膀胱癌是泌尿系統第二好發的癌症，目前是台灣十大癌症中排行第七名。膀胱癌的治療主要由手術切除，而為預防癌細胞未清除乾淨，治療上還會配合化學藥物及放射 線的治療。但不論化學藥物或是放射線在生理上都會對患者造成副作用，另外癌細胞也容易對化學藥物或是放射線產生抗藥性或是抗敏性，導致治療失敗。為了解決當前對於膀胱癌治療上的盲點，目前正積極研究在治療上添加天然中草藥或食品作為增敏劑(sensitizer)，幫助降低現階段臨床治療劑量來毒殺癌細胞，幫助病患降低生理上的副作用及抗藥性，甚至避免復發及轉移的發生。我們的先前研究中發現，桑葚萃取物(Mulberry water extract)對於膀胱癌細胞(TSGH)合併太平洋紫杉醇(paclitaxel, dose: 3 nM)及放射線(dose: 10 Gy)都比單獨使用藥物有較佳的毒殺效果，並且更進一步發現桑葚萃取物在合併紫杉醇或放射線48小時後都會造成 TSGH 停滯在細胞週期中的 G2/M phase，並且促進 mitotic catastrophe相關蛋白如 Aurora A的表現。處理至 72 小時後癌細胞則發現因 apoptosis 而造成細胞死亡。本計畫除了要深入了解 mitotic catastrophe作用機制外，還要進一步了解透過 mitotic catastrophe 引發 apoptosis 與只發生 apoptosis 相比是否對膀胱癌細胞有較佳的毒殺效果。另外在動物實驗上，利用 xenograft model 觀察桑葚萃取物合併紫杉醇或是放射線是否也可以誘發 mitotic catastrophe 並且能抑制腫瘤的生長。本計劃的研究成果期望能給予膀胱癌治療新的策略，並開發桑葚萃取物為保健食品。 Bladder cancer is the second predilection urinary system cancer, and is the seventh of Taiwan's top ten cancers. The treatment of bladder cancer is basically by cystectomy combined with chemotherapy and radiation to prevent the incomplete removal of cancer. However, both chemicals and radiation will cause serious side effects to the patient, in addition to the development of resistance to chemotherapy or radiation by cancer cells that leads to treatment failure. In order to resolve the disadvantages for the treatment of bladder cancer, it is currently a new trend in cancer research to add natural products from herbs or food as a sensitizer in the treatment, hoping to reduce the dose used in clinical cancer treatment to reduce the cytotoxicity of chemo- or radiotherapy, physiological side effects and drug resistance, and even to prevent recurrence and metastasis. Our previous studies found that Mulberry water extract (MWE) combined with paclitaxel (dose: 3 nM) or radiation (dose: 10 Gy) for bladder cancer cell line (TSGH 8301) has a better cytotoxic effect than the use of drug or radioation alone, and further found that MWE combined with paclitaxel or radiation caused cycle arrest in the G2 / M phase at 48 hours in TSGH cell, and promotes the expression of mitotic catastrophe-related proteins, such as Aurora A. The combined treatment subsequently induced apoptotic cell death of cancer cells at 72 hours. In this project we will continue to clarify the molecular mechanisms of mitotic catastrophe induced by combined treatment of MWE and chemo- or radiotherapy, and aim to identify the advantage of using mitotic catastrophe to induce apoptosis over the direct apoptosis in bladder cancer treatment. The tumor xenograft model in nude mice will be also performed to demonstrate the efficacy of the combined treatments in vivo. The results of present project will provide an alternative strategy for bladder cancer treatment and information for the development of Mulberry water extract as health food.
