Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Staszica 11, Lublin, Poland.
Ann Hematol. 2010 Nov;89(11):1115-24. doi: 10.1007/s00277-010-0988-z. Epub 2010 May 25.
Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs-fludarabine and cladribine-in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis.
尽管最近引入了许多治疗方案，但慢性淋巴细胞白血病（CLL）仍然是一种无法治愈的疾病。因此，迫切需要为 CLL 患者发现新型、毒性更低且更有效的药物。在这项研究中，我们试图评估辛伐他汀，作为一种广泛用于降低胆固醇的药物，无论是作为单一药物还是与嘌呤类似物 - 氟达拉滨和克拉屈滨联合使用，都对 CLL 细胞的凋亡和 DNA 损伤的影响。实验是在新诊断的未经治疗的患者的血液和骨髓细胞的体外短期细胞培养中进行的。我们分析了活性半胱天冬酶-3的表达和 BCL-2/BAX 比值作为凋亡的标志物，以及磷酸化组蛋白 H2AX（称为 γH2AX）和活化的 ATM 激酶（共济失调毛细血管扩张突变激酶）的表达，作为 DNA 损伤的报告者。我们的研究结果表明，辛伐他汀诱导 CLL 细胞凋亡，同时降低 BCL-2/BAX 比值，其促凋亡作用是肿瘤特异性的，不会影响正常淋巴细胞。我们观察到辛伐他汀+氟达拉滨和辛伐他汀+克拉屈滨的组合在诱导凋亡方面具有协同作用。有趣的是，单独使用辛伐他汀和联合使用辛伐他汀引起的凋亡率与疾病进展标志物（如 ZAP-70 和 CD38 表达或根据 Rai 分类的临床分期）无关。我们还观察到大多数分析样本中 γH2AX 表达的增加与 ATM 的激活平行。结果表明，辛伐他汀可作为单一药物用于 CLL 患者的治疗，也可与嘌呤类似物联合使用，在高危和预后良好的患者中同样有效。辛伐他汀作用的机制之一是诱导 DNA 损伤，最终导致凋亡。
