Leukemia Research 36 (2012) 1311–1314 Contents lists available at SciVerse ScienceDirect Leukemia Research jo ur nal homep age: www.elsevier.com/locate/leukres Nilotinib and imatinib inhibit cytarabine cellular uptake: Implications for combination therapy Josy S. Naud, Karim Ghani, Pedro O. de Campos-Lima, Manuel Caruso ∗ Centre de Recherche en Cancérologie de l’Université Laval, L’Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Québec, Canada a r t i c l e i n f o Article history: Received 6 February 2012 Received in revised form 17 June 2012 Accepted 20 June 2012 Available online 12 July 2012 Keywords: Imatinib Nilotinib Cytarabine CML Chemotherapy Bcr-Abl a b s t r a c t The tyrosine kinase inhibitor (TKI) imatinib has been used for a decade to treat chronic myeloid leukemia (CML). A very efficient response is obtained with patients in chronic phase, but its efficacy in late phase patients is often transient. The combination of imatinib or of the new TKI nilotinib with cytarabine is a new treatment approach proposed for CML. We have investigated the effect of imatinib and nilotinib on cytarabine uptake, and have found that both molecules inhibit cytarabine transport. These results should impact on the design of clinical trials that investigate the combination of TKIs and nucleoside analogs. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction Chronic myeloid leukemia (CML) is characterized by a recip- rocal translocation between chromosomes 9 and 22. This genetic modification leads to the generation of the bcr-abl fusion gene that encodes a chimeric protein with constitutive tyrosine kinase activity [1]. Imatinib (Gleevec) is a very efficient inhibitor of the Bcr-Abl fusion protein that has been used for a decade to treat CML patients and acute lymphoblastic leukemia (ALL) patients that harbor a very similar chromosome translocation. An efficient and sustained response to imatinib is obtained in patients with CML in chronic phase but its efficacy is generally transient in late stages CML (accelerated and blast crisis phases) [2–4]. Moreover, ima- tinib is not an optimal treatment for 30–35% of the patients in chronic phase; some patients have to discontinue treatment due to side effects, and others lose or do not achieve a complete cyto- genetic response, which significantly increases the risk of disease progression [2]. Thus, new therapeutic approaches that increase the cytogenetic response would be beneficial to CML patients. Nilotinib (Tasigna) is a rationally designed Bcr-Abl inhibitor with greater potency and specificity than imatinib [1]. Furthermore, it is ∗ Corresponding author at: Centre de Recherche en Cancérologie de l’Université Laval, L’Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, 9 rue McMahon, Québec G1R 2J6, Québec, Canada. Tel.: +1 418 525 4444x15537; fax: +1 418 691 5439. E-mail address: manuel.caruso@crhdq.ulaval.ca (M. Caruso). active against several Bcr-Abl mutants that are resistant to imatinib [1]. Nilotinib efficacy was first demonstrated in patients who failed imatinib therapy but its superiority over imatinib has been also confirmed in newly diagnosed CML patients [1,5–7]. Treatments that combine imatinib with other chemothera- peutic agents are also actively investigated in CML and ALL patients. The combination of imatinib with the nucleoside ana- log cytarabine was an obvious regimen to test in the clinic since cytarabine combined to interferon alpha was the previous stan- dard of care for CML before the imatinib era [8], and that several in vitro studies reported synergistic activities with imatinib and cytarabine [9–11]. A similar combination treatment could be envis- aged for nilotinib that is also able to synergize with cytarabine [12]. Nucleosides use specific transporters to enter into cells, with the equilibrative nucleoside transporter 1 (ENT1) being the main cytarabine transporter; its low abundance in acute myeloid leukemia blasts correlates with a lack of response to cytarabine treatment [13]. Few years ago it was reported that some p38 MAPK inhibitors could block nucleoside transport, and that this inhibi- tion occurs in a p38 MAPK-independent manner [14]. This finding was later extended to other types of kinase inhibitors that have different protein targets. Imatinib was tested and it was among the most efficient to block nucleoside transport; it inhibited uridine and thymidine transport by almost 70% at a 10 M concentration [15]. In another study, it was also reported that imatinib would inhibit the uptake of the nucleosidic analog fludarabine with a similar order of magnitude [16]. 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.06.012