合併survivin抑制劑與 mTOR抑制劑誘發腎癌細胞調控型細胞壞死之分子機制及療效

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题名: 合併survivin抑制劑與 mTOR抑制劑誘發腎癌細胞調控型細胞壞死之分子機制及療效
作者: 趙政漢
Chao, Cheng-Han
描述: 博士
分子與細胞生物研究所
日期: 2013
关键词: 腎細胞癌
survivin抑制劑
mTOR抑制劑
調控型細胞壞死
renal cell carcinoma
survivin inhibitor
mTOR inhibitor
necroptosis
摘要: 腎細胞癌(renal cell carcinoma, RCC)是最致命的泌尿系統癌症之一，在美國2012年研究預估與腎細胞癌相關死因約有13,570人，在臺灣約一年有500人罹患腎細胞癌。新的標靶藥物治療，針對哺乳動物雷帕黴素靶蛋白（mTOR）和酪氨酸激?作阻斷，包括美國食品和藥物管理局（FDA）批准的藥物temsirolimus， everolimus，sorafenib，和sunitinib，是可以改善臨床預後。由於RCC是一個富含血管的疾病，腫瘤血管生成在RCC生長中扮演重要的作用，而這些藥物破壞血管生成的能力即代表治療的有效性。然而，耐藥性是一個新興的問題。因為即使目前FDA批准的藥物治療後，雖然其臨床反應率是提高，但大多數晚期RCC患者最終會因為他們的疾病而死亡。因此我們需要建立使用其它不同的標靶藥物合併處理做為一個新策略，來改善臨床預後。
本篇研究發現survivin抑制劑YM155，可以協同增強mTOR抑制劑temsirolimus對於RCC細胞株在體外和體內異種移植(xenograft)模型中的抗癌活性。為了瞭解合併藥物治療抑制腫瘤細胞生長的機制，我們使用了兩種抑制細胞死亡的廣效型抑制藥物，分別是抑制細胞凋亡的Z-VAD-fmk，以及抑制細胞壞死的Necrostatin-1 (Nec-1)。我們研究發現合併temsirolimus與YM155抑制細胞生長的情形可受Nec-1調控，但不受Z-VAD-fmk調控；同時Nec-1的前處理不但可以回復腫瘤細胞受temsirolimus和YM155造成的細胞生長抑制，也可以回復受影響的細胞外型。由於Nec-1是廣泛性抑制細胞壞死的藥物，顯示temsirolimus和YM155的藥物合併處理可能是透過誘發細胞走向調控型細胞壞死(necroptosis)。此外，運用免疫組織化學染色法可發現在合併治療藥物下的移植瘤，其生物標誌物CD31和血管內皮生長因子顯著減少，表示temsirolimus/YM155組合減少了異種移植中組織的血管生成。本篇研究結果發現，合併治療YM155和temsirolimus可被視為對手術治療和/或化療無效的腎細胞癌的一個新的標靶治療，值得後續作進一步研究。
Renal cell carcinoma (RCC) is one of the most lethal urinary malignancies and causes about 13,570 estimated cancer-related deaths in the United States in 2012 . RCC accounts for about 500 new cancer cases per year in Taiwan. New targeted therapy focusing on mammalian target of rapamycin (mTOR) and tyrosine kinase for this disease include the Food and Drug Administration (FDA)-approved agents temsirolimus, everolimus, sorafenib, and sunitinib. All of them have been proved to improve clinical outcomes. Because RCC is a highly vascular disease and angiogenesis involves a critical role in development and progression of RCC, the potency to disrupt angiogenesis is responsible for the effectiveness of these agents. However, drug resistance is an emerging problem because most patients with advanced RCC will eventually die of their disease, even clinical response rates improved after treatment with above FDA-approved agents. A new strategy of cocktail targted therapy to improve clinical outcomes is needed.
We report here that YM155, a survivin suppressor, synergistically augmented the anticancer activity of mTOR inhibitor, temsirolimus in RCC cell lines in vitro and in xenograft models in vivo. In our study, necrostatin-1 was found to prevent the cell death induced by combined treatment, and could recover the cell shape and the intracellular survivin levels. On the other hand, pan-caspase inhibitor Z-VAD.fmk could not either restore the downregulated suvivin level induced by combined treatment of YM155 and temsirolimus or prevent the cell death. It is concluded that the synergistic effect is mainly through the necroptotic pathway. In addition, the temsirolimus/YM155 combination lead to a strong reduction in angiogenesis. The biomarkers, CD31 and VEGF, were markedly reduced under combined treatment by immunohistochemical stains of tumor graft.
These findings suggest that combined treatment of YM155 and temsirolimus may be considered as a new targeted therapy for renal cell carcinoma that is refractory to surgical intervention and/or chemotherapy, and certainly will open an exciting avenue for further investigation.
URI: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/78344
http://thesis.nthu.edu.tw/cgi-bi ... p;i=sGH000938235.id
显示于系所: [分子與細胞生物研究所] 博碩士論文