ABCG2: determining its relevance in clinical drug resistance

Abstract

Multidrug resistance is a major obstacle to successful cancer treatment. One mechanism by which cells can become resistant to chemotherapy is the expression of ABC transporters that use the energy of ATP hydrolysis to transport a wide variety of substrates across the cell membrane. There are three human ABC transporters primarily associated with the multidrug resistance phenomenon, namely Pgp, MRP1, and ABCG2. All three have broad and, to a certain extent, overlapping substrate specificities, transporting the major drugs currently used in cancer chemotherapy. ABCG2 is the most recently described of the three major multidrug-resistance pumps, and its substrates include mitoxantrone, topotecan, irinotecan, flavopiridol, and methotrexate. Despite several studies reporting ABCG2 expression in normal and malignant tissues, no trials have thus far addressed the role of ABCG2 in clinical drug resistance. This gives us an opportunity to critically review the disappointing results of past clinical trials targeting Pgp and to propose strategies for ABCG2. We need to know in which tumor types ABCG2 contributes to the resistance phenotype. We also need to develop standardized assays to detect ABCG2 expression in vivo and to carefully select the chemotherapeutic agents and clinical trial designs. This review focuses on our current knowledge about normal tissue distrubution, tumor expression profiles, and substrates and inhibitors of ABCG2, together with lessons learned from clinical trials with Pgp inhibitors. Implications of SNPs in the ABCG2 gene affecting the pharmacokinetics of substrate drugs, including many non-chemotherapy agents and ABCG2 expression in the SP population of stem cells are also discussed.

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

“…Importantly, BCRP expression was observed in the synovial tissue from RA patients prior to therapy. This finding suggests that BCRP expression may be intrinsically associated with the inflammatory status of RA synovial tissue, rather than being a therapy-induced phenomenon as is commonly observed in anticancer treatment (27)(28)(29)(30).…”

“…BCRP expression and functional activity in cancer cells is highly variable (27). There may be epigenetic reasons for this, since aberrant promoter methylation inactivates the BCRP gene (31,32) or alternatively, some alterations in environmental conditions may up-regulate BCRP expression as observed under hypoxic conditions (30) or after folate supplementation to sustain folate homeostasis (33).…”

“…With respect to hematologic cells, BCRP has been identified in hematopoietic stem cells (40) and dendritic cells (41). From a treatment perspective, BCRP has been recognized to mediate the cellular export of several anticancer drugs (8,(27)(28)(29), and its expression has been associated with poor clinical outcome in the treatment of acute myeloid leukemia (42). Beyond this, DMARDs, such as MTX, sulfasalazine, and LEF, can also be extruded from cells via BCRP (8,10,13,43).…”

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

“…Overexpression of BCRP is associated with resistance to a wide range of different anticancer agents including mitoxantrone, camptothecins, anthracyclines, flavopiridol and antifolates (Table 1) (Assaraf, 2006;Robey et al, 2007). More recently, BCRP has also been shown to confer resistance to some purine analogues such as 9-(2-phosphonylmethoxyethyl)adenine and cladribine (Takenaka et al, 2007).…”

“…Several studies have been dedicated to determine relationships between the expression of BCRP in human cancers and clinical outcome for several drugs (summarised in Robey et al, 2007). Expression of BCRP has been reported in different types of leukaemia (AML and ALL) and solid tumours.…”