title: 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: Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors: Rie
authors: R
authors: Nishi
authors: Takahiro
authors: T
authors: Yamauchi
authors: Eiju
authors: E
authors: Negoro
authors: Haruyuki
authors: H
authors: Takemura
authors: Takanori
authors: T
authors: Ueda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001087:Arabinonucleosides; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; C493272:YC137; D003561:Cytarabine; C028771:9-arabinofuranosylguanine