Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents

Molecular Cancer

Research

Francisco Hernandez¹  Dana Vejmelkova²  Marek Trneny²  Lucie Lorkova³  Martin Vokurka³  Jana Pospisilova³  Ondrej Vit³  Vojtech Kulvait³  Bokang Maswabi³  Pavel Klener⁴  Jan Molinsky⁴  Lucie Lateckova⁴  Petra Vockova⁴  Magdalena Klanova⁴  Jiri Petrak⁵  Radek Jaksa⁶  Cory Mavis⁶ 

[1] Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA;First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic;Institute of Pathological Physiology, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic;Institute of Pathological Physiology, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic;First Department of Medicine - Department of Hematology, General University Hospital and Charles University in Prague, Prague, Czech Republic;Institute of Pathological Physiology, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic;Institute of Hematology and Blood Transfusion, Prague, Czech Republic;Institute of Pathology, General University Hospital and Charles University in Prague, Prague, Czech Republic;

关键词: Mantle cell lymphoma (MCL);    Cytarabine;    Drug resistance;    Nucleotide salvage pathway;    Proteomics;    Mass spectrometry;   

DOI  :  10.1186/1476-4598-13-159

 received in 2014-01-29, accepted in 2014-06-23,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive.MethodsFive araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies.ResultsMarked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts.ConclusionsAcquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.

【 授权许可】

Unknown   
© Klanova et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.