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標題: | 新型HDAC6 抑制劑合併化療藥物於人類急性白血病之抗癌作用探討 The anti-cancer effects of novel HDAC6 inhibitor combination with chemotherapeutic agents in human acute leukemia |
作者: | Yi-Jyun Lin 林怡君 |
指導教授: | 楊家榮 |
關鍵字: | 組蛋白去乙醯?6,急性白血病,合併藥物治療,Ku70,微小管動態, Histone deacetylase 6,acute leukemia,combination therapy,Ku70,microtubule dynamics, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | 實驗目的:急性白血病的標準化療於目前臨床上有其限制,vincristine 與doxorubicin皆為急性白血病的常用藥物,然而兩者分別具有神經毒性與心毒性等嚴重副作用,且抗藥性的問題亦逐漸出現,故需要提供其他有效的治療策略。組蛋白去乙醯酶6(histone deacetylase 6,HDAC6)被發現在急性白血病細胞中異常增加且參與癌細胞的調控,故抑制HDAC6 被認為是有潛力的急性白血病細胞治療策略。藥物合併治療的目的在於降低個別藥物的使用劑量,增強療效、減低藥物產生不良反應的機會,是癌症治療常見的用藥方式。本研究目的為探討新型HDAC6 抑制劑Compound A 分別與vincristine 或doxorubicin 進行藥物合併治療對於急性白病細胞的抑制情形與機轉。
實驗方法:本文透過細胞存活檢測試驗評估不同藥物濃度下細胞的存活情形,並利用流式細胞儀觀察細胞週期的分佈。細胞內蛋白質的表現由西方墨點法偵測。免疫沉澱法用以檢測Ku70 乙醯化、Ku70 與Bax 間的作用,以及Ku70 與γ-H2AX間的作用;藉由HDAC6 過量表現的方式確認Compound A 的作用機轉是否來自於其抑制HDAC6 活性。藥物合併指數由CompuSyn 軟體計算出。 實驗結果:Compound A 與doxorubicin 合併使用能促進急性骨髓性白血病細胞株HL-60 之DNA 損害反應,調控Ku70 乙醯化與Bax 轉移至粒線體,進而造成協同性細胞凋亡;而Compound A 與vincristine 合併使用會干擾微小管的動態平衡,使急性淋巴性白血病細胞株MOLT-4 停滯在有絲分裂週期,細胞無法正常分裂而死亡。證實HDAC6 抑制劑與doxorubicin 或vincristine 合併使用能增加藥物療效,是有潛力的治療方式。 結論:本研究提供HDAC6 抑制劑的研發方向與急性白血病治療的發展策略,經由合併藥物的治療方式增強療效,降低個別藥物劑量。 Objective. There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce cardiomyopathy and neurotoxicity, respectively. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, the effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpress in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to enhance efficacy of chemotherapy drugs of acute leukemia, this study will investigate the effects of combination Compound A, a histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells. Methods. Cell viability experiments were determined by MTT assay, and cell cycle distributions was analyzed by flow cytometry. Protein expression was evaluated by Western blot. Immuneprecipitation was used to detect acetylation of Ku70, interaction between Bax and Ku70, and Ku70 interaction with γ-H2AX. Overexpression HDAC6 to ensure the anti-cancer effect of Compound A through inhibition HDAC6 activity. The combination index was measured by CompuSyn software. Results. Combination Compound A and doxorubicin induces DNA damage respond on human acute myeloid leukemia cell line HL-60. Compound A can also increase Ku70 acetylation and release Bax to mitochondria. Thus, combination Compound A and doxorubicin induce cell death synergistically. Combination Compound A and vincristine, by constant, may alter microtubule dynamics, triggering acute lymphoblastic leukemia cell line MOLT-4 arrest in mitosis followed by induction of the apoptotic pathway. Conclusion. The results demonstrate the novel strategy for the treatment of acute leukemia by combination HDAC6 inhibitor with chemotherapy drugs. The combination therapy can induce efficacy effects with lower doses of individual drugs. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19090 |
DOI: | 10.6342/NTU201602773 |
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顯示於系所單位: | 藥學系 |
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