title: Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia.
abstract: The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation.
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, G12 0ZD, United Kingdom.
authors.forename: Kamilla M E
authors.initials: KM
authors.lastname: Laidlaw
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, G12 0ZD, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Berhan
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Suhu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Giovannino
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, G12 0ZD, United Kingdom.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Aggarwal
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Atlanta Veterans Administration Hospital, Atlanta, GA 30322, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.affiliation: Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, G12 0ZD, United Kingdom.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jørgensen
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Atlanta Veterans Administration Hospital, Atlanta, GA 30322, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D007099:Imipramine / Q000494:pharmacology* / Q000627:therapeutic use; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D007099:Imipramine
keywords: NADPH oxidase; chronic myeloid leukemia; imipramine blue; nilotinib; tyrosine kinase inhibitor