Knillová J, Bouchal J, Hlobilková A, Strnad M, Kolár Z
Institute of Pathology, Laboratory of Molecular Pathology, Faculty of Medicine, Palacky University, CZ-77515 Olomouc, Czech Republic.
Neoplasma. 2004;51(5):358-67.
Currently, mechanisms leading to both apoptosis induction and the development of hormone-independence of prostate carcinoma cells are intensively studied. Attention is also given to the possibility of restoring cell sensitivity to hormone-antagonists. The present study focuses on the effect of the combined synthetic cyclin-dependent kinase [CDK] inhibitor, olomoucine and the antiandrogen bicalutamide on hormone-insensitive (DU-145) and hormone-sensitive (LNCaP) prostate cancer cell lines. In both cell lines reduction in cell viability was significantly higher when olomoucine and bicalutamide were applied in combination when compared to separate application of both these drugs. The setting of optimal concentrations for both substances was important for the final effect on both cell lines. The proliferation arrest was accompanied by a decrease in cyclin D1 expression and the activation of p21Waf1/Cip1 and p27Kip1 pathways in both cell lines. Contrary to the previously described effect of 200 microM olomoucine, weak AR induction after treatment with effective concentrations of olomoucine was not seen in the hormone- insensitive cell line DU-145. The related reaction of DU-145 and LNCaP cell lines to treatment with combined olomoucine and bicalutamide likely provides evidence that the inhibitory effect of bicalutamide may not only be associated with its antiandrogenic properties. The tested substances probably influence different regulatory pathways and these have co-operative impact on the cell cycle outcome. Understanding antitumor and antihormone actions of both agents is essential for the development of novel therapeutic schemes integrating substances with different action. Our results show that the combination of synthetic CDK inhibitors and hormone- antagonists may be one of a number of possible alternatives.
目前，人们正在深入研究导致前列腺癌细胞凋亡诱导和激素非依赖性发展的机制。同时也关注恢复细胞对激素拮抗剂敏感性的可能性。本研究聚焦于合成的细胞周期蛋白依赖性激酶（CDK）抑制剂olomoucine与抗雄激素药物比卡鲁胺联合应用对激素不敏感（DU-145）和激素敏感（LNCaP）前列腺癌细胞系的影响。与单独使用这两种药物相比，联合应用olomoucine和比卡鲁胺时，两种细胞系的细胞活力降低更为显著。确定两种物质的最佳浓度对最终作用于两种细胞系很重要。两种细胞系中，增殖停滞伴随着细胞周期蛋白D1表达的降低以及p21Waf1/Cip1和p27Kip1通路的激活。与之前报道的200微摩尔olomoucine的作用相反，在激素不敏感细胞系DU-145中，用有效浓度的olomoucine处理后未观察到弱雄激素受体（AR）诱导现象。DU-145和LNCaP细胞系对联合应用olomoucine和比卡鲁胺治疗的相关反应可能证明，比卡鲁胺的抑制作用可能不仅与其抗雄激素特性有关。所测试的物质可能影响不同的调节通路，并且这些通路对细胞周期结果具有协同作用。了解这两种药物的抗肿瘤和抗激素作用对于开发整合具有不同作用的物质的新型治疗方案至关重要。我们的结果表明，合成CDK抑制剂与激素拮抗剂的联合应用可能是多种可能的选择之一。
