Pipoxolan誘導人類口腔鱗狀細胞癌細胞之細胞凋亡與增加對Cisplatin的敏感性

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Title:	Pipoxolan誘導人類口腔鱗狀細胞癌細胞之細胞凋亡與增加對Cisplatin的敏感性 Pipoxolan hydrochloride-induced apoptosis and -enhanced sensitivity to Cisplatin in human oral squamous cell carcinoma cells
Authors:	林松源;Sung-Yuan Lin
Contributors:	醫學院基礎醫學研究所
Keywords:	細胞凋亡;Pipoxolan;Cisplatin
Date:	2009
Issue Date:	2010-09-29 12:13:54 (UTC+8)
Abstract:	目前研究的目的是探討Pipoxolan執行抑制的效應與造成細胞凋亡的分子機轉，並且進一步研究Pipoxolan如何增強Cisplatin於人類口腔鱗狀細胞腫瘤細胞(OSCC)的敏感性。本實驗使用pipoxolan濃度(1.56, 3.12, 6.25, 12.5, 25 ,50,and 100 μg/mL)，再利用MTT分析方法研究其在人類口腔鱗狀細胞腫瘤細胞(OSCC):HSC-3細胞增生的效應；以及利用流式細胞儀研究OSCC細胞於細胞週期的不同階段時期的分佈情形。接著，使用DAPI staining, DNA fragmentation 和 flow cytometer研究Pipoxolan在OSCC細胞造成細胞凋亡的效應，影響細胞週期與細胞凋亡的因素包括：p53, Bax, Bcl-2, cytochrome c, PARP and caspase 3, 8 9 expressions，藉由Western blotting來進行分析。實驗結果顯示，OSCC細胞以Pipoxolan 50 μg/ml處理24小時之後明顯地誘導OSCC細胞造成細胞凋亡；此外，OSCC細胞會因Pipoxolan其細胞週期於G0/G1 phase停止。然後細胞凋亡會伴隨著Bax/Bcl-2 ratio增加、cytochrome c的釋放、procaspases-9 和 -3的cleavage以及PARP的hydrolysis 。OSCC細胞以Pipoxolan處理觀察到細胞凋亡相關的分子訊息例如：P53的表現明顯地增加，因此首次目前研究的報告，P53的誘導與粒線體凋亡系統可能參與Pipoxolan於OSCC細胞的抗增生活性。尤其是Pipoxolan有效地加重Cisplatin於人類口腔鱗狀細胞腫瘤細胞(OSCC).的細胞毒性。因此，研究Pipoxolan可能誘導人類口腔鱗狀細胞腫瘤細胞(OSCC)的細胞凋亡效應，進一步或許Pipoxolan可以輔助Cisplatin在口腔癌方面有著潛力性的治療效果。 The aim of the present study was to investigate the molecular mechanisms by which pipoxolan exerts inhibitory effects and apoptotic activity, and investigated how pipoxolan enhances sensitivity to Cisplatin in human oral squamous cell carcinoma cells (OSCC). The effects of pipoxolan (1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL) on the proliferation of OSCC cells and on the distribution of cells within different phases of the cell cycle were investigated indirectly using the MTT assay and flow cytometry, respectively. The effects of pipoxolan on the apoptosis of OSCC cells was investigated by DAPI staining, DNA fragmentation and flow cytometry. Factors affecting the cell cycle and apoptosis, including p53, Bax, Bcl2, cytochrome c, PARP and caspase 3, 8 9 expressions, were examined using Western blotting. The results show that after 24 h of exposure to 50 μg/ml pipoxolan, pipoxolan showed that it significantly induced apoptosis in OSCC cells. In addition, OSCC cells were arrested in the G0/G1 phase by pipoxolan treatment. Apoptosis was associated with an increased Bax/Bcl-2 ratio, cytochrome c release, cleavage of procaspases-9 and -3, and hydrolysis of PARP. Significant increase in the levels of apoptosis-related signals such as p53 was observed in pipoxolan treated OSCC cells. Thus, the present study reports, for the first time, that induction of p53 and the mitochondrial apoptotic system may participate in the anti-proliferative action of pipoxolan in OSCC cancer cells. Notably, pipoxolan is sufficient to aggravate Cisplatin-induced cytotoxicity in OSCC cells. Altogether, this study suggested the effects of pipoxolan to induce apoptosis in OSCC and therapeutic potential in oral cancer by being an adjunct to Cisplatin.
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