Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance
Open Access
- 3 November 2008
- journal article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 8 (1), 318
- https://doi.org/10.1186/1471-2407-8-318
Abstract
Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2), epirubicin (MCF-7EPI), paclitaxel (MCF-7TAX-2), or docetaxel (MCF-7TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.Keywords
This publication has 54 references indexed in Scilit:
- PAC Fixed Dose: Pharmacokinetics of a 1-Hour Paclitaxel Infusion and Comparison to BSA-Normalized Drug DosingOncology Research and Treatment, 2006
- cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistanceBreast Cancer Research and Treatment, 2005
- Cyclosporin A Is a Broad-Spectrum Multidrug Resistance ModulatorClinical Cancer Research, 2005
- Molecular mechanisms of drug resistanceThe Journal of Pathology, 2005
- Inhibition study of rabbit liver cytosolic reductases involved in daunorubicin toxicationJournal of Enzyme Inhibition and Medicinal Chemistry, 2005
- Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancerAnti-Cancer Drugs, 2003
- Multidrug resistance in cancer: role of ATP–dependent transportersNature Reviews Cancer, 2002
- Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1British Journal of Haematology, 2001
- Low-Level Doxorubicin Resistance in Benzo[a]pyrene-Treated KB-3-1 Cells Is Associated with Increased LRP Expression and Altered Subcellular Drug DistributionToxicology and Applied Pharmacology, 2000
- Relationship between the inhibition of azidopine binding to P-glycoprotein by MDR modulators and their efficiency in restoring doxorubicin intracellular accumulationCancer Letters, 1996