Effects of iron deprivation on multidrug resistance of leukemic K562 cells.
OBJECTIVE
Multidrug resistance (MDR) compromises the efficacy of chemotherapy. Many approaches have been used to reduce MDR; however, the results are poor. It has been reported that iron deprivation downregulates MDR genes. To investigate the relationship of iron with MDR and early growth response gene-1 (EGR1), we investigated the effect of iron deprivation on expression and/or function of multidrug resistance-1 (MDR1), early growth response gene-1 (EGR1), ferritin heavy chain gene (H-Fn) and MDR1-encoded P-glycoprotein (P-gp) in the K562 leukemic cell line.


METHODS
The cells were stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and incubated with either FeCl(3) or the iron-chelating drug DFO. The mRNA levels of MDR1, EGR1 and H-Fn were detected by RT-PCR. The protein expression and function of P-gp were measured by immunohistochemical staining and flow cytometry, respectively.


RESULTS
DFO significantly reduced the intracellular iron level, and led to approximately 70% reduction of MDR1 mRNA, approximately 50% of reduction of H-Fn mRNA and approximately 30% reduction of P-gp protein in TPA-differentiated K562 cells. The P-gp pump function, measured by daunorubicin exclusion, was also reduced by DFO treatment.


CONCLUSIONS
These results suggest a close relationship between iron deprivation and reduced MDR1/P-gp expression and function. DFO may be used together with chemotherapeutic drugs to achieve better clinical efficacy.
Fang
Dingzhu
D
Department of Pediatrics, Affiliated XinHua Hospital, Jiaotong University, Shanghai, China.
Bao
Yixiao
Y
Li
Xiaobin
X
Liu
Fang
F
Cai
Kang
K
Gao
Ju
J
Liao
Qingkui
Q
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002712:Chlorides; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D010703:Phorbol Esters; D001052:Apoferritins; D007501:Iron; C024555:ferric chloride