Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells.
The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.
Peng
Zhi
Z
The Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Xiao
Zhijian
Z
Wang
Yi
Y
Liu
Peng
P
Cai
Yinglin
Y
Lu
Shihong
S
Feng
Wenli
W
Han
Zhong Chao
ZC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D003630:Daunorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D034741:RNA, Small Interfering; D003630:Daunorubicin