癌症是人體內每個部位或器官的細胞異常增生的通稱，是造成全球嚴重死亡問題的因素之一。對於治療癌症，雖然現今已有許多療法成功改善並降低死亡率，但仍有許多問題及挑戰需要面臨，包括癌症的轉移、不正常增生，甚至在治療上，化療藥物或放射線治療等等的副作用會造成病人嚴重的不適。對於治療癌症，尋找有效且低副作用的新療法是目前最需要的。目前臨床上，苯二氮卓類藥物-導眠靜是廣泛用於麻醉前鎮靜的藥品，透過影響中樞神經系統的γ-氨基丁酸A型受體來達到其抗焦慮、抗抑鬱和鎮靜的效果。除此之外，導眠靜也會透過位在周邊組織中的粒線體外膜傳輸蛋白-外周苯二氮卓受體來影響周邊組織的功能。過去實驗中，我們發現導眠靜能夠抑制乙型轉型生長因子所促使的乳癌細胞移行，此結果顯示:導眠劑可能具有抑制癌症的上皮-間質轉換，因此本研究的假說為:導眠靜能夠抑制乙型轉型生長因子引發的癌症生長以及上皮-間質轉換。首先我們觀察導眠靜對於不同癌症細胞的影響。我們的結果顯示導眠靜能夠抑制乙型轉型生長因子依賴型或非依賴型癌細胞生長、爬行和侵入。另外我們也發現MDA-MB-231的間質相關蛋白如纖連蛋白、波形纖維蛋白和1-整合蛋白和MCF-7及A549因乙型轉型生長因子而引發的上皮-間質轉換都會被導眠靜抑制。在機制上，我們使用外周苯二氮卓受體的抑制劑:PK11195來與導眠靜競爭受體位置。實驗的結果顯示，利用PK11195能夠反轉導眠靜對於乙型轉型生長因子引發之A549生長以及MDA-MB-231爬行的抑制，證明導眠靜會透過外周苯二氮卓受體來行使抑制效果。為了更加確定導眠靜會減少乙型轉型生長因子的效果，利用西方墨點法來觀察MCF-7中因乙型轉型生長因子而觸發的Smad2/3磷酸化，發現導眠靜會降低乙型轉型生長因子所活化的Smad2/3。
由以上的結果，我們認為導眠靜會抑制乙型轉型生長因子促使的癌細胞增生與上皮間質轉型透過鍵結外周苯二氮卓受體。在未來會更進一步探討導眠靜抑制癌細胞的機制以及外周苯二氮卓受體的參與機制，來更加證明並解釋導眠靜的抑制作用。

Cancer is a generic term for a large group of diseases that can affect any part of the body, causing severe death problem worldwide. Although cancer therapy has been improved and the survival rate of patients is raised, there are still factors such as cancer metastasis, abnormal proliferation, etc. making cancer difficult to be cured. Patients receiving regular treatment, such as chemotherapy and radiation experienced side effects leading to poor life quality of patients. Thus, new therapeutic strategies are necessary for the treatment of cancer. Midazolam (MDZ), an imidazole benzodiazepine derivative, is a common sedative drug as it potent anxiolytic, hypnotic, amnestic properties through the potentiation of GABA receptor in central nervous system. MDZ also bind to the structurally and pharmacologically distinct peripheral benzodiazepine receptor (PBR) located on the outer mitochondrial membrane in peripheral tissues. Previous studies from our lab have shown that MDZ inhibited transforming growth factor-β-driven breast cancer cell migration, implying an inhibitory role of MDZ in epithelial-mesenchymal transition (EMT). Thus, we hypothesize that MDZ inhibits cancer cell proliferation and EMT. The results showed that MDZ inhibited TGF-β dependent or independent cancer cell proliferation, as accessed by MTT and EdU assay in MCF-7, A549 and MDA-MB 231. In addition, we also found that MDZ inhibited cancer cell migration and invasion as examined by wound healing assay and transwell migration/invasion assay, respectively. Furthermore, the mesenchymal markers, including fibronectin, vimentin and β1-integrein in MDA-MB-231 and TGF-β-induced EMT in MCF-7 and A549 were suppressed by MDZ. In addition, by performing different dose of a PBR inhibitor, PK11195, we found that PK11195 reversed the inhibitory effect of MDZ on A549 proliferation and MDA-MB-231 migration. These results suggest that MDZ inhibits cancer TGF-β dependent or independent behaviors through PBR. To further investigate the mechanism of the Midazolam inhibition to cancer progression, we found that Midazolam inhibited TGF-β-induced Smad2/3 phosphorylation in MCF-7 by using Western blot.
Taken together, MDZ inhibits TGF-β-induced cancer cell proliferation and epithelial-mesenchymal transition through the binding of PBR. Further studies regarding to the mechanisms of how MDZ inhibits cancer and the involvement of PBR will be conducted in the future.

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