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The tricyclic antidepressant, nortriptyline induces apoptosis in bladder cancer cells in vitro and has antitumor effect in vivo.
bladder cancer cell
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|摘要:||膀胱癌占全球癌症死亡率的第五位，目前其治療方式主要為化學治療；但仍有副作用的影響。Nortriptyline 是一種抗憂鬱的藥物。除了主要用於治療憂鬱症，對於夜尿症、頭痛等也有療效。在憂鬱症用藥對於癌症治療的研究中，目前發現其能誘導癌細胞的細胞凋亡機制，例如: SSRIs, SNRIs 或是TCA。在2004年，Nortriptyline 被報導能殺死人類骨肉瘤細胞；然而，在膀胱癌細胞並沒有相關的研究。因此，我們想要研究Nortriptyline 對於膀胱癌細胞是否也有抗癌的效果。在此研究中，我們利用Nortriptyline處理人類膀胱癌細胞TCCSup和老鼠膀胱癌細胞MBT-2。以MTT assay來測其細胞存活率、以PI染細胞觀察處理後細胞中DNA的變化、以Annexin V-FITC stain來測定細胞膜完整性、以西方墨點法觀察細胞周期及細胞凋亡之相關蛋白的變化、以JC-1是否聚集來測定粒線體膜電位的變化，還有使用流式細胞儀偵測細胞凋亡相關受體表現量及可誘導粒線體功能損壞因子之變化。由結果顯示，Nortriptyline處理膀胱癌細胞後，細胞生長受到抑制，還有DNA斷裂、PS蛋白外翻、粒線體膜電位過極化、細胞週期停滯等現象；由蛋白質表現量也可發現，促凋亡蛋白Bax、Bak、cytochrome C、smac/diable、c-caspase 9、c-caspase 3、c-PARP、c-caspase 8等皆上升；抑制凋亡蛋白Bcl-2下降，此外細胞週期調控蛋白cyclin D1、CDK4等蛋白表現量也下降。在流式細胞儀檢測結果可得，死亡受體表現量不變、ROS下降、鈣離子濃度上升。在in vitro實驗中，我們證實了Nortriptyline藉由細胞凋亡途徑導致膀胱癌細胞死亡和細胞週期停滯。在機制方面，Nortriptyline會誘導非依賴死亡受體活化的caspase 8及增加細胞內鈣離子的濃度進而影響粒線體功能失調。在in vivo實驗中，我們也以動物實驗證實Nortripytline確實能有抑制腫瘤生長的作用。綜合以上之結果，我們得知Nortriptyline有潛力成為膀胱癌的抗癌藥物。|
Bladder cancer is the fifth most common malignancy in the world, and its surgery is always followed by chemotherapy with side-deefects. Nortriptyline is a tricyclic antidepressant (TCA) and has been used in the treatment of major depression, childhood bedwetting, and chronic illnesses such as chronic pain and migraine. Apoptosis induction in cancer cell by antidepressants, including Sellective serotonin reuptake inhibitors (SSRIs), Serotonin Norepinephrine Reuptake inhibitor (SNRIs) or TCA, had also been reported. In 2004, Nortriptyline was reported to kill human osteosarcoma cells only. However, the antitumor effects of Nortriptyline on bladder cancer cells is unknown. In this study, we aim to determine whether Nortriptyline has antitumor effect in bladder cancer cell lines and the within mechanism. The two bladder cancers, TCCSup (human bladder cancer cell lines) and MBT-2 (mouse bladder cancer cell line) were treated with different concentrations of Nortriptyline. MTT assay was used to determine the effects of Nortriptyline on the viability of these cells. The cell cycle arrest was detected through PI staining. The membrane integrity was determined by flow cytometry through Annexin V-FITC staining. Apoptosis and cell cycle associtaed protein variation were detected by western blot. And some apoptosis pathway associated proteins and the factors may infected mitochondira were detected by flow cytometry. We found that Nortriptyline inhibited the viability of bladder cancer cells in a dose- and time-dependent manners by apoptosis pathway. DNA damaged, PS protein flipped to out-side membrane, mitochondria membrane potential hyperpolarization were also detected. It also promoted cell cycle arrest depended on dose. In western blot datas, many pro-apoptosis proteins, Bax, Bak, cytochrome C, smac/diable, c-caspase 9, c-caspase 3, c-PARP, c-caspase 8 and so on, were increased and Bcl-2, inhibitor of apoptosis protein, was decreased. In flow ctometry analysis datas, the variation of Fas, DR4 and DR5 were no changed. And the levels of ROS was decreased and Calcium was incrased. Taken together, we found Nortriptyline can induced bladder cancer cells apoptosis and cell cycle arrest. In mechanism, it can induced death receptor-independent activated caspase 8 and promote the levels of calcium in cells. In vivo, intraperitoneal injection administration of Nortriptyline significantly suppressed the growth of s.c. MBT-2. In brief, the data provide insight into the molecular mechanisms underlying Nortriptyline induced apoptosis in bladder cancer cells and rendered this compound a potential anticancer drug for Bladder cancer.
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