病毒唑对白血病的治疗机制研究

Study on the mechanism of ribavirin in treat ment of leukemia

为了探索治疗慢性粒细胞白血病(chronic myeloid leukemia,CML)的新方法,研究了病毒唑单药及与伊马替尼联合治疗CML的效果及机制。结果显示,病毒唑、伊马替尼单药均可以抑制K562细胞株增殖,2种药对K562细胞株的IC50值分别为92.2、0.145μmol/L,与20μmol/L的病毒唑联合使伊马替尼的IC50值下降至0.077μmol/L;病毒唑单药可以下调K562细胞株和CML患者原代细胞mTOR/4EBP1/eIF4E信号通路关键蛋白mTOR、4EBP1、eIF4E的磷酸化水平,与伊马替尼联合,上述信号通路关键蛋白的磷酸化水平下调更明显;病毒唑单药可增加K562细胞株中eIF4E与4EBP1的结合,减少与eIF4G的结合,抑制eIF4F翻译起始复合物的形成,与伊马替尼联合后上述作用更强,表现出协同抑制eIF4F组装的作用。这些体外实验提示病毒唑单药具有抗白血病作用,而且能增强伊马替尼的抗CML作用。

In order to develop new therapeutic approaches for chronic myeloid leukemia（CML）,the study investigated the antileukemia effect and mechanism of ribavirin alone or plus imatinib in CML.The results show that ribavirin or imatinib alone has anti-proliferation effect on K562 cell line,the IC50 values of ribavirin and imatinib against to K562 cell line are 92.2μmol/L and0.145μmol/L,respectively.Combined with 20μmol/L of ribavirin,the IC50 value of imatinib decreases to 0.077μmol/L.Ribavirin reduces the phosphorylation levels of mTOR,4EBP1,eIF4 Eproteins in the mTOR/4EBP1/eIF4 Esignaling pathway in K562 cell line and CML patient primary cells.The combination of ribavirin with imatinib reduces the phosphorylation level of these proteins more significantly than that with ribavirin alone.Ribavirin can increase the combination of eIF4 Eand 4EBP1,decrease the combination of eIF4 Eand eIF4Gin K562 cell line,therefore,inhibit the assembly of eIF4 Ftranslation initiation complex.When combined with imatinib,inhibition effect on assembly of eIF4 Ftranslation initiation complex is more obvious.These studies in vitro demonstrate that ribavirin inhibits the proliferation of K562 cell line,the combination of ribavirin with imatinib enhances anti-leukemic effects.