大黃素誘導大鼠神經膠質瘤細胞株細胞凋亡及抗藥性之分子機轉; The molecular mechanisms of emodin-induced apoptosis and drug resistance in rat C6 glioma cell line

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題名:	大黃素誘導大鼠神經膠質瘤細胞株細胞凋亡及抗藥性之分子機轉;The molecular mechanisms of emodin-induced apoptosis and drug resistance in rat C6 glioma cell line
作者:	郭子靖;Tzu-Ching Kuo
貢獻者:	中國醫藥大學：醫學研究所
關鍵詞:	大黃素;大鼠神經膠質瘤細胞株;活性氧物質;細胞凋亡;抗藥性;存活路徑;DNA傷害;內質網壓力;Emodin;rat C6 glioma cell line;reactive oxygen species;apoptosis;drug resistance;survival pathway;DNA damage;ER stress
日期:	2006-05-23
上傳時間:	2009-08-13 14:50:16 (UTC+8)
摘要:	大黃素emodin（1，3，8-trihydroxy-6-methylanthraquinonl）是一種蒽醌類（anthraquinone）化合物，存在於許多中國傳統中草藥材中，具有抗病毒、細菌感染、刺激細胞激素的分泌、血管舒張、保護肝臟功能以及抑制腫瘤等多種生物活性；最近許多抗癌相關研究發現，大黃素能夠有效抑制HER-2/neu過度表現之肺癌以及乳癌，而與其同為蒽醌類化合物的蘆薈大黃素（Aloe-emodin）則對神經膠質瘤有明顯抑制效果；本研究即利用大黃素針對大鼠神經膠質瘤細胞株（Rat C6 glioma cell line）來探討其是否具有抑制神經腫瘤的抗癌能力；結果發現，於短時間處理大黃素12小時後，大黃素能夠有效抑制C6細胞的增生並產生大量活性氧物質（ROS）來誘導C6細胞產生細胞凋亡，然而令人意外的是，當長時間處理大黃素72小時後，C6細胞會對大黃素產生抗藥性，經深入研究之後，結果發現，經大黃素長時間處理（72小時）之後，C6細胞能夠明顯地抑制p53、Bax、Fas以及caspase-3等凋亡相關蛋白的表現，並大量表現抗氧化酵素（SOD、catalase）清除大黃素對C6細胞所造成的氧化性傷害，此外，發現C6細胞的抗藥性基因（p-glycoprotein和MRP1、2、3、6）亦會大量表達以此降低藥物在細胞內的蓄積程度，並且C6細胞還會活化MAPK存活路徑和DNA傷害的修補蛋白，恢復細胞的活性，此外， C6細胞的COX-2以及MMP-9會大量表現，顯示出此神經膠質瘤細胞的侵襲轉移能力增強，而經大黃素刺激所產生的內質網壓力（ER stress）方面，C6細胞以大量表現GRP78來減輕內質網壓力所帶來的細胞凋亡程度，並藉由GRP78抑制GADD153的機制來提高Bcl-2基因的表現，以此補償內質網以及粒線體凋亡路徑所帶來的細胞傷害，這些結果都更進一步地證實C6細胞是進行多重路徑來對大黃素產生抗藥性。 Emodin（1，3，8-trihydroxy-6-methylanthraquinonl）is an active component from the widely used traditional Chinese herb, it has been reported that emodin possesses a number of biological activities such as anti-virus, anti-bacteria, stimulation of cytokine release, vasorelaxative, hepatoprotective, and anti-tumor activity. Recently studies had shown that emodin could effectly inhibit the proliferation of HER2/neu overexpression tumors such as lung and breast carcinoma, and that aloe-emodin as the similar structure compound as emodin had been reported the strongly inhibition of glioma cells, so we want to test whether or not emodin also has the suppressive effect on glioma cells. Results indicated that emodin inhibited the proliferation and induced apoptosis of C6 cells in the short time treatment（12 hr）, but then surprising results shown that C6 cells resurvive in the long time treatment（72 hr） with emodin and induced drug resistance to emodin. Furthermore, we found that C6 cells overcomed emodin-induced apoptosis by inhibition of the expression and activation of apoptosis associated proteins including p53, Bax, Fas and caspase-3. C6 cells could express antioxidant proteins such as SOD and catalase to decrease ROS-induced cytotoxity of emodin and also overexpress multi-drug resistance proteins including p-glycoprotein and MRP1, MRP2, MRP3, MRP6 to decrease the intracellular accumulation of emodin. We also found that C6 cells would active the MAPK survival pathway and express DNA repair associated proteins to recover the cell activity. In our results, COX-2 and MMP-9 were also expressing in the long time treatment which shown the strongly invasion activity of C6 cells. C6 cells could also express chepron molecule GRP78 to decrease emodin-induced ER stress which would cause apoptosis in C6 cells, and then GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 which could balance the ER-induced and mitochondria-induced apoptosis of C6 cells. These results suggested that C6 glioma cells induced drug resistance to emodin through expressing multiple mechanisms.
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