title: Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells.
abstract: Identification of imatinib mesylate as a potent inhibitor of the Abl kinase and the subsequent findings that this compound displays growth inhibitory and pro-apoptotic effects in Bcr-Abl+ cells, has deeply conditioned CML treatment. Unfortunately the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance. A wide variety of molecular mechanisms can underlie such resistance mechanisms. In the recent years, heme oxygenase-1 (HO-1) expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress and this cytoprotective role has already been demonstrated for several solid tumors and acute leukemias. The aim of the present study was to investigate the effect of HO-1 expression on cell proliferation and apoptosis in chronic myeloid leukemia cells, K562 and LAMA-84 cell lines following imatinib treatment. Cells were incubated for 24h with Imatinib (1 μM) alone or in combination with Hemin (10μM), an inducer of HO-1. In addition, cells were also treated with HO byproducts, bilirubin and carbon monoxide (CO), or with a protease inhibitor (Ed64) to inhibit HO-1 nuclear translocation. Pharmacological induction of HO-1 was able to overcome the effect of imatinib. The cytoprotective effect of HO-1 was further confirmed after silencing HO-1 by siRNA. Interestingly, neither bilirubin nor CO was able to protect cells from Imatinib-induced toxicity. By contrast, the protective effect of HO-1 was mitigated by the addition of E64d, preventing HO-1 nuclear translocation. Finally, imatinib was able to increase the formation of cellular reactive oxygen species (ROS) and this effect was reversed by HO-1 induction or the addition of N-acetylcisteine (NAC). In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve its enzymatic byproducts, but rather the nuclear translocation of HO-1 following proteolytic cleavage.
authors.affiliation: Department of Clinical and Molecular Biomedicine Section of Hematology, Ferrarotto Hospital, University of Catania, Catania, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tibullo
authors.forename: Ignazio
authors.initials: I
authors.lastname: Barbagallo
authors.forename: Cesarina
authors.initials: C
authors.lastname: Giallongo
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.forename: Nunziatina
authors.initials: N
authors.lastname: Parrinello
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Fabio
authors.initials: F
authors.lastname: Stagno
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Li Volti
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D051547:Heme Oxygenase-1