1-?基?唑-4-醛類緣化合物誘導人類血癌細胞株凋亡之探討; Apoptosis induced by 1-benzyl carbazole-4-carboxaldehyde derivatives in human leukemia cell lines

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Title:	1-?基?唑-4-醛類緣化合物誘導人類血癌細胞株凋亡之探討;Apoptosis induced by 1-benzyl carbazole-4-carboxaldehyde derivatives in human leukemia cell lines
Authors:	羅美婷;Lo, mei ting
Contributors:	中國醫藥學院藥物化學研究所
Keywords:	細胞凋亡;細胞週期;人類血癌細胞株;apoptosis;cell cycle;human leukemia cell lines
Date:	1990
Issue Date:	2009-12-03 09:29:55 (UTC+8)
Abstract:	摘要藉由細胞週期停滯、誘導細胞凋亡與細胞分化以達到抑制癌細胞的增殖，是目前用來篩選有效抗癌藥的重要指標。我們探討一系列合成之1-■基■■-4-醛類緣化合物對人類血癌細胞株生長增殖之作用。以PI螢光染色法偵測經此系列化合物處理24小時後HL60、U937及K562之細胞增殖率，結果發現此系列所有的化合物皆有抑制細胞增殖率的作用，且成劑量依存性。但其中以LCY-12有最強的細胞生長抑制作用，其對HL60、U937及K562細胞之IC50 分別為2.58、0.77、19.49 μM。觀察以LCY處理之細胞形態及DAPI染色之細胞核，發現這些細胞呈現凋亡的形態特徵，細胞形狀有皺縮的現象，核內染色質凝聚，核呈斷裂的情形，同時伴隨有凋亡小體的產生。利用DNA電泳檢測分析LCY-11、12、15、16及LCY-12、14、16、42經IC50 濃度處理後HL60及U937細胞之DNA，發現細胞DNA斷裂成小片段。除此之外，利用西方墨點法觀察以LCY-12處理之HL60細胞，其蛋白質表現量的變化，發現Bcl-2表現量增加，Bax表現量減少，caspase 3、8、9被活化，且PARP被分解。　　Caspase專一性抑制劑明顯地減少了LCY-12或LCY-16處理的細胞內caspase的活性，並且提昇了細胞增殖率。　　LCY-12、LCY-16會使HL60細胞週期抑制在G2/M期，而使U937細胞週期抑制在S期，細胞週期抑制發生的時間是在明顯細胞凋亡之前。　　為了探討細胞週期抑制可能的機制，我們以西方墨點法分析cyclin、CKI蛋白質表現的變化，發現LCY-12處理之HL60細胞，其cyclin B、cdc25c、p21表現量增加，而cyclin A表現量不變。以上結果顯示，LCY-12抑制癌細胞增殖的作用，可能與誘導細胞凋亡及抑制細胞週期進行有關。; Abstract Synthesized 1-benzyl carbazole-4-carboxaldehyde derivatives ( LCY ) examined for their growth inhibition effects in human leukemia cell lines. HL60, U937, and K562 cells were treated with these compounds for 24 hours and their proliferation was determined by the propidium iodide DNA staining method. A dose-dependent decrease in the cell proliferation rate was observed for all compounds. LCY-12 had the highest growth inhibitory, and its IC50 were 2.58, 0.77, and 19.49 μM for HL60, U937, and K562 cells, respectively. DAPI-stained cells revealed evident characteristics of apoptosis, which include cell shrinking, chromatin condensation, fragmentation of nuclei, and formation of apoptotic bodies. DNA from treated HL60 and U937 cells displayed a characteristic inter-nucleosomal ladder of DNA fragments. Furthermore, down-regulation of Bcl-2, up-regulation of Bax, activation of caspase 3, 8, and 9, and cleavage of PARP were detected by Western blotting method in LCY-12-treated HL60 cells. Caspase inhibitors significantly reduced LCY-12-induced caspase activity and cell death. In addition, LCY-12 and LCY-16 induced G2/M arrest in HL60 cells, and S arrest in U937 cells. The induction of cell cycle arrest occurred before the onset of apoptosis. Western blotting analysis of cyclins and CKIs revealed that LCY-12 induced the expression of cyclin B, cdc25c and p21 proteins. These results indicated that the ability of LCY-12 to inhibit cell proliferation may be mediated by the induction of apoptosis and cell cycle arrest.
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