A multidrug transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA

Greenebaum Cancer Center of the University of Maryland, Baltimore MD 21201, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/1999; 95(26):15665-70. DOI: 10.1073/pnas.95.26.15665
Source: PubMed


MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that displays an ATP-dependent reduction in the intracellular accumulation of anthracycline anticancer drugs in the absence of overexpression of known multidrug resistance transporters such as P glycoprotein or the multidrug resistance protein. RNA fingerprinting led to the identification of a 2.4-kb mRNA that is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells. The mRNA encodes a 655-aa [corrected] member of the ATP-binding cassette superfamily of transporters that we term breast cancer resistance protein (BCRP). Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected cells. BCRP is a xenobiotic transporter that appears to play a major role in the multidrug resistance phenotype of MCF-7/AdrVp human breast cancer cells.

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    • "yle et al . , 1998 ) . BCRP is a half - transporter member of the ABCG subfamily ( ABCG2 ) with a size of 72 kDa . BCRP probably functions as a homodimer . The expression of BCRP overlaps largely with that of P - gp , because the protein can be found in tissues such as the placenta , prostate , small intestine , brain , colon , liver , and ovary ( Doyle et al . , 1998 ) . Overexpression of BCRP is associated with resistance to a wide range of different anticancer agents : anthracyclines , mitoxantrone , flavopiridol , camptothecins , and antifolates ( Assaraf , 2006 ; Bihorel et al . , 2007 ; Robey et al . , 2007 ) . FIGURE 2 | Key HBMC correlations of compound 1 ."
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    ABSTRACT: Three new dimeric naphthoquinones, 5,4′-dihydroxy-1′-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,5′,8′-tetraone (1), 5′,8′-dihydroxy-5-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (2) and 8,5′,8′-trihydroxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY and J resolved. Compounds 1-3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1-3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism.
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    • "ATP-binding cassette (ABC) transporters, which transport a variety of molecules including chemotherapeutic drugs, are known to mediate the multidrug resistance of BC [4] [5] [6]. ABCG2 protein, also called breast cancer resistance protein (BCRP), belongs to the family of ABC transporters, mediating high levels of resistance to a variety of anticancer agents [7] [8] [9]. "
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    ABSTRACT: The genetic variants of the ATP-binding cassette, subfamily G, member 2 ( ABCG2 ) are known to be involved in developing cancer risk and interindividual differences in chemotherapeutic response. The polymorphisms in ABCG2 gene were genotyped by using PCR-RFLP assays. We found that ABCG2 G34A GA/AA genotype, C421A AA genotype, and haplotypes 34A-421C and 34G-421A were significantly associated with increased risk for developing breast carcinoma. Furthermore, ABCG2 C421A AA homozygote had a significant enhanced therapeutic response in patients with neoadjuvant anthracycline-based chemotherapy. Moreover, ABCG2 G34A AA genotype carriers displayed a longer OS in ER positive patients or PR positive patients after postoperative anthracycline-based chemotherapy. These results suggested that the ABCG2 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis for breast carcinoma patients.
    Full-text · Article · Nov 2015
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    • "Many intrinsic and acquired properties such as overexpression of anti-apoptotic proteins, drug efflux transporters , and detoxifying enzymes make CSCs resistant to anticancer drugs [16]. ATP-binding cassette sub-family G member 2 (ABCG2) is a major multidrug resistance pump that renders cancer cells resistant to chemotherapeutic drugs [17], which is a downstream target of sonic hedgehog (SHH)-glioma-associated oncogene homolog (GLI) pathway [18]. SHH signal is critical for the tumorigenesis of primary gastric CSCs that is mediated through Patched 1 (PTCH1) and smoothened (SMO) receptors, where the absence or presence of HH ligands controls the PTCH1 and SMO activities [19]. "
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    ABSTRACT: Drug resistance in gastric cancer largely results from the gastric cancer stem cells (GCSCs), which could be targeted to improve the efficacy of chemotherapy. In this study, we identified a subpopulation of GCSCs enriched in holoclones that expressed CD44(+)/Musashi-1(+) stem cell biomarkers, capable of self-renewal and proliferation. Enriched CD44(+)/Musashi-1(+) GCSCs demonstrated elevated expression of sonic hedgehog (SHH) and glioma-associated oncogene homolog 1 (GLI1), the well-known signaling pathway molecules involving in the drug resistance. Further, CD44(+)/Musashi-1(+) cells exhibited high drug efflux bump activity and were resistant to doxorubicin (Dox)-induced apoptosis, and unregulated the ATP-binding cassette sub-family G member 2 (ABCG2) expression,. The above effects on apoptosis were reversed in the presence of GLI inhibitors, GANT61 and GDC-0449, or by the knockdown of GLI1/SHH. Upon knockdown of GLI1, expression of ABCG2 was downregulated the antitumor effects were significantly improved as observed in the gastric cancer xenograft. Collectively, our study revealed that co-expression of CD44(+)/Musashi-1(+) could be used to identify GCSCs, which also accounts for the drug resistance in gastric cancer. SHH-GLI and its downstream effector ABCG2 could be better targeted to possibly improve the efficacy of chemotherapy in drug-resistant gastric cancers. Copyright © 2015. Published by Elsevier Ireland Ltd.
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