乳癌一直是女性癌症死亡的重要原因之一,在美國乳癌死亡率約為26%,在國內根據衛生署統計乳癌佔女性病患死亡已達到第2位,僅次於子宮頸癌,但似乎每年有增加的趨勢,因此乳癌治療乃是女性的健康主題,相信能找到更多的抗癌症的治療方法或藥物是許多人努力的方向,也是癌症患者的福音。在許多的研究報告中可以發現抗癌藥物誘發癌細胞進行apoptosis是目前著重的一個研究方向(尤其是Bcl-2 protein),而初步研究發現AZ-1(Bis-Aziridinoquinonyl thiaethers)對乳癌細胞BC-M1具有致死作用,發現AZ-1引起細胞死亡率在濃度0.5μM、24小時對BC-M1造成接近50%的致死率,而且在48小時更有接近99%的致死率。而AZ-1對細胞毒性分析則發現在0.125-1.98μM濃度下對Skin Fibroblast的死亡並不明顯但對BC-M1則毒性明顯,另外以AZ-1與Pacilitaxel(Taxol)及Tamoxifen比較下,發現再0.5μM濃度以上,AZ-1對於BC-M1致死率比taxol和tamoxifen高,而對於Fibroblast細胞毒性則相差不多。 接下來利用流式細胞儀發現,在低劑量下AZ-1能部分抑制細胞週期的進行。利用西方點墨法發現cdk2表現量下降而cyclin B變化卻不明顯。此外在流式細胞儀的結果中發現,隨著劑量的提高,sub-G1 峰逐漸的升高。利用DNA螢光染色亦發現有DNA斷裂的現象。在NMR的分析上發現隨著劑量的增加,CH3/CH2的比值也跟著提升;而測得caspase-3酵素活性上,發現愈高劑量酵素活性也跟著提高。利用西方墨點法發現,隨著劑量的增高,pro-Caspase 3與TIAR的蛋白表現量隨之下降。綜合以上我們推測AZ-1造成乳癌細胞的死亡的方式為細胞凋亡的路徑。
Breast cancer remains a major health issue in many countries. The death rate of breast cancer is about 26% in USA. According to the statistics of department of health, the breast cancer has taken the second place which cause the death of female patients, only next to cervical cancer and increasing by yearly in Taiwan. It is believed that the prevention is most important thing and the other found out more anti-cancer drugs to cure the breast cancer patients. According the recent reports, it is better choice that the anti-cancer drugs could induce the cancer cell death by apoptosis pathway. In our preliminary data, we found that the Az-1( Bis-Aziridinoquinonyl thiaethers) induce cell death of breast cancer BC-M1 by dose-dependent manner and time-course. Base on the MTT cytototoxicity assay in our result, the AZ-1 was with lower lethal effect on human fibroblast cell in 2μM. Comparing the effect of cell death on BC-M1 cell induced by AZ-1、pacilitacel and tamoxifen, we found that the AZ-1 was better than these two compounds. The AZ-1 could induce the BC-M1 cell arrest in G0/G1 phase minor. In western blot, we find cdk2 expression decrease, but cyclin B no effect. The signal of BC-M1 cell progress on apoptosis pathway induced by AZ-1 were including the CH2/CH3 peak ratio increasing by dose-dependent manner determined by NMR analysis, and also in caspase-3 enzyme activity increasing. In western blot, we find pro-caspase and TIAR level were increased. From the above result, we propose that the AZ-1 could induce the BC-M1 cell progress the apoptosis pathway.
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