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

Laidlaw, K. M.E. et al. (2016) Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia. Oncotarget, 7(32), pp. 51651-51664. (doi: 10.18632/oncotarget.10541) (PMID:27438151)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jorgensen, Dr Heather and Berhan, Mr Samuel and Holyoake, Professor Tessa
Authors: Laidlaw, K. M.E., Berhan, S., Liu, S., Silvestri, G., Holyoake, T. L., Frank, D. A., Aggarwal, B., Bonner, M. Y., Perrotti, D., Jorgensen, H. G., and Arbiser, J. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals LLC
ISSN:1949-2553
ISSN (Online):1949-2553
Copyright Holders:Copyright © 2016 Impact Journals, LLC
First Published:First published in Oncotarget 7(17):51651-51664
Publisher Policy:Reproduced under a Creative Commons License

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