Imatinib increases cytotoxicity of melphalan and their combination allows an efficient killing of chronic myeloid leukemia cells

BCR/ABL positive cells are known to be resistant to DNA damage induced by chemotherapy while they are sensitive to imatinib (IM), a tyrosine kinase inhibitor (TKI). To evaluate whether this drug can increase the activity of cytotoxic drugs on BCR/ABL positive cells, we measured the toxicity of cytosine arabinoside (ARA-C), hydroxyurea (HU) and melphalan (MEL), after a pretreatment of 24h with IM on K562 cell line. The highest cytotoxic effect was seen when the TKI was followed by MEL; our results indicate that inhibition of BCR/ABL activity by IM increased the cytotoxicity of MEL by favoring the DNA damage induced by this drug and by shortening the time for DNA repair at the G2/M checkpoint. A stronger activation of some genes involved in both intrinsic and extrinsic apoptotic pathways was also observed with IM/MEL combination compared to IM or MEL alone. The drugs association was further tested in a type of BaF3 cells (TonB.210) where the BCR-ABL expression is inducible by doxycycline; in this model it was confirmed that a reduction of BCR/ABL activity resulted in an increased susceptibility to the cytotoxic effect of MEL. Furthermore, we studied the effect of IM/MEL treatment on the proliferative potential of myeloid progenitors of six CML patients at diagnosis. The analysis of CFU-GM and BFU-E colonies demonstrated that the IM/MEL combination was more effective than IM alone in reducing the overall number of colonies and the number of copies of BCR/ABL. In conclusion, our work shows that inhibition of BCR/ABL activity increases the toxicity of MEL and allows an efficient killing of leukemic cells, suggesting that a clinical development of this approach could have therapeutic advantages for CML patients. © 2011 John Wiley & Sons A/S.