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

Abstract

// Kamilla M.E. Laidlaw 1 , Samuel Berhan 1 , Suhu Liu 2 , Giovannino Silvestri 6 , Tessa L. Holyoake 1 , David A. Frank 2 , Bharat Aggarwal 3 , Michael Y. Bonner 4, 5 , Danilo Perrotti 6 , Heather G. Jørgensen 1, * , Jack L. Arbiser 4, 5, * 1 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 2 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA 3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA 5 Atlanta Veterans Administration Hospital, Atlanta, GA 30322, USA 6 Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA * These authors contributed equally to this work Correspondence to: Heather G. Jørgensen, email: heather.jorgensen@glasgow.ac.uk Jack L. Arbiser, email: jarbise@emory.edu Keywords: chronic myeloid leukemia, tyrosine kinase inhibitor, imipramine blue, nilotinib, NADPH oxidase Received: April 06, 2016      Accepted: June 30, 2016      Published: July 12, 2016 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.