphoma cell lines 53 Table 6. CI value of combination of DOX and Imatinib on CLBL1-8.0 54 Table 7. CI value of combination of DOX and Imatinib on UL-1 55 Table 8. CI value of the combination of DOX and Imatinib on MDCK at 48 hr 56 Figures 57 Figure 1. Effect of doxorubicin on the cell viability of canine lymphoma cell lines 57 Figure 2. Effect of doxorubicin on the cell cycle in canine lymphoma cell lines 59 Figure 3. The effect of doxorubicin on apoptosis in canine lymphoma cells 60 Figure 4. Effect of imatinib on the cell viability of canine lymphoma cell lines 61 Figure 5. Effect of imatinib on the cell cycle in canine lymphoma cell lines 62 Figure 6. The effect of doxorubicin on apoptosis in canine lymphoma cells 63 Figure 7. Immunobloting detection and quantification of ABCG2/BCRP, ABCB1/P-gp and ABCC1/MRP1 protein expression in canine lymphoma cell lines 64 Figure 8. Immunoblotting detection of p-Akt and Akt protein expression in canine lymphoma cell lines 65 Figure 9. The doxorubicin accumulation, uptake and efflux among the canine lymphoma cell lines 66 Figure 10. Effect of imatinib reversing resistance of doxorubicin on the cell viability of canine lymphoma cell lines 67 Figure 11. Assessment of the combination of DOX and imatinib by normalized isobologram and combination index curves on CLBL1-8.0 68 Figure 12. Assessment of the combination of DOX and imatinib by normalized isobologram and combination index curves on UL-1 69 Figure 13. Effect of imatinib potentiation of the effect of doxorubicin in MDCK 70 Figure 14. Assessment of the combination of DOX and imatinib by normalized isobologram and combination index curves on MDCK 71 Figure 15. Effect of imatinib reversing resistance of doxorubicin on the cell cycle on CLBL1-8.0 72 Figure 16. Effect of imatinib reversing resistance of doxorubicin on the cell cycle on UL-1 73 Figure 17. Effect of imatinib on the intracellular accumulation of doxorubicin in CLBL-1, CLBL1-8.0 and UL-1 cells 74 Figure 18. Effect of DOX and imatinib on the ABC transporters protein expression in CLBL1-8.0 in 24 and 48 hr 75 Figure 19. The effect of imatinib on the efflux of doxorubicin 76 Figure 20. The effect of imatinib on the passive uptake of doxorubicin 77 Figure 21. Effect of imatinib on p-Akt/Akt in CLBL1-8.0 in 24 and 48 hr 78 References 79 | |
| dc.language.iso | en | |
| dc.title | 藉由克服抗藥性以提升Doxorubicin在犬淋巴癌的抗癌效果 | zh_TW |
| dc.title | Enhance Anti-Tumor Effect of Doxorubicin in Canine Lymphoma by Overcoming Drug Resistance | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 林辰栖(Chen-Si Lin),李繼忠(Jih-Jong Lee) | |
| dc.contributor.oralexamcommittee | 廖泰慶(Tai-Ching Liao),廖光文(Kuang-Wen Liao),蔡女滿(Nu-Man Tsai) | |
| dc.subject.keyword | 犬淋巴癌,多重抗藥性,Doxorubicin,Imatinib,ABC transporter,P-glycoprotein, | zh_TW |
| dc.subject.keyword | Canine lymphoma,Multidrug resistance,Doxorubicin,Imatinib,ABC transporter,P-glycoprotein, | en |
| dc.relation.page | 94 | |
| dc.identifier.doi | 10.6342/NTU201700159 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-01-23 | |
| dc.contributor.author-college | 獸醫專業學院 | zh_TW |
| dc.contributor.author-dept | 分子暨比較病理生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子暨比較病理生物學研究所 | |
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