Down-regulation of P-glycoprotein expression by sustained intracellular acidification in K562/Dox cells.
We have investigated the involvement of intracellular pH (pH(i)) in the regulation of P-glycoprotein (P-gp) in K562/DOX cells. The selective Na(+)/H(+) exchanger1 (NHE1) inhibitor cariporide and the "high K(+)" buffer were used to induce the sustained intracellular acidification of the K562/DOX cells that exhibited more alkaline pH(i) than the K562 cells. The acidification resulted in the decreased P-gp activity with increased Rhodamine 123 (Rh123) accumulation in K562/DOX cells, which could be blocked by the P-gp inhibitor verapamil. Moreover, the acidification decreased MDR1 mRNA and P-gp expression, and promoted the accumulation and distribution of doxorubicin into the cell nucleus. Interestingly, these processes were all pH(i) and time-dependent. Furthermore, the change of the P-gp expression was reversible with the pH(i) recovery. These data indicate that the tumor multidrug resistance (MDR) mediated by P-gp could be reversed by sustained intracellular acidification through down-regulating the P-gp expression and activity, and there is a regulative link between the pH(i) and P-gp in K562/DOX cells.
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Ying
Y
Lu
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China. Electronic address: pang@ihcams.ac.cn.
Tianxiang
T
Pang
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Jianxiang
J
Wang
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Dongsheng
D
Xiong
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Li
L
Ma
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Bin
B
Li
State key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road No. 288, Tianjin 300020, China.
Qinghua
Q
Li
Department of Molecular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Shigeo
S
Wakabayashi
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000143:Acids / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020014:K562 Cells; D020112:Rhodamine 123 / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000143:Acids; D000903:Antibiotics, Antineoplastic; D027682:Cation Transport Proteins; D006146:Guanidines; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D020112:Rhodamine 123; C093373:cariporide; D004317:Doxorubicin; D014700:Verapamil