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Novel mechanisms of drug resistance in leukemia
1University of Maryland Greenebaum Cancer Center, Baltimore 21201, USA.
Abstract:
A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanism, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, but more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with outcome in AML. Despite these findings, functional efflux assays indicate the presence of non-Pgp, non-MRP transporters in AML. Recently, a novel ABC transporter, breast cancer resistance protein (BCRP) was cloned and sequenced in our laboratory. Transfection and overexpression of BCRP in drug-sensitive cells confers drug-resistance to the cells. BCRP is a half-transporter, and may homodimerize or form heterodimers (with a yet unknown half-transporter) to produce an active transport complex. Relatively high expression of BCRP mRNA is observed in approximately 30% of AML cases, suggesting a potential role for this new transporter in drug resistance in leukemia.
Insights
Drug resistance in acute leukemia is a major challenge. This review explores intracellular drug transport mechanisms, focusing on the novel breast cancer resistance protein (BCRP) and its potential role in chemotherapy resistance in acute myeloid leukemia (AML).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance is a key challenge in treating acute leukemia.
- Mechanisms include impaired apoptosis and reduced intracellular drug levels.
- Intracellular drug transport is a critical factor in chemotherapy resistance.
Purpose of the Study:
- To review intracellular drug transport resistance mechanisms in acute leukemia.
- To highlight the role of ATP-binding cassette (ABC) transporters, including P-glycoprotein (Pgp), multidrug resistance protein (MRP), and lung resistance protein (LRP).
- To introduce the novel ABC transporter, breast cancer resistance protein (BCRP), and its potential contribution to drug resistance.
Main Methods:
- Review of existing literature on drug resistance mechanisms in acute leukemia.
- Focus on ATP-binding cassette (ABC) transporters involved in drug efflux.
- Discussion of the cloning, sequencing, and functional characterization of BCRP.
Main Results:
- Expression of Pgp, MRP, and LRP has been correlated with prognosis in acute myeloid leukemia (AML), though with varying degrees of certainty.
- Functional assays suggest the presence of non-Pgp, non-MRP transporters in AML.
- Overexpression of the novel BCRP transporter in drug-sensitive cells confers drug resistance.
- BCRP mRNA is highly expressed in approximately 30% of AML cases.
Conclusions:
- BCRP is a novel ABC half-transporter implicated in drug resistance in acute myeloid leukemia (AML).
- BCRP may form active transport complexes through homodimerization or heterodimerization.
- The high prevalence of BCRP expression in AML suggests its significant role in clinical drug resistance.
- Further research into BCRP and other novel transporters is crucial for overcoming chemotherapy resistance.