Resistance of human leukemic cell lines to 1-beta-D-arabinofuranosylcytosine: characterization of an experimental model.
1-beta-D-arabinofuranosylcytosine (ara-C) is an antimetabolite used for the treatment of acute myelogenous leukemia. The ability of ara-C to kill neoplastic cells has been correlated to the induction of apoptosis. The clinical use of ara-C is limited by the development of drug resistance. Alterations in drug-induced apoptosis play a critical role in ara-C resistance. In particular, the proto-oncogene bcl-2 has been implicated in this phenomenon. To better understand the molecular basis of the role of bcl-2 in ara-C resistance, we investigated the relationship between the cytotoxic effect of ara-C, the expression levels and the subcellular localization of bcl-2 in three human leukemic cell lines (HL-60, KG1, J111). We have also evaluated the effects of ara-C on the J111 leukemic cell line (showing the lowest levels of Bcl-2 and the highest sensitivity to ara-C) overexpressing the bcl-2 oncogene. The model we developed here will allow further studies on the role of post-translational events involving bcl-2 (such as translocation and/or phosphorylation) in the cellular response to ara-C treatment.
Gariboldi
M B
MB
Dipartimento di Biologia Strutturale e Funzionale, Section of Pharmacology, University of Insubria, I-20129 Milan, Italy.
Ravizza
R
R
Marras
E
E
Perletti
G
G
De Simone
A
A
Piccinini
F
F
Monti
E
E
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000964:Antimetabolites, Antineoplastic; D007527:Isoenzymes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha