Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 377, Issue 2, Pages 441-446Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2008.10.005
Keywords
Multidrug resistance; P-glycoprotein; Na+/H+ exchanger1; Intracellular pH
Categories
Funding
- General Program of the National Natural Science Foundation of China [30570358]
- Programs of Chinese Ministry of Personnel Foundation for Returned Overseas Chinese Senior Scholars
- Key Program of Science and Technology Commission Foundation of Tianjin China [08JCZDJC19100]
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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 pHi 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 pHi and time-dependent. Furthermore, the change of the P-gp expression was reversible with the pHi recovery. These data indicate that the tumor multidrug resistance (MDR) mediated by P-gp could be reversed by sustained intracellular acidification through clown-regulating the P-gp expression and activity, and there is a regulative link between the pHi and P-gp in K562/DOX cells. (C) 2008 Elsevier Inc. All rights reserved.
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