Komina Oxane, Nosske Ellen, Maurer Margarita, Wesierska-Gadek Jozefa
Cell Cycle Regulation Group, Division, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
J Exp Ther Oncol. 2011;9(1):27-35.
Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential against rapidly dividing cancers and malignancies, characterized by the accumulation of transformed cells due to deregulation of apoptosis, such as multiple myeloma. In the present study we addressed the possibility that pharmacological CDK inhibitors like Roscovitine (ROSC) may be effective against human multiple myeloma cells that have acquired resistance to doxorubicin (DOX). For this purpose we selected an experimental model of human multiple myeloma-sensitive (RPMI-8226s) and doxorubicin-resistant (RPMI-8226(DOX40)) cell lines. Exposure of RPMI-8826 cells to ROSC markedly increased the proportion of hypoploid cells, representing cells undergoing apoptosis, in both sensitive and resistant cells. Unlike ROSC, DOX at high dosage did not elevate the apoptosis rate in the RPMI-8226(DOX40) cell line. Our results show that ROSC has the capacity to induce apoptosis in the RPMI-8226(DOX40) cells overexpressing the P-gp glycoprotein. Since ROSC not only inhibits cell cycle-related CDKs but also negatively regulates kinases involved in the regulation of transcription, its administration to quiescent multidrug-resistant cells might be advantageous. Inhibition of transcription of pro-survival genes such as BCL2 and MCL-1 as well as destabilization of survivin seems to improve its therapeutic efficacy.
细胞周期蛋白依赖性激酶（CDK）的小分子抑制剂对快速分裂的癌症和恶性肿瘤显示出很高的治疗潜力，这些癌症和恶性肿瘤的特征是由于细胞凋亡失调导致转化细胞积累，如多发性骨髓瘤。在本研究中，我们探讨了像Roscovitine（ROSC）这样的药理学CDK抑制剂可能对已获得对阿霉素（DOX）耐药性的人多发性骨髓瘤细胞有效的可能性。为此，我们选择了人多发性骨髓瘤敏感（RPMI - 8226s）和阿霉素耐药（RPMI - 8226(DOX40)）细胞系的实验模型。将RPMI - 8826细胞暴露于ROSC后，在敏感和耐药细胞中，代表正在经历凋亡的细胞的亚二倍体细胞比例均显著增加。与ROSC不同，高剂量的DOX并未提高RPMI - 8226(DOX40)细胞系的凋亡率。我们的结果表明，ROSC有能力在过表达P - gp糖蛋白的RPMI - 8226(DOX40)细胞中诱导凋亡。由于ROSC不仅抑制细胞周期相关的CDK，还对参与转录调控的激酶产生负调控作用，将其应用于静止的多药耐药细胞可能具有优势。抑制诸如BCL2和MCL - 1等促生存基因的转录以及使生存素不稳定似乎可提高其治疗效果。
