Inactivation of deoxycytidine kinase and overexpression of P-glycoprotein in AraC and daunorubicin double resistant leukemic cell lines

• Published in: Leukemia research 2003-05, Vol.27 (5), p.445-453
• Main Authors: Veuger, Marjan J.T, Honders, M.Willy, Spoelder, Hananja E, Willemze, Roel, Barge, Renée M.Y
• Format: Article
• Language: English
• Subjects: 2-Chloroadenosine - analogs & derivatives; 2-Chloroadenosine - pharmacology; Acute myeloid leukemia; Alternative Splicing; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Biological Transport - drug effects; Biological Transport - genetics; Buthionine Sulfoximine - pharmacology; Calcium Channel Blockers - pharmacology; Cytarabine (AraC); Cytarabine - pharmacology; Daunorubicin; Daunorubicin - pharmacology; Decitabine; Deoxyadenosines - pharmacology; Deoxycytidine kinase; Deoxycytidine Kinase - antagonists & inhibitors; Deoxycytidine Kinase - biosynthesis; Deoxycytidine Kinase - genetics; DNA Mutational Analysis; DNA, Neoplasm - genetics; Double resistance; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Glutathione - antagonists & inhibitors; Hematologic and hematopoietic diseases; Humans; Idarubicin - pharmacology; Leukemia - genetics; Leukemia - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Methotrexate - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; P-glycoprotein; Rats; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured - drug effects; Verapamil - pharmacology
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/S0145-2126(02)00224-2

AraC resistance in vitro is explained by inactivation of dCK, while resistance to DNR is described by overexpression of multidrug efflux pumps like Pgp or MRP. Thusfar, no correlation between resistance mechanisms in vitro and in patients with AML has been documented. We generated AraC and DNR double resistant cell lines to investigate resistance mechanisms of both agents. In these cell lines involvement of dCK was extensively investigated and Pgp expression and activity was determined. Our data implicate that similar resistance mechanisms like inactivation of dCK coincided by alternatively spliced dCK forms and overexpression of Pgp are induced in single—as well as in double resistant leukemic cell lines.