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Molecules 2014, 19(3), 3356-3375; doi:10.3390/molecules19033356

Nilotinib Enhances the Efficacy of Conventional Chemotherapeutic Drugs in CD34+CD38 Stem Cells and ABC Transporter Overexpressing Leukemia Cells

State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
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Received: 21 October 2013 / Revised: 11 March 2014 / Accepted: 11 March 2014 / Published: 19 March 2014
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Abstract

Incomplete chemotherapeutic eradication of leukemic CD34+CD38 stem cells is likely to result in disease relapse. The purpose of this study was to evaluate the effect of nilotinib on eradicating leukemia stem cells and enhancing the efficacy of chemotherapeutic agents. Our results showed that ABCB1 and ABCG2 were preferentially expressed in leukemic CD34+CD38 cells. Nilotinib significantly enhanced the cytotoxicity of doxorubicin and mitoxantrone in CD34+CD38 cells and led to increased apoptosis. Moreover, nilotinib strongly reversed multidrug resistance and increased the intracellular accumulation of rhodamine 123 in primary leukemic blasts overexpressing ABCB1 and/or ABCG2. Studies with ABC transporter-overexpressing carcinoma cell models confirmed that nilotinib effectively reversed ABCB1- and ABCG2-mediated drug resistance, while showed no significant reversal effect on ABCC1- and ABCC4-mediated drug resistance. Results from cytotoxicity assays showed that CD34+CD38 cells exhibited moderate resistance (2.41-fold) to nilotinib, compared with parental K562 cells. Furthermore, nilotinib was less effective in blocking the phosphorylation of Bcr-Abl and CrkL (a substrate of Bcr-Abl kinase) in CD34+CD38 cells. Taken together, these data suggest that nilotinib particularly targets CD34+CD38 stem cells and MDR leukemia cells, and effectively enhances the efficacy of chemotherapeutic drugs by blocking the efflux function of ABC transporters. View Full-Text
Keywords: nilotinib; leukemia stem cells; multidrug resistance; ATP-binding cassette transporters; ABCG2; ABCB1 nilotinib; leukemia stem cells; multidrug resistance; ATP-binding cassette transporters; ABCG2; ABCB1
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Wang, F.; Wang, X.-K.; Shi, C.-J.; Zhang, H.; Hu, Y.-P.; Chen, Y.-F.; Fu, L.-W. Nilotinib Enhances the Efficacy of Conventional Chemotherapeutic Drugs in CD34+CD38 Stem Cells and ABC Transporter Overexpressing Leukemia Cells. Molecules 2014, 19, 3356-3375.

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