Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia

摘要: Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation currently in clinical trials. Because intrinsically short-lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support survival chronic lymphocytic leukemia (CLL) cells, we hypothesized inhibition synthesis by HHT would decrease Mcl-1 expression and induce apoptosis CLL. In primary CLL induced significant independent prognostic characteristics patients. This was associated with decreased levels cells. reduction evident as early 2 hours continued next 6-8 hours, whereas death started increase for 24 hours. Reduction level due proteasome degradation rather than transcription or caspase cleavage. inhibitor SNS-032 synergistic killing. Although stromal cells protected from toxicity fludarabine, this induction reversed HHT, which overcame cell–mediated protection. Thus, these results provide rationale development single agent combinations.