Troadec Samuel, Blairvacq Mélina, Oumata Nassima, Galons Hervé, Meijer Laurent, Berthou Christian
Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, 29609, Brest Cedex, France.
Current address: Institut Universitaire Technologique, Département de Génie Biologique, Brest, France.
J Biomed Sci. 2015 Jul 17;22(1):57. doi: 10.1186/s12929-015-0163-x.
Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.
In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and -resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.
These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.
尽管甲磺酸伊马替尼彻底改变了慢性髓性白血病的治疗方式，但一些患者会随着白血病的进展而产生耐药性。对在Bcr-Abl驱动的慢性髓性白血病中失调的信号通路进行替代性或额外靶向治疗，可能为改善临床反应和克服耐药性提供可行的选择。
在本研究中，我们研究了CR8异构体（R-CR8和S-CR8）以及MR4（细胞周期蛋白依赖性激酶（CDK）抑制剂Roscovitine的三种衍生物）在体外对慢性髓性白血病发挥抗白血病活性的能力，然后我们解析了它们的作用机制。我们表明，这些CDK抑制剂是伊马替尼敏感和耐药的慢性髓性白血病细胞系生长停滞和凋亡的有效诱导剂。CR8和MR4通过线粒体途径诱导剂量依赖性凋亡，并通过下调与Bcr-Abl转化细胞存活密切相关的短命存活和抗凋亡因子Mcl-1、XIAP和survivin，进一步激活半胱天冬酶8/10和9。
这些结果表明，CDK抑制剂可能构成治疗慢性髓性白血病的一种补充方法。
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