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A Manual Small Molecule Screen Approaching High-throughput Using Zebrafish Embryos
Published on: November 8, 2014
Progress in characterizing ABC multidrug transporters in zebrafish
Joanna R Thomas1, William J E Frye1, Robert W Robey1
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Zebrafish have proved to be invaluable for modeling complex physiological processes shared by all vertebrate animals. Resistance of cancers and other diseases to drug treatment can occur owing to expression of the ATP-dependent multidrug transporters ABCB1, ABCG2, and ABCC1, either because of expression of these transporters by the target cells to reduce intracellular concentrations of cytotoxic drugs at barrier sites such as the blood-brain barrier (BBB) to limit penetration of drugs into privileged compartments, or by affecting the absorption, distribution, and excretion of drugs administered orally, through the skin, or directly into the bloodstream. We describe the drug specificity, cellular localization, and function of zebrafish orthologs of multidrug resistance ABC transporters with the goal of developing zebrafish models to explore the physiological and pathophysiological functions of these transporters. Finally, we provide context demonstrating the utility of zebrafish in studying cancer drug resistance. Our ultimate goal is to improve treatment of cancer and other diseases which are affected by ABC multidrug resistance transporters.
Insights
Zebrafish models reveal how ATP-dependent multidrug resistance transporters affect drug efficacy. Understanding these transporters is key to improving treatments for cancer and other diseases.
Area of Science:
- Comparative physiology
- Molecular biology
- Pharmacology
Background:
- ATP-dependent multidrug resistance transporters, including ABCB1, ABCG2, and ABCC1, contribute to drug resistance in various diseases.
- These transporters limit drug penetration into critical areas like the blood-brain barrier (BBB) and affect drug absorption, distribution, and excretion.
- Zebrafish share conserved physiological processes with other vertebrates, making them a valuable model organism.
Purpose of the Study:
- To characterize zebrafish orthologs of multidrug resistance ABC transporters.
- To investigate the drug specificity, cellular localization, and function of these zebrafish transporters.
- To establish zebrafish models for studying the physiological and pathophysiological roles of ABC transporters in drug resistance.
Main Methods:
- Identification and characterization of zebrafish ABC transporter genes.
- Analysis of transporter expression patterns and cellular localization using zebrafish models.
- Assessment of drug transport activity and specificity in zebrafish systems.
Main Results:
- Detailed description of the drug specificity, cellular localization, and function of zebrafish ABCB1, ABCG2, and ABCC1 orthologs.
- Demonstration of conserved functions of these transporters between zebrafish and mammals.
- Validation of zebrafish as a model for studying multidrug resistance mechanisms.
Conclusions:
- Zebrafish orthologs of ABC multidrug resistance transporters are functionally conserved and suitable for modeling drug resistance.
- These models will aid in understanding the role of ABC transporters in disease and in developing strategies to overcome drug resistance.
- The study highlights the utility of zebrafish in advancing cancer drug resistance research and improving therapeutic outcomes.
