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標題: | 新型HDAC6選擇性抑制劑之抗多發性骨髓瘤與阿茲海默症活性與機轉探討 Effects and action mechanisms of novel HDAC6 inhibitor in multiple myeloma and Alzheimer’s disease |
作者: | Fang-I Huang 黃芳儀 |
指導教授: | 楊家榮 |
關鍵字: | 多發性骨髓瘤細胞,組蛋白去乙醯化?6,bortezomib,合併治療,骨髓基質細胞,協同作用, Multiple myeloma cells,histone deacetylase 6,bortezomib,combination therapy,bone marrow stromal cells,synergistic effect, |
出版年 : | 2019 |
學位: | 博士 |
摘要: | 多發性骨髓瘤(multiple myeloma, MM)是B細胞惡性腫瘤,好發於年長者(65歲以上),在台灣,每年估計有500名病患確診為多發性骨髓瘤。阿茲海默症(Alzheimer’s disease, AD),為最主要造成失智症的原因之一,約有60-80%失智患者同時患有阿茲海默症,在台灣約每100人就有一人為失智症。以上二者疾病都經過多年的研究,但至今我們仍在尋找更好的治療策略,然而台灣已於2018年3月正式邁向高齡化社會,預計將會有越來越多人遭受這樣的疾病,因此急需尋求更好的解決方法。
組蛋白乙醯化(Histone acetyltransferase, HAT)和脫乙醯化 (Histone deacetylae, HDAC)是調節基因表達和轉錄的重要表現的遺傳機制。組蛋白去乙醯化酶6(Histone deacetylae, HDAC6)是HDAC家族的獨特成員,不僅參與組蛋白乙醯化和脫乙醯化,而且還靶向幾種非組蛋白基質,如α-tubulin,cortactin和熱休克蛋白90(Hsp90),以調節腫瘤細胞增殖,轉移,侵襲和有絲分裂。另外研究發現HDAC6 konckout小鼠沒有器官損傷。可見HDAC6是治療疾病的新靶點。在本論文中,我們研究了HDAC6抑制劑在調節MM生長和AD中神經保護中的作用。 在第三章,我們發現HDAC6抑制劑與bortezomib(BTZ)的組合可以增加ubiquitinated protein的積累,然後引起進一步的細胞凋亡。HDAC6合併BTZ可以阻斷蛋白酶體和聚集體(aggresome)路逕是錯誤折疊蛋白清除的兩個主要途徑,同時維持MM穩定生長。HDAC6在聚集體途徑中有重要作用,因為它可以結合ployubiquitinated protein的蛋白質和動力蛋白馬達(dynein),然後將這種蛋白質轉運到聚集體中以進一步降解。此外,我們發現合併治療還可以抑制MM黏著於骨髓基質細胞(BMSC),降低MM-BMSC共培養體系中vascular endothelial growth factor (VEGF),Interleukin 6 (IL-6)的表現量以及MM生長,表示聯合治療擾亂骨髓微環境。此外,在異種移植SCID小鼠模行中MPT0G413-BTZ組合治療組中腫瘤生長顯著降低。我們的研究表明,合併治療具有協同抑制MM活性,為合併治療的臨床評估提供方法,以改善患者多發性骨髓瘤的癒後。 在第四章,我們使用AD模型研究HDAC6抑制劑的作用和機制。我們發現有兩種減少tau蛋白磷酸化和聚集的途徑與neurofibrillary tangle (NFT)的形成相關。一種是HDAC6抑制活性導致乙醯化Hsp90的增加,其反過來降低Hsp90和HDAC6的結合,並且磷酸化tau被轉移至Hsp90複合物,然後導致磷酸化tau蛋白的泛素化。另一種是通過Akt磷酸化顯著增加無活性形式的phospho-glycogen synthase kinase-3β (phospho-GSK3β)以減少tau磷酸化。基於這一發現,我們發現HDAC6抑制劑具有改善AD表徵的能力,包括tau蛋白過度磷酸化和聚集,神經保護作用以及學習和記憶缺陷的改善,使其成為進一步發展AD治療的潛力藥物。 Multiple myeloma (MM) is a B cell malignancy. In Taiwan, There an estimated 500 patients diagnosed with multiple myeloma each year. Alzheimer's disease (AD) is one of the most common causes of dementia. About 60-80% of patients with dementia suffer from Alzheimer's disease. That means one in every 100 people in Taiwan is dementia. However, Taiwan has been an aging society. It is expected that more and more people will suffer from such diseases, so it is urgent to seek better solution. Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (Hsp90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. There is no organ damage in HDAC6 konckout mice. HDAC6 is a new target to cure the disease. In this thesis, we investigated the function of HDAC6 inhibitors in regulating multiple myeloma growth and neuroprotecting in AD. In the third chapter, we report the combination HDAC6 inhibitors with bortezomib (BTZ) can increase the accumulation of ubiquitinated proteins then cause further apoptosis. HDAC6 combined with bortezomib could block proteasomal and aggresomal pathways, two major pathways for misfolded protein clearance to maintain MM homeostasis at the same time. HDAC6 plays an important role in aggresomal pathway since it can bind polyubiquitinated proteins and dynein motors, then transport this protein cargo to aggresome for further degradation. Moreover, we found that the combination therapy can also inhibit MM adherence to bone marrow stromal cells (BMSC) and decreas VEGF, IL-6 levels and MM growth in MM-BMSC co-culture system, suggest combination treatment disturbed bone marrow microenvironment. In addition, tumor growth was significantly reduced in MPT0G413-BTZ combination treatment group in xenograft SCID mouse model. Our studies demonstrate that the combination therapy exhibits synergic anti-MM viability, providing the framework for clinical evaluation of combined therapy to improve patient’s outcome in multiple myeloma. In the forth chapter, we investigate the effects and mechanism of the HDAC6 inhibitor by using an AD model. We found that there are two pathway of decreasing tau protein phosphorylation and aggregation correlated with the formation of NFTs. One is HDAC6 inhibitory activity led to the increase of acetylated Hsp90, which in turn decreased the binding of Hsp90 and HDAC6, and phosphorylated tau was transferred to the Hsp90 complex then leading to the ubiquitination of phosphorylate tau proteins. The other one is a significant increased the inactive form phospho-glycogen synthase kinase-3β (phospho-GSK3β) through Akt phosphorylation to reduce the tau phosphorylation. Base on this findings, we found that the ability of HDAC6 inhibitors to improve Alzheimer’s disease phenotypes including tau hyperphosphorylation and aggregation, neuroprotective effects upon ubiquitination, and amelioration of learning and memory deficits, makes it a potential agent for further development as a treatment for Alzheimer’s disease. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78848 |
DOI: | 10.6342/NTU201900205 |
全文授權: | 有償授權 |
電子全文公開日期: | 2024-03-11 |
顯示於系所單位: | 藥學系 |
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