Robey RW, Polgar O, Deeken J, To KW, Bates SEABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26: 39-57
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 distribution, 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.
- SourceAvailable from: Rishil J Kathawala
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- "ABCG2 is localized apically in polarized cells, such as blood– brain barrier and intestinal enterocytes, where it can influence the oral absorption and pharmacokinetics of several anticancer drugs  . Human ABCG2 has a broad substrate profile that includes several anticancer drugs, ranging from organic anion conjugates, nucleoside analogs, organic dyes, and tyrosine kinase inhibitors (TKIs) to anthracyclines  . Although evidence of ABCG2 involvement in clinical MDR is accumulating, there is no lack of conflicting results between ABCG2 expression and drug response  . "
ABSTRACT: Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [(3)H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [(3)H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [(3)H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.Biochemical pharmacology 02/2014; 89(1). DOI:10.1016/j.bcp.2014.02.012 · 4.65 Impact Factor
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- "Another important MDR protein, breast cancer resistance protein BCRP (ABCG2), was cloned from a mitoxantrone-resistant subline of the breast cancer cell line MCF-7 . BCRP lends resistance to many cytostatics, including mitoxantrone and topotecan  . Its role in the resistance of ovarian cancer to topotecan is well described . "
ABSTRACT: Ovarian cancer is the leading cause of death among gynaecological malignancies. Multiple drug resistance makes cancer cells insensitive to chemotherapy. In this study, we developed six primary ovarian cancer cell lines (W1MR, W1CR, W1DR, W1VR, W1TR, and W1PR) resistant to drugs such as methotrexate, cisplatin, doxorubicin, vincristine, topotecan, and paclitaxel. A chemosensitivity assay MTT test was performed to assess drug cross-resistance. Quantitative real-time polymerase chain reaction and Western blot were also performed to determine mRNA and protein expression of genes involved in chemoresistance. We observed high cross-resistance to doxorubicin, vincristine, and paclitaxel in the cell lines resistant to these agents. We also found a significant correlation between resistance to these drugs and increased expression of P-gp. Two different mechanisms of topotecan resistance were observed in the W1TR and W1PR cell lines. We did not observe any correlation between MRP2 transcript and protein levels. Cell lines resistant to agents used in ovarian cancer treatment remained sensitive to methotrexate. The main mechanisms of drug resistance were due to P-gp expression in the doxorubicin, vincristine, and paclitaxel resistant cell lines and BCRP expression in the topotecan resistant cell line.01/2013; 2013:241763. DOI:10.1155/2013/241763
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- "(DOC) 20.LiJ,CusatisG,BrahmerJ,SparreboomA,RobeyRW,etal.(2007)Association ofvariantABCG2andthepharmacokineticsofepidermalgrowthfactor receptortyrosinekinaseinhibitorsincancerpatients.CancerBiolTher6:432– 438. 21.SparreboomA,GelderblomH,MarshS,AhluwaliaR,ObachR,etal.(2004) "
ABSTRACT: We have developed a rapid, simple and reliable, antibody-based flow cytometry assay for the quantitative determination of membrane proteins in human erythrocytes. Our method reveals significant differences between the expression levels of the wild-type ABCG2 protein and the heterozygous Q141K polymorphic variant. Moreover, we find that nonsense mutations on one allele result in a 50% reduction in the erythrocyte expression of this protein. Since ABCG2 polymorphisms are known to modify essential pharmacokinetic parameters, uric acid metabolism and cancer drug resistance, a direct determination of the erythrocyte membrane ABCG2 protein expression may provide valuable information for assessing these conditions or for devising drug treatments. Our findings suggest that erythrocyte membrane protein levels may reflect genotype-dependent tissue expression patterns. Extension of this methodology to other disease-related or pharmacologically important membrane proteins may yield new protein biomarkers for personalized diagnostics.PLoS ONE 11/2012; 7(11):e48423. DOI:10.1371/journal.pone.0048423 · 3.23 Impact Factor