Burthem J, Rees-Unwin K, Mottram R, Adams J, Lucas G S, Spooncer E, Whetton A D
Division of Laboratory and Regenerative Medicine, Stopford Building, Manchester, UK.
Leukemia. 2007 Aug;21(8):1708-14. doi: 10.1038/sj.leu.2404762. Epub 2007 Jun 7.
Evidence from cell line-based studies indicates that rho-kinase may play a role in the leukaemic transformation of human cells mediated by the BCR/ABL tyrosine kinase, manifest clinically as chronic myeloid leukaemia (CML). We therefore employed two separate inhibitors, Y-27632 and fasudil, to inhibit the activity of rho-kinase against ex vivo CD34(+) cells collected from patients with CML. We compared the effects of rho-kinase inhibition in those cells with the effects of direct inhibition of BCR/ABL using the specific inhibitor imatinib. We found that inhibition of rho-kinase inhibited the effective proliferation, and reduced survival of CML progenitor cells. When combined with imatinib, rho-kinase inhibition added to the anti-proliferative and pro-apoptotic effects of the BCR/ABL inhibitor. Our studies may indicate therapeutic benefit in some cases for the combination of rho-kinase inhibitors with imatinib.
基于细胞系研究的证据表明，Rho激酶可能在由BCR/ABL酪氨酸激酶介导的人类细胞白血病转化过程中发挥作用，临床上表现为慢性髓性白血病（CML）。因此，我们使用了两种不同的抑制剂Y-27632和法舒地尔，来抑制Rho激酶对从CML患者体内采集的体外CD34(+)细胞的活性。我们将这些细胞中Rho激酶抑制的效果与使用特异性抑制剂伊马替尼直接抑制BCR/ABL的效果进行了比较。我们发现，抑制Rho激酶可抑制CML祖细胞的有效增殖，并降低其存活率。当与伊马替尼联合使用时，Rho激酶抑制增强了BCR/ABL抑制剂的抗增殖和促凋亡作用。我们的研究可能表明，在某些情况下，Rho激酶抑制剂与伊马替尼联合使用具有治疗益处。
