title: Imatinib increases cytotoxicity of melphalan and their combination allows an efficient killing of chronic myeloid leukemia cells.
abstract: 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 24 h 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.
authors.affiliation: Division of Hematology, Department of Biomedical Sciences, Ospedale Ferrarotto, University of Catania, Catania, Italy.
authors.forename: Cesarina
authors.initials: C
authors.lastname: Giallongo
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.forename: Daniele
authors.initials: D
authors.lastname: Tibullo
authors.forename: Nunziatina
authors.initials: N
authors.lastname: Parrinello
authors.forename: Ignazio
authors.initials: I
authors.lastname: Barbagallo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Del Fabro
authors.forename: Fabio
authors.initials: F
authors.lastname: Stagno
authors.forename: Concetta
authors.initials: C
authors.lastname: Conticello
authors.forename: Alessandra
authors.initials: A
authors.lastname: Romano
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiarenza
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage; D004249:DNA Damage; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D016313:Genes, abl / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D014410:Tumor Stem Cell Assay
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate; D008558:Melphalan; D006918:Hydroxyurea