Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia

• Type of Material: Article
• Authors: Kamilla M.E. Laidlaw, University of Glasgow; Samuel Berhan, University of Glasgow; Suhu Liu, Harvard University; Giovannino Silvestri, University of Maryland; Tessa L. Holyoake, University of Glasgow; David A. Frank, Harvard University; Bharat Aggarwal, MD Anderson Cancer Center; Michael Y. Bonner, Emory University; Danilo Perrotti, University of Maryland; Heather G. Jørgensen, University of Glasgow; Jack Arbiser, Emory University
• Language: English
• Date: 2016-08-09
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Laidlaw et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.10541
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 7
• Issue: 32
• Start Page: 51651
• End Page: 51664
• Grant/Funding Information: J.L.A. was supported by the grant RO1 AR47901and P30 AR42687, and NIH-NCI grant CA163800 (D.P.). Emory Skin Disease Research Core Center Grant from the National Institutes of Health, a Veterans Administration Hospital Merit Award, as well as funds from the Margolis Foundation, Rabinowitch-Davis Foundation for Melanoma Research and the Betty Minsk Foundation for Melanoma Research. J.L.A. was supported by the grant RO1 AR47901and P30 AR42687, and NIH-NCI grant CA163800 (D.P.). Emory Skin Disease Research Core Center Grant from the National Institutes of Health, a Veterans Administration Hospital Merit Award, as well as funds from the Margolis Foundation, Rabinowitch-Davis Foundation for Melanoma Research and the Betty Minsk Foundation for Melanoma Research.
• Keywords: imipramine blue; NADPH oxidase; tyrosine kinase inhibitor; Oncology; chronic myeloid leukemia; nilotinib; Life Sciences & Biomedicine; Cell Biology; Science & Technology
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

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.