Research Papers:
Multifactorial resistance to aminopeptidase inhibitor prodrug CHR2863 in myeloid leukemia cells: down-regulation of carboxylesterase 1, drug sequestration in lipid droplets and pro-survival activation ERK/Akt/mTOR
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Abstract
Sue Ellen Verbrugge1,11, Marjon Al1, Yehuda G. Assaraf2, Sarah Kammerer1,3,12, Durga M.S.H. Chandrupatla1,3, Richard Honeywell3, Rene P.J. Musters4, Elisa Giovannetti3, Tom O’Toole5, George L. Scheffer6, David Krige7,13, Tanja D. de Gruijl3, Hans W.M. Niessen6, Willem F. Lems1, Pieternella A. Kramer8, Rik J. Scheper6, Jacqueline Cloos9, Gert J. Ossenkoppele10, Godefridus J. Peters3 and Gerrit Jansen1
1 Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
2 The Fred Wyszkowsky Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa, Israel
3 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
4 Department of Physiology, VU University, Amsterdam, The Netherlands
5 Department of Molecular Cell Biology, VU University, Amsterdam, The Netherlands
6 Departments of Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, Amsterdam, The Netherlands
7 Chroma Therapeutics Ltd, Abingdon, United Kingdom
8 Isala Hospital, Zwolle, The Netherlands
9 Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
10 Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
11 Present address: Department of Clinical Chemistry, UMCU, Utrecht, The Netherlands
12 Present address: Institute of Biophysics, Medical University of Graz, Graz, Austria
13 Present address: Immunocore Ltd, Oxford, UK
Correspondence to:
Gerrit Jansen, email:
Keywords: aminopeptidase, carboxylesterase, lipid droplets, mTOR, rapamycin
Received: August 11, 2015 Accepted: October 04, 2015 Published: October 19, 2015
Abstract
Aminopeptidase inhibitors are receiving attention as combination chemotherapeutic agents for the treatment of refractory acute myeloid leukemia. However, the factors determining therapeutic efficacy remain elusive. Here we identified the molecular basis of acquired resistance to CHR2863, an orally available hydrophobic aminopeptidase inhibitor prodrug with an esterase-sensitive motif, in myeloid leukemia cells. CHR2863 enters cells by diffusion and is retained therein upon esterase activity-mediated conversion to its hydrophilic active metabolite drug CHR6768, thereby exerting amino acid depletion. Carboxylesterases (CES) serve as candidate prodrug activating enzymes given CES1 expression in acute myeloid leukemia specimens. We established two novel myeloid leukemia sublines U937/CHR2863(200) and U937/CHR2863(5uM), with low (14-fold) and high level (270-fold) CHR2863 resistance. The latter drug resistant cells displayed: (i) complete loss of CES1-mediated drug activation associated with down-regulation of CES1 mRNA and protein, (ii) marked retention/sequestration of the prodrug, (iii) a substantial increase in intracellular lipid droplets, and (iv) a dominant activation of the pro-survival Akt/mTOR pathway. Remarkably, the latter feature coincided with a gain of sensitivity to the mTOR inhibitor rapamycin. These finding delineate the molecular basis of CHR2863 resistance and offer a novel modality to overcome this drug resistance in myeloid leukemia cells.
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