合成的苯乙酸衍生物H6, SCK6對人類子宮頸癌細胞的生長抑制作用; Growth inhibitory effects of synthetic phenylacetatic acid derivatives on human cervical cancer cells

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Title:	合成的苯乙酸衍生物H6, SCK6對人類子宮頸癌細胞的生長抑制作用;Growth inhibitory effects of synthetic phenylacetatic acid derivatives on human cervical cancer cells
Authors:	楊雅茹;Ya-Ju Yang
Contributors:	中國醫藥大學醫學研究所
Keywords:	苯乙酸;苯乙酸衍生物;分化作用;子宮頸癌;細胞凋亡;phenylacetate;phenylacetate derivatives;differentiation;cervical cancer;apoptosis
Date:	1993
Issue Date:	2009-12-24 10:58:46 (UTC+8)
Abstract:	苯乙酸能經由數種不同的作用機制誘導腫瘤細胞的生長停止與分化作用。本論文是探討兩種合成的苯乙酸衍生物4-Fluoro-N-butyl- phenylacetamides (H6) 及2-Fluoro-N-butylphenylacetamides (SCK6) 處理兩種子宮頸癌細胞株Hela-S3及Ca Ski的生物活性作用。結果顯示，H6及SCK6皆具有抑制癌細胞增殖及癌細胞凋亡之作用，並呈現劑量及時間依存性，其IC50約在1.0~1.5 mM，ID50約為3天。由細胞形態的改變、GIEMSA及DAPI螢光染色、DNA斷片的結果得知，此二種合成的化合物明顯誘導細胞凋亡。以H6及SCK6處理會使細胞內Bax表現量增加，Bcl-2表現量減少，PARP被分解斷裂，造成DNA無法修補而斷裂成特殊的片段，引起細胞的死亡。在H6及SCK6抑制癌細胞增殖作用機制研究中，我們分析此兩種合成化合物對細胞週期的影響，結果發現以1 mM H6處理會造成子宮頸癌細胞株Hela-S3停在細胞週期的S期，而以2 mM SCK6處理Ca Ski則會干擾細胞週期的進行。進一步分析一些與細胞週期相關的蛋白質變化，結果顯示H6處理Hela-S3細胞後，會使cyclin-dependent kinase 1 (cdk 1), cdk 2, cyclin A與cyclin B蛋白表現量降低。另外，以H6處理Hela-S3細胞，不會影響p53蛋白質的表現。歸納其總反應機制，我們認為H6是透過S期細胞週期調節因子cdks和cyclins的負向調節，而且是p53-independent的路徑，造成子宮頸癌細胞週期停滯在S期。除此之外，Bcl-2蛋白質表現量的降低與Bax蛋白質的活化可能是H6及SCK6誘導細胞凋亡的機轉之一。; Abstract Phenylacetate was found to induce tumor cytostasis and differentiation through several mechanisms. In this study, we investigated the activity of the synthetic phenylacetate derivatives treatment of human cervical cancer cells, Hela-S3 and Ca Ski cells. The two synthetic phenylacetate derivatives are 4-Fluoro-N-butylphenylacetamides (H6) and 2-Fluoro-N -Butylphenylacetamides (SCK6). Results showed that the anti -proliferative and apoptosis effects of these two synthetic compounds, and with a dose- and time-dependent response. The IC50 values were between 1.0 ~ 1.5 mM and ID50 value were about 3 days. Moreover, both of them significantly induced apoptosis evidenced by morphological changes, GIEMSA and DAPI staining and DNA fragmentation. H6 and SCK6 increased the expression of Bax protein, whereas decreased the expression of Bcl-2 protein. They also induced proteolytic cleavage of poly (ADP-ribose) polymerase, and then presented DNA fragmentation and apoptosis. To search the mechanism of antiproliferative effect of H6 and SCK6, cell cycle analysis was performed. Results showed that 1 mM H6 induced S phase arrest in Hela-S3 cells, and 2 mM SCK6 may interfere in proceeding of cell cycle in Ca Ski cells. Western blot analysis of S phase regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase 1 (cdk 1), cdk 2, cyclin A and cyclin B were decreased after treatment with H6. However, the protein level of the p53 was not change. Taken together, these results suggest that down-regulation S-phase association cdks and cyclins may contribute to H6-mediated S-phase arrest. Furthermore, the decrease of Bcl-2 and activation of Bax maybe the effector mechanism through H6 and SCK6 induced apoptosis.
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