Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells.
The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed.
Löfgren
Christina
C
Department of Hematology, Huddinge University Hospital, Stockholm, Sweden. christina.lofgren@hematol.hs.sll.se
Hjortsberg
Linn
L
Blennow
Malin
M
Lotfi
Kourosh
K
Paul
Christer
C
Eriksson
Staffan
S
Albertioni
Freidoun
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D009705:Nucleosides / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009705:Nucleosides; D014750:Vincristine; D003630:Daunorubicin