小蘗鹼對肺癌細胞生長抑制之研究; The investigation of berberine on cell growth inhibition of lung cancers

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Title:	小蘗鹼對肺癌細胞生長抑制之研究;The investigation of berberine on cell growth inhibition of lung cancers
Authors:	梁峰賓
Contributors:	中國醫藥學院中國藥學研究所
Keywords:	小蘗鹼;肺癌;細胞週期;berberine;ling cancer;cell cycle
Date:	1992
Issue Date:	2009-12-22 10:30:47 (UTC+8)
Abstract:	細胞週期調控系統中，最重要的分子為cyclin-dependent kinases（Cdks），以及其活性調控蛋白cyclins，藉由不同cyclin-Cdk complexes的組合可調節細胞進入不同的細胞週期，例如cyclin D-Cdk4/6以及cyclin E-Cdk2的活化可使得細胞週期由G1期進入至S期，而cyclin B/Cdk 1的活化促進細胞由G2期進入M期，然而，經由與Cdk inhibitors（CdkIs）結合，這些活化型的cyclin-Cdk complexes的活性就被抑制，使得細胞週期的進行停止。小蘗鹼（Berberine）為異奎啉（isoquinoline）類的植物生物鹼，具有多方面的藥理作用，包含著抗發炎以及抗微生物的活性。過去的研究已指出小蘗鹼於使用於血癌、胃癌與食道癌細胞上，具有抗腫瘤的效果。儘管如此，但是關於小蘗鹼對人類非小細胞肺癌細胞（NSCLCs）的效應未曾有文獻報導，且小蘗鹼抗腫瘤之分子作用機轉亦不清楚。於本實驗中，以人類非小細胞肺癌細胞株H1299跟H1299/p53用來研究小蘗鹼藉由調控細胞週期相關分子而使得細胞生長抑制的作用。以小蘗鹼（100 μM）連續處理三天，肺癌細胞的生長明顯被抑制，且呈現劑量及處理時間依存性的效果，並造成細胞週期停滯於G1期。由蛋白質西方墨點分析之結果顯示小蘗鹼的生長抑制作用可能是與減少細胞內cyclin D3、Cdk2和Cdk4蛋白量的表現以及增加cyclin E、p16和p21的表現量有關。由於上述分子在蛋白質表現量上的變化使得Cdk2和Cdk4激酶活性降低並導致retinoblastoma protein-p130無法被磷酸化。除此之外，ERK蛋白量與活性的減少可能亦牽涉其中。總而言之，小蘗鹼對於腫瘤細胞生長的抑制作用，是透過調控細胞週期相關分子cyclins、Cdks和CdkIs的表現量，而就以上結果顯示，小蘗鹼可能為癌症治療提供另一新藥的來源。; The central components of the cell-cycle regulatory system are cyclin-dependent kinases（Cdks）, whose activity depends on association with regulatory proteins called cyclins. Oscillations in the activities of various cyclin-Cdk complexes leads to the initiation of various cell-cycle events. For instance﹐activation of cyclin D-Cdk4/6 and cyclin E-Cdk2 makes the cell-cycle progress from G1 into S phase. However, the activities of cyclin-Cdk complexes can be suppressed by the binding of Cdk inhibitor proteins（CdkIs）. Then﹐the progression of cell-cycle may be paused. Berberine, an isoquinoline plant alkaloid﹐has multiple pharmacological actions﹐including anti-inflammatory and anti-microbial activities. Although berberine had been demonstrated to have antineoplastic function on leukemia﹐gastric and esophageal cancer cells. Little is known about the cellular and molecular mechanisms of antitumor effect of berberine. In this study, human NSCLC cell lines H1299 and H1299/p53 were used to examine the antitumor effect of berberine. Treatment with berberine caused a dose-dependent growth inhibition. Data from flow cytometry analysis indicated that berberine-mediated antiproliferation effect related to G1 phase arrest. Moreover, this berberine-induced growth inhibition was associated with decrease the expression levels of cyclin D3、Cdk2 and Cdk4 proteins and increase in cyclin E、p16 and p21 protein. In vitro kinase assay indicated that berberine inhibited the Cdk2 and Cdk4 kinase activities and consequently lead to hypophosphorylated of retinoblastoma protein-p130. In addition﹐decrease in ERK protein level and activity is also observed. Taken together, berberine can inhibit cancer cell growth by directly modulating the expression of mutiple cell cycle regulatory molecules, such as cyclins、Cdks and CdkIs. These results suggest that berberine may be used as a potent agent for cancer therapy.
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