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ABC multidrug transporters: structure, function and role in chemoresistance
1University of Guelph, Department of Molecular & Cellular Biology, Guelph Ontario, N1G 2W1, Canada. fsharom@uoguelph.ca
Pharmacogenomics
|December 25, 2007
Summary
Multidrug efflux pumps like P-glycoprotein (ABCB1) contribute to cancer chemoresistance. Genetic variations in these ATP-binding cassette (ABC) transporters may influence drug response, but their clinical impact is still debated.
Area of Science:
- Molecular Biology and Pharmacology
- Cancer Biology and Therapeutics
- Genetics and Personalized Medicine
Background:
- Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps, P-glycoprotein (ABCB1), MRP1 (ABCC1), and ABCG2 (BCRP), are critical for cellular defense against xenobiotics.
- These transporters are implicated in chemoresistance in human tumors, limiting the efficacy of cancer chemotherapy.
- The interaction of drugs with these efflux pumps involves hydrophobic and H-bonding interactions within their substrate-binding pockets.
Purpose of the Study:
- To review the role of ABC-superfamily multidrug efflux pumps in chemoresistance and normal physiology.
- To discuss the challenges and controversies surrounding the clinical application of efflux pump modulators in cancer treatment.
- To explore the potential impact of single nucleotide polymorphisms (SNPs) in ABC drug-efflux pumps on drug response and disease susceptibility.
Main Methods:
- Literature review and synthesis of existing research on ABC transporters, chemoresistance, and pharmacogenetics.
- Analysis of the functional interactions between drugs and efflux pump proteins.
- Discussion of genetic variations (genotypes and haplotypes) and their potential effects on transporter expression and function.
Main Results:
- ABC transporters are crucial for protecting tissues but also mediate drug resistance in tumors.
- Clinical trials using efflux pump modulators have yielded disappointing results.
- The precise role of genetic polymorphisms in ABC transporters regarding drug response and disease susceptibility remains unclear and controversial.
Conclusions:
- While ABC efflux pumps are vital for normal physiology and contribute to cancer chemoresistance, their modulation for therapeutic benefit has faced significant hurdles.
- Further research is needed to elucidate the complex effects of genetic variations in these transporters on clinical outcomes.
- The clinical significance of ABC transporter genotypes and haplotypes in cancer therapy and disease susceptibility requires further investigation and validation.
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