Iseki H, Ko T C, Xue X Y, Seapan A, Townsend C M
Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA.
J Gastrointest Surg. 1998 Jan-Feb;2(1):36-43. doi: 10.1016/s1091-255x(98)80101-7.
Pancreatic cancers frequently carry mutations in the K-ras, p53, and p16 genes, which regulate cell proliferation. Transition from G1 to S phase of the cell cycle requires activation of cyclin-dependent kinase 2 (Cdk2) which is inhibited by olomoucine and roscovitine. The purpose of this study was to determine whether olomoucine and roscovitine can block Cdk2 kinase activity and inhibit proliferation of four human pancreatic cancer cell lines with various genetic alterations. Human pancreatic carcinoma cell lines BxPC-3, PANC-1 Capan-2, and CAV were treated with olomoucine or roscovitine. Cdk2 kinase activity was determined using histone H1 as the substrate. Cell cycle distribution was analyzed by DNA flow cytometry. Cell numbers were quantitated by Coulter counter. Olomoucine and roscovitine blocked Cdk2 activity in all four pancreatic cancer cell lines. Both compounds also inhibited cell proliferation in a dose-dependent fashion. Roscovitine was at least threefold more potent than olomoucine for both Cdk2 activity and cell proliferation. We have shown that Cdk inhibitors, olomoucine and roscovitine, block proliferation of human pancreatic cancer cells regardless of their mutations in K-ras p53, or p16 genes. These compounds represent a novel therapeutic strategy with potential therapeutic benefits for pancreatic cancers.
胰腺癌常常携带K-ras、p53和p16基因的突变，这些基因调控细胞增殖。细胞周期从G1期过渡到S期需要激活细胞周期蛋白依赖性激酶2（Cdk2），而olomoucine和roscovitine可抑制该激酶。本研究的目的是确定olomoucine和roscovitine是否能阻断Cdk2激酶活性，并抑制四种具有不同基因改变的人胰腺癌细胞系的增殖。用人胰腺癌细胞系BxPC-3、PANC-1、Capan-2和CAV分别用olomoucine或roscovitine处理。以组蛋白H1为底物测定Cdk2激酶活性。通过DNA流式细胞术分析细胞周期分布。用库尔特计数器对细胞数量进行定量。olomoucine和roscovitine在所有四种胰腺癌细胞系中均阻断了Cdk2活性。这两种化合物还以剂量依赖性方式抑制细胞增殖。对于Cdk2活性和细胞增殖，roscovitine的效力至少是olomoucine的三倍。我们已经表明，Cdk抑制剂olomoucine和roscovitine可阻断人胰腺癌细胞的增殖，无论它们在K-ras、p53或p16基因中是否存在突变。这些化合物代表了一种对胰腺癌具有潜在治疗益处的新型治疗策略。
