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Non-P-glycoprotein drug export mechanisms of multidrug resistance
1University of Arizona Cancer Center, Bone Marrow Transplant Program, Tucson 85724-5024, USA.
Abstract:
A variety of cellular mechanisms of multidrug resistance (MDR) have been identified in human drug-resistant cell lines, and may play an important role in the clinical response of hematologic malignancies to chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux is the most well-characterized cellular mechanism of MDR; however, several other non-P-gp membrane transporter proteins have also been implicated in the development of an MDR phenotype in hematologic malignancies. These include the MDR-related protein (MRP), the lung-resistance protein (LRP), and the transporter of antigenic peptides (TAP). The transporter proteins MRP and TAP are both members of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transmembrane transporters, but each has distinct differences in substrate specificity. Despite effective modulation of P-gp, one or more of these alternate mechanisms of drug resistance may contribute to an MDR phenotype in tumor cell lines. Development of multifunctional MDR modulators or novel therapeutics may be necessary to effectively circumvent MDR in hematologic malignancies.
Insights
Multidrug resistance (MDR) in hematologic malignancies involves P-glycoprotein (P-gp) and other transporters like MRP and TAP. Targeting these alternative mechanisms is crucial for effective chemotherapy.
Area of Science:
- Cellular and Molecular Biology
- Pharmacology
- Hematology
Background:
- Multidrug resistance (MDR) is a significant challenge in treating hematologic malignancies.
- P-glycoprotein (P-gp) is a well-known mediator of MDR through drug efflux.
- Alternative MDR mechanisms involving other membrane transporters are implicated in treatment failure.
Purpose of the Study:
- To review the cellular mechanisms of MDR in hematologic malignancies beyond P-gp.
- To highlight the role of non-P-gp transporters such as MRP, LRP, and TAP.
- To discuss the implications for chemotherapy response and therapeutic strategies.
Main Methods:
- Literature review of cellular mechanisms of multidrug resistance.
- Analysis of the role of various membrane transporter proteins in MDR.
- Examination of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family.
Main Results:
- P-gp is a primary MDR mechanism, but other transporters contribute significantly.
- MDR-related protein (MRP), lung-resistance protein (LRP), and transporter of antigenic peptides (TAP) are key non-P-gp mediators.
- These transporters, including MRP and TAP from the ABC family, exhibit distinct substrate specificities.
- Alternative resistance mechanisms can persist even when P-gp is modulated.
Conclusions:
- Multiple cellular mechanisms, including non-P-gp transporters, contribute to MDR in hematologic cancers.
- Effective circumvention of MDR may require targeting these alternative pathways.
- Development of novel, multifunctional MDR modulators or therapeutics is essential for improved clinical outcomes.