Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhodamine 123 (Rh123) is a fluorescent dye which locates in the mitochondria of cells. It is a substrate for P-glycoprotein (Pgp) and can, therefore, be used as a molecular probe in studies of the multidrug resistance (MDR) phenotype. However, not all MDR cells overexpress Pgp. In some, the MDR phenotype is associated with expression of an alternative transporter molecule, the multidrug resistance-associated protein (MRP). We have studied the accumulation and efflux of Rh123 in MDR cells having both Pgp-mediated and MRP-associated phenotypes. In the mouse tumour parental cell line, EMT6/P, Rh123 accumulates rapidly to reach plateau levels by 90 min. Confocal microscopy confirms a localisation to the mitochondria. In the MDR subline, EMT6/AR1.0, which overexpresses Pgp and which is 10-fold resistant to Rh123 cytotoxicity, accumulation is dramatically reduced. Efflux of Rh123 from both resistant and parental lines is rapid but can be inhibited by reduced temperature or by the presence of cyclosporin A (5 micrograms/ml). Efflux from the parental line is probably due to the presence of very low, but detectable, levels of Pgp but the existence of other mechanisms cannot be ruled out. In contrast, the human lung cancer parental cell line COR-L23/P, and its MRP-associated (but Pgp-negative) MDR subline, COR-L23/R (which is 23-fold resistant to Rh123 cytotoxicity), accumulate Rh123 at similar rates for the first 30 min. The curves then diverge so that, at 180 min, the resistant cells contain only 70% of the Rh123 of parental cells. Confocal microscopy demonstrates a similar distribution of fluorescence in resistant and parental cells. Essentially no efflux of Rh123 occurs from parental cells, whereas 70% of the content is lost from resistant cells over a period of 150 min. Such efflux may again be inhibited by reduced temperature but cyclosporin A (5 micrograms/ml) has little effect. These observations should be borne in mind when interpreting Rh123 efflux data in terms of MDR mechanisms.
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PMID:A comparison of rhodamine 123 accumulation and efflux in cells with P-glycoprotein-mediated and MRP-associated multidrug resistance phenotypes. 799 26

The cancer stem cell paradigm postulates that dysregulated tissue-specific stem cells or progenitor cells are precursors for cancer biogenesis. Consequently, identifying cancer stem cells is crucial to our understanding of cancer progression and for the development of novel therapeutic agents. In this study, we demonstrate that the overexpression of Twist in breast cells can promote the generation of a breast cancer stem cell phenotype characterized by the high expression of CD44, little or no expression of CD24, and increased aldehyde dehydrogenase 1 activity, independent of the epithelial-mesenchymal transition. In addition, Twist-overexpressing cells exhibit high efflux of Hoechst 33342 and Rhodamine 123 as a result of increased expression of ABCC1 (MRP1) transporters, a property of cancer stem cells. Moreover, we show that transient expression of Twist can induce the stem cell phenotype in multiple breast cell lines and that decreasing Twist expression by short hairpin RNA in Twist-overexpressing transgenic cell lines MCF-10A/Twist and MCF-7/Twist as well as in MDA-MB-231 partially reverses the stem cell molecular signature. Importantly, we show that inoculums of only 20 cells of the Twist-overexpressing CD44(+)/CD24(-/low) subpopulation are capable of forming tumors in the mammary fat pad of severe combined immunodeficient mice. Finally, with respect to mechanism, we provide data to indicate that Twist transcriptionally regulates CD24 expression in breast cancer cells. Taken together, our data demonstrate the direct involvement of Twist in generating a breast cancer stem cell phenotype through down-regulation of CD24 expression and independent of an epithelial-mesenchymal transition.
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PMID:Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. 2001 40

Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P < 0.05). The growth of stem and H460 cells treated with a combination of T. chinensis var. and cisplatin was also significantly inhibited (P < 0.05). Rh-123 was significantly accumulated in the intracellular region and showed delayed efflux in stem cells treated with T. chinensis var. (P < 0.05), compared to those treated with verapamil. T. chinensis var.-treated stem cells showed significant downregulation of the ABCC1, ABCB1, and LRP mRNA and MRP1, MDR1, and LRP (P < 0.05) compared to H460 cells. Thus, T. chinensis var.-mediated downregulation of MRP1, MDR1, and LRP might contribute to the reversal of drug resistance in non-small cell lung cancer stem cells.
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PMID:Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var. 2770 81

Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi and affects 8 million people worldwide. The main chemotherapy is based on benznidazole. The efficacy in the treatment depends on factors such as the parasite strain, which may present different sensitivity to treatment. In this context, the expression of ABC transporters has been related to chemotherapy failure. ABC transporters share a well-conserved ABC domain, responsible for ATP binding and hydrolysis, whose the energy released is coupled to transport of molecules through membranes. The most known ABC transporters are ABCB1 and ABCC1, involved in the multidrug resistance phenotype in cancer, given their participation in cellular detoxification. In T. cruzi, 27 ABC genes were identified in the genome. Nonetheless, only four ABC genes were characterized: ABCA3, involved in vesicular trafficking; ABCG1, overexpressed in strains naturally resistant to benznidazole, and P-glycoprotein 1 and 2, whose participation in drug resistance is controversial. Considering P-glycoprotein genes are related to ABCC subfamily in T. cruzi according to the demonstration using BLASTP alignment, we evaluated both ABCB1-like and ABCC-like activities in epimastigote and trypomastigote forms of the Y strain. The transport activities were evaluated by the efflux of the fluorescent dyes Rhodamine 123 and Carboxyfluorescein in a flow cytometer. Results indicated that there was no ABCB1-like activity in both T. cruzi forms. Conversely, results demonstrated ABCC-like activity in both epimastigote and trypomastigote forms of T. cruzi. This activity was inhibited by ABCC transport modulators (probenecid, indomethacin, and MK-571), by ATP-depleting agents (sodium azide and iodoacetic acid) and by the thiol-depleting agent N-ethylmaleimide. Additionally, the presence of ABCC-like activity was supported by direct inhibition of the thiol-conjugated compound efflux with indomethacin, characteristic of ABCC subfamily members. Taken together, the results provide the first description of native ABCC-like activity in T. cruzi epimastigote and trypomastigote forms, indicating that the study of the biological role for that thiol transporter is crucial to reveal new molecular mechanisms for therapeutic approaches in the Chagas disease.
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PMID:Functional Characterization of ABCC Proteins from Trypanosoma cruzi and Their Involvement with Thiol Transport. 2949 56