Combination of guanine arabinoside and Bcl-2 inhibitor YC137 overcomes the cytarabine resistance in HL-60 leukemia cell line.

Abstract

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.

• Authors: Rie Nishi, Takahiro Yamauchi, Eiju Negoro, Haruyuki Takemura, Takanori Ueda
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 4 Pg. 502-7 (Apr 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23320492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Japanese Cancer Association.

Chemical References

• Arabinonucleosides
• Proto-Oncogene Proteins c-bcl-2
• Thiazoles
• YC137
• Cytarabine
• 9-arabinofuranosylguanine

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis
• Arabinonucleosides (administration & dosage, pharmacology)
• Cytarabine (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Thiazoles (pharmacology)