Decitabine, a DNA methyltransferase inhibitor, reduces P-glycoprotein mRNA and protein expressions and increases drug sensitivity in drug-resistant MOLT4 and Jurkat cell lines.
Multidrug resistance (MDR) is a major clinical obstacle in the treatment of several cancers including hematological malignancies and solid tumors. The ATP-binding cassette transporter B1 (ABCB1) gene and its product, P-glycoprotein (P-gp), is one molecule that is involved in drug resistance. Here we report on the effect of decitabine (5-aza-2'-deoxycytidine), an inhibitor of DNA methyltransferase, on ABCB1 mRNA and P-gp expressions in drug-resistant MOLT4 and Jurkat cells. We found that decitabine treatment reduced ABCB1 mRNA and P-gp expressions in MOLT4/daunorubicin-resistant and Jurkat/doxorubicin-resistant cells. The decrease in the expression of ABCB1 mRNA and P-gp was accompanied by increased sensitivity to anticancer drugs in both drug-resistant cell lines. Our data suggest that DNA methylation is one of the mechanisms underlying ABCB1/P-gp overexpression in drug-resistant hematopoietic cell lines. The modulation of ABCB1/P-gp by DNA methylation inhibitors may be an effective strategy to overcome P-gp-related drug resistance.
Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. knjond@toyaku.ac.jp
Kenji
K
Onda
Rieko
R
Suzuki
Sachiko
S
Tanaka
Hirokazu
H
Oga
Kitaro
K
Oka
Toshihiko
T
Hirano
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine