Imatinib (Glivec) and Nilotinib (AMN107) have been developed as selective targeted inhibitors of Bcr-Abl chimaeric tyrosine kinase activated in CML and other malignancies characterized by the t(9;22) translocation (Manley P.W., et al. Biochim Biophys Acta 1754(1–2):3–13, 2005). Both agents are considered innovative targeted cell death promoting agents designed for treatment of human leukemias. During the course of their evaluation as apoptosis-promoting agents in human K-562 leukemia cells, we observed that both agents in addition to blocking Bcr-Abl tyrosine kinase, promoted production of hemoglobin but to different extent. Imatinib caused hemoglobin production in 6–7% of cells at concentration of 0.01 μM to 0.5 μM. This proportion reached 54% in the presence of 90 μM of Hemin. Nilotinib alone, on the other hand, caused hemoglobin production in 66% of cells at a concentration of 0.01 μM. This proportion increased to 75% in the presence of 30 μM of Hemin. These findings indicate that:

  1. Imatinib and Nilotinib are weak and potent inducers of hemoglobin biosynthesis, respectively.

  2. Treatment of K-562 cells with either Imatinib (0.5 μM) and Nilotinib (0.01 μM) enhanced the ability of Hemin to promote erythroid differentiation.

  3. This ability of Nilotinib to induce hemoglobin accumulation at concentrations lower than those causing apoptosis, suggest that this agent may be clinically useful by promoting hemoglobin biosynthesis in diseases characterized by hemoglobin deficiency (hemoglobinopathies). We are currently investigating the mechanism whereby Nilotinib can selective activate the globin gene expression in K-562 leukemia cells.

Disclosures: Paul W Manley is a full-time emploee of Novartis Pharma AG.

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