Quantitative study of the drug efflux kinetics from sensitive and MDR human breast cancer cells.
Cancer multidrug resistance (MDR) is a major impediment to effective chemotherapy in human cancer, in which P-glycoprotein and Multidrug Resistance-Associated protein figure prominently. Design and exploitation of novel clinical MDR inhibitors is greatly hindered by a lack of understanding of drug efflux dynamics in drug-sensitive and resistant cells. The aim of our study was to provide a microelectrode method for measuring the multidrug transporter mediated efflux of doxorubicin as well as a corresponding data analysis method for quantifying the efflux kinetic parameters. We performed experiments using carbon fiber microelectrode to detect doxorubicin efflux from a monolayer of human breast cancer MCF-7 cells and derived MDR cells (MCF-7/ADR), established a material transport model and proposed a novel inverse method to quantitatively characterize the diffusion dynamics. The kinetic parameters of doxorubicin efflux from MCF-7 and MCF-7/ADR cells in the presence or absence of MDR inhibitors were estimated. Our investigations showed the average initial doxorubicin efflux rate of MCF-7/ADR that was 5.2 times faster than of MCF-7. After treatment by tetramethylpyrazine or verapamil, the drug efflux rate of the MCF-7/ADR cells was reduced by about half that of those without inhibitors. The novel methodology presented suggests new and expanded applications for computer-aided reconstruction of the drug efflux process, microelectrode design, and high-throughput drug screening.
Zhou
Chenguang
C
Pharmaceutical and Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China.
Shen
Peng
P
Cheng
Yiyu
Y
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D004058:Diffusion / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008839:Microelectrodes; D008954:Models, Biological; D011719:Pyrazines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D011719:Pyrazines; D004317:Doxorubicin; D014700:Verapamil; C017953:tetramethylpyrazine