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)

Membrane vesicles prepared from cells expressing the multidrug resistance-associated protein (MRP) transport glutathione S-conjugates of hydrophobic substrates in an ATP dependent manner. Purified MRP possesses ATPase activity which can be further stimulated by anticancer drugs or leukotriene C4. However, the detailed relationship between ATP hydrolysis and drug transport has not been established. How the ATPase activity of MRP is regulated in the cell is also not known. In this report, we have examined the effects of different nucleotides on the ATPase activity of purified MRP. We have found that pyrimidine nucleoside triphosphates have little effect on enzymatic activity. In contrast, purine nucleotides dATP, dGTP, and adenosine 5'-(beta,gamma-imido)triphosphate function as competitive inhibitors. Somewhat unexpectedly, low concentrations of all the nucleoside diphosphates (NDPs) tested, except UDP, stimulate the ATPase activity severalfold. ADP or GDP at higher concentrations was inhibitory, reflecting NDP binding to the substrate site. On the other hand, the enhancement of hydrolysis at low NDP concentrations must reflect interactions with a separate site. Therefore, we postulate the presence of at least two types of nucleotide binding sites on the MRP, a catalytic site(s) to which ATP preferentially binds and is hydrolyzed and a regulatory site to which NDPs preferentially bind and stimulate hydrolysis. Interestingly, the stimulatory effects of drugs transported by MRP and NDPs are not additive, i.e. drugs are not able to further stimulate the NDP-activated enzyme. Hence, the two activation pathways intersect at some point. Since both nucleotide binding domains of MRP are likely to be required for drug stimulation of ATPase activity, the two sites that we postulate may also involve both domains.
 ...
PMID:Stimulation of ATPase activity of purified multidrug resistance-associated protein by nucleoside diphosphates. 972 96

In contrast to the parent triptycene (code name TT0), triptycene bisquinone (code name TT2) is cytostatic (IC50: 300 nM) and cytotoxic (IC50: 230 nM) in wild-type (WT), drug-sensitive HL-60 cells (HL-60-S) at day 4. Therefore, the effects of this new quinone antitumor drug were assessed and compared to those of daunorubicin (DAU, daunomycin) in the multidrug-resistant (MDR) HL-60-RV and HL-60-R8 sublines, which respectively overexpress P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). In contrast to DAU, which loses its cytostatic [resistance factors (RFs): 22.9-35.7] and cytotoxic (RFs: 23.8-31.3) activities in MDR sublines, TT2 decreases tumor cell proliferation (RFs: 0.9-1.3) and viability (RFs: 0.9-1.5) as effectively in HL-60-S as in HL-60-RV and HL-60-R8 cells at days 2 and 4. Similarly, DAU inhibits the rate of DNA synthesis less effectively in MDR than in parental HL-60 cells (RFs: 8.1-11.9) but TT2 decreases the incorporation of 3[H]-thymidine into DNA to the same degree in HL-60-S, HL-60-RV and HL-60-R8 cells (RFs: 1.2). In contrast to DAU, which is inactive, the advantage of TT2 is its ability to block the cellular transport of purine and pyrimidine nucleosides in WT tumor cells, an effect which persists in both MDR sublines (RFs: 1.0-1.2). Moreover, the concentrations of DAU which induce maximal DNA cleavage in HL-60-S cells at 24 h lose all or most of their DNA-damaging activity in HL-60-RV and HL-60-R8 cells, whereas treatments with 4 microM TT2 produce similar peaks of DNA fragmentation in all WT and MDR cell lines. Since TT2 not only mimics the antitumor effects of DAU but also blocks nucleoside transport and retains its effectiveness in MDR cells that have already developed different mechanisms of resistance to DAU, this new quinone antitumor drug might be valuable to develop new means of polychemotherapy.
 ...
PMID:A synthetic triptycene bisquinone, which blocks nucleoside transport and induces DNA fragmentation, retains its cytotoxic efficacy in daunorubicin-resistant HL-60 cell lines. 1171 86

MRP8 (ABCC11) is a recently identified cDNA that has been assigned to the multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporters, but its functional characteristics have not been determined. Here we examine the functional properties of the protein using transfected LLC-PK1 cells. It is shown that ectopic expression of MRP8 reduces basal intracellular levels of cAMP and cGMP and enhances cellular extrusion of cyclic nucleotides in the presence or absence of stimulation with forskolin or SIN-1A. Analysis of the sensitivity of MRP8-overexpressing cells revealed that they are resistant to a range of clinically relevant nucleotide analogs, including the anticancer fluoropyrimidines 5'-fluorouracil (approximately 3-fold), 5'-fluoro-2'-deoxyuridine (approximately 5-fold), and 5'-fluoro-5'-deoxyuridine (approximately 3-fold), the anti-human immunodeficiency virus agent 2',3'-dideoxycytidine (approximately 6-fold) and the anti-hepatitis B agent 9'-(2'-phosphonylmethoxynyl)adenine (PMEA) (approximately 5-fold). By contrast, increased resistance was not observed for several natural product chemotherapeutic agents. In accord with the notion that MRP8 functions as a drug efflux pump for nucleotide analogs, MRP8-transfected cells exhibited reduced accumulation and increased efflux of radiolabeled PMEA. In addition, it is shown by the use of in vitro transport assays that MRP8 is able to confer resistance to fluoropyrimidines by mediating the MgATP-dependent transport of 5'-fluoro-2'-deoxyuridine monophosphate, the cytotoxic intracellular metabolite of this class of agents, but not of 5'-fluorouracil or 5'-fluoro-2'-deoxyuridine. We conclude that MRP8 is an amphipathic anion transporter that is able to efflux cAMP and cGMP and to function as a resistance factor for commonly employed purine and pyrimidine nucleotide analogs.
 ...
PMID:MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)adenine. 1276 37

Multidrug resistance (MDR) is the main cause of diminished success in cancer chemotherapy. ABC transport proteins are considered to be one important factor of MDR. Besides P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2), Multidrug Resistance-associated Protein 1 (MRP1, ABCC1) is associated with non-response to chemotherapy in different cancers. While considerable effort was spent in overcoming MDR during the last two decades, almost nothing is known with respect to activators of transport proteins. In this work we present certain pyrrolo[3,2-d]pyrimidine derivatives with variations at positions 4 and 5 and purine analogs with variations at position 6 as novel activators of MRP1-mediated transport of the MRP1 substrate calcein AM and the anticancer drug daunorubicin in low nanomolar concentration range. Two different MRP1 overexpressing cell lines were used, the doxorubicin-selected human lung cancer cell line H69 AR and the transfected Madin-Darby Canine Kidney cell line MDCK II MRP1. No effect was observed in the sensitive counterparts H69 and MDCK II wild type (wt). Derivatives with higher molecular weight possessed also inhibitory properties at low micromolar concentrations, although most compounds were rather poor MRP1 inhibitors. Purine analogs derived from potent MRP1 inhibitors of the pyrrolopyrimidine class showed equal activating, but no inhibiting effects at all. All tested compounds were non-toxic and had only minor impact on P-gp or BCRP, showing no inhibition or activation.
 ...
PMID:Pyrrolopyrimidine derivatives and purine analogs as novel activators of Multidrug Resistance-associated Protein 1 (MRP1, ABCC1). 2781 Mar 53

The multidrug resistance (MDR) phenomenon in cancer cells is the major obstacle leading to failure of chemotherapy accompanied by the feature of intractable and recurrence of cancers. As significant contributors that cause MDR, ABC superfamily proteins can transport the chemotherapeutic drugs out of the tumor cells by the energy of adenosine triphosphate (ATP) hydrolysis, thereby reducing their intracellular accumulation. The ABC transports like ABCB1, ABCC1 and ABCG2 have been extensively studied to develop modulators for overcoming MDR. To date, no reversal agents have been successfully marketed for clinical application, and little information about the ABC proteins bound to specific inhibitors is known, which make the design of MDR inhibitors with potency, selectivity and low toxicity a major challenge. In recent years, it has been increasingly recognized that pyrimidine-based derivatives have the potential for reversing ABC-mediated MDR. In this review, we summarized the pyrimidine-based inhibitors of ABC transporters, and mainly focused on their structure optimizations, development strategies and structure-activity relationship studies in hope of providing a reference for medicinal chemists to develop new modulators of MDR with highly potency and fewer side effects.
 ...
PMID:Pyrimidine: A promising scaffold for optimization to develop the inhibitors of ABC transporters. 3249 62