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Combination of guanine arabinoside and Bcl-2 inhibitor YC137 overcomes the cytarabine resistance in HL-60 leukemia cell line
Article first published online: 24 FEB 2013
© 2013 Japanese Cancer Association
Volume 104, Issue 4, pages 502–507, April 2013
How to Cite
(Cancer Sci 2013; 104: 502–507)
- Issue published online: 22 MAR 2013
- Article first published online: 24 FEB 2013
- Accepted manuscript online: 15 JAN 2013 07:54AM EST
- Manuscript Accepted: 27 DEC 2012
- Manuscript Revised: 24 DEC 2012
- Manuscript Received: 23 AUG 2012
- Ministry of Education, Culture, Sports, Science, and Technology of Japan. Grant Number: 23501307
- Japan Gout Research Foundation
Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia. After being transported into leukemic cells, ara-C is phosphorylated, by several enzymes including deoxycytidine kinase (dCK), to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Therefore, the cytotoxicity of ara-C depends on the production of ara-CTP and the induction of apoptosis. Here, we established a new ara-C-resistant acute myeloid leukemia cell line (HL-60/ara-C60) with dual resistance characteristics of the anti-antimetabolic character of decreased ara-CTP production and an increase in the antiapoptotic factors Bcl-2 and Bcl-XL. We further attempted to overcome resistance by augmenting ara-CTP production and stimulating apoptosis. A relatively new nucleoside analog, 9-β-d-arabinofuranosylguanine (ara-G), and the small molecule Bcl-2 antagonist YC137 were used for this purpose. HL-60/ara-C60 was 60-fold more ara-C-resistant than the parental HL-60 cells. HL-60/ara-C60 cells exhibited low dCK protein expression, which resulted in decreased ara-CTP production. HL-60/ara-C60 cells were also refractory to ara-C-induced apoptosis due to overexpression of Bcl-2 and Bcl-XL. Combination treatment of ara-C with ara-G augmented the dCK protein level, thereby increasing ara-CTP production and subsequent cytotoxicity. Moreover, the combination of ara-C with YC137 produced a greater amount of apoptosis than ara-C alone. Importantly, the three-drug combination of ara-C, ara-G and YC137 provided greater cytotoxicity than ara-C+ara-G or ara-C+YC137. These findings suggest possible combination strategies for overcoming ara-C resistance by augmenting ara-CTP production and reversing refractoriness against the induction of apoptosis in ara-C resistant leukemic cells.