ABC transporters in the balance: is there a role in multidrug resistance?
1Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Bldg. 10, Rm. 12C103, Bethesda, MD 20892, USA.
Abstract:
Drug resistance can occur at several levels and is the major cause of treatment failure in oncology. The ABC (ATP-binding cassette) transporters, beginning with the discovery of P-glycoprotein (Pgp) almost 30 years ago, have been intensively studied as potential mediators of drug resistance. Although we understand that drug resistance is almost certainly multifactorial, investigators have attempted to link anticancer drug resistance to overexpression of ABC transporters and the consequent reduction in drug accumulation. A body of evidence implicated Pgp as being important in clinical outcome; however, critical studies aimed at proving the hypothesis using Pgp inhibitors in clinical trials have to date failed. Identification of the MRP (multidrug resistance protein)/ABCC subfamily expanded the possible mechanisms of reduced drug accumulation, and the discovery of ABCG2 added a new chapter in these investigations. Correlative studies examining ABCG2 and the ABCC subfamily members in clinical drug resistance have been less avidly pursued, while basic molecular studies of structure and function have proceeded briskly. Recently, studies have focused on how single nucleotide polymorphism in multidrug transporters might affect the pharmacokinetics and pharmacodynamics of anticancer agents. These studies suggest an important role for ABC transporters in pharmacology, independent of the ultimate determination of their role in multidrug resistance.
Insights
Drug resistance in cancer is a major challenge. ATP-binding cassette (ABC) transporters, like P-glycoprotein (Pgp), are studied for their role, but clinical trials with Pgp inhibitors have failed, suggesting complex mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance is a primary cause of cancer treatment failure.
- ATP-binding cassette (ABC) transporters, including P-glycoprotein (Pgp), have been investigated as mediators of this resistance.
- Despite extensive research, the direct clinical impact of targeting Pgp in overcoming drug resistance remains inconclusive.
Purpose of the Study:
- To review the multifaceted role of ABC transporters in anticancer drug resistance.
- To discuss the evolution of research from Pgp to other ABC transporters like MRP/ABCC and ABCG2.
- To explore emerging research on single nucleotide polymorphisms (SNPs) in ABC transporters and their impact on drug efficacy.
Main Methods:
- Literature review and synthesis of existing research on ABC transporters and drug resistance.
- Analysis of evidence implicating Pgp and other ABC transporters in clinical outcomes.
- Examination of studies investigating the functional and genetic aspects of ABC transporters.
Main Results:
- While Pgp has been extensively studied, clinical trials with Pgp inhibitors have not definitively proven its role in overcoming resistance.
- The discovery of MRP/ABCC and ABCG2 subfamilies has broadened the understanding of drug efflux mechanisms.
- Emerging research highlights the potential influence of ABC transporter SNPs on drug pharmacokinetics and pharmacodynamics.
Conclusions:
- The role of ABC transporters in clinical drug resistance is complex and likely multifactorial.
- Further correlative studies are needed for ABCC and ABCG2 transporters in clinical settings.
- ABC transporters play a significant role in drug pharmacology, irrespective of their definitive contribution to multidrug resistance.
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