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

We have previously obtained, by exposure to near continuous increasing concentrations of cisplatin, a panel of human ovarian cancer cell lines that exhibit a wide range of primary resistance to the drug (9- to > 400-fold). These cells had strikingly increased (4- to 50-fold) levels of glutathione (GSH) as compared with the drug-sensitive cells of origin (A. K. Godwin et al., Proc. Natl. Acad. Sci. USA, 89: 3070-3074, 1992). Utilizing this panel of resistant cell lines, we evaluated cross-resistance to classical alkylating agents, natural product drugs, and irradiation. We observed that cross-resistance to carboplatin paralleled that of cisplatin, culminating in approximately 250-fold resistance. Similarly, melphalan cross-resistance continued to increase to > 400-fold and again paralleled the primary cisplatin resistance. Cell lines with low to very high levels of resistance to cisplatin are 8- to 850-fold resistant to the epipodophyllotoxin derivative etoposide. Cross-resistance is also observed for other natural product drugs, including Adriamycin (approximately 80-fold), mitoxantrone (approximately 440-fold), and taxol (approximately 40-fold). Cross-resistance to irradiation is, however, modest (< 2-fold). The cells with the greatest primary resistance to cisplatin most commonly had the highest cross-resistance to the other drugs examined. The cross-resistance to the natural product category drugs was found not to be mediated by the products of either the multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes based on lack of coordinate increased expression or amplification of these genes as assessed by Northern and Southern blot analyses. Furthermore, verapamil failed to markedly increase drug sensitivity. Although there was no indication that these natural product drug efflux pumps were operative, we observed decreased doxorubicin accumulation in these cell lines cross-resistant to natural products. In addition, alternations in DNA topoisomerase II mRNA levels, which have been observed in a variety of human tumor cell lines selected in vitro for resistance to etoposide or teniposide, were not detected. Only intracellular levels of GSH correlated with cross-resistance to these diverse anticancer agents and partial loss of resistance was associated with a marked decrease in glutathione levels. In the absence of alternative mechanisms, we speculate that the very broad clinically relevant cross-resistance seen in this model system may, at least in part, be the direct result of GSH-mediated drug inactivation or may be due to a combination of GSH conjugation to drug and conjugate efflux mediated by the putative ATP-dependent glutathione S-conjugate export pump.
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PMID:Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. 810 43

We recently reported that GS-X pump activity, as assessed by ATP-dependent transport of the glutathione-platinum complex and leukotriene C4, and intracellular glutathione (GSH) levels were remarkably enhanced in cis-diamminedichloroplatinum(II) (cisplatin)-resistant human leukemia HL-60 cells (Ishikawa, T., Wright, C. D., and Ishizuka, H. (1994) J. Biol. Chem. 269, 29085-29093). Now, using Northern hybridization and RNase protection assay, we provide evidence that the multidrug resistance-associated protein (MRP) gene, which encodes a human GS-X pump, is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells, whereas amplification of the MRP gene is not detected by Southern hybridization. Culturing HL-60/R-CP cells in cisplatin-free medium resulted in reduced MRP mRNA levels, but these levels could be induced to rise within 30 h by cisplatin and heavy metals such as arsenite, cadmium, and zinc. The increased levels of MRP mRNA were closely related with enhanced activities of ATP-dependent transport of leukotriene C4 (LTC4) in plasma membrane vesicles. The glutathione-platinum (GS-Pt) complex, but not cisplatin, inhibited ATP-dependent LTC4 transport, suggesting that the MRP/GS-X pump transports both LTC4 and the GS-Pt complex. Expression of gamma-glutamylcysteine synthetase in the cisplatin-resistant cells was also co-induced within 24 h in response to cisplatin exposure, resulting in a significant increase in cellular GSH level. The resistant cells exposed to cisplatin were cross-resistant to melphalan, chlorambucil, arsenite, and cadmium. These observations suggest that elevated expression of the MRP/GS-X pump and increased GSH biosynthesis together may be important factors in the cellular metabolism and disposition of cisplatin, alkylating agents, and heavy metals.
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PMID:Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. 866 1

Cells exposed to calcein acetoxymethyl ester (calcein AM) in the growth medium become fluorescent following cleavage of calcein AM by cellular esterases to produce the fluorescent derivative calcein. It has previously been shown by others that multidrug resistant cells which overexpress P-glycoprotein accumulate much less fluorescent calcein than the corresponding parental cells. We have now examined the transport of calcein in multidrug resistant cells which overexpress an alternative transporter, the multidrug resistance-associated protein (MRP). Accumulation of calcein fluorescence was greatly reduced in the MRP-overexpressing human lung cancer cell lines COR-L23/R and MOR/R compared with their parental lines. Energy depletion resulted in a considerably increased accumulation in the resistant lines. Treatment of resistant cells with buthionine sulfoximine (BSO), which depletes cellular glutathione (GSH), did not affect calcein accumulation, in marked contrast to our previous results for daunorubicin or the fluorescent probe rhodamine 123. Genistein, verapamil, cyclosporin A and ouabain were also each able to modify, to some extent, accumulation of daunorubicin, whilst having essentially no effect on calcein accumulation. However, the organic anion transport inhibitor probenecid was able to increase accumulation of both calcein and daunorubicin in the resistant cells. Genistein and verapamil treatment preferentially reduced the GSH content of resistant cells, whilst probenecid did not. However, probenecid caused a clear decrease in release of GSH from resistant cells into the medium.
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PMID:On the relationship between the probenecid-sensitive transport of daunorubicin or calcein and the glutathione status of cells overexpressing the multidrug resistance-associated protein (MRP). 884 45

1. Multidrug resistance (MDR) is a phenomenon originally seen in cultured tumor cells that, following selection for resistance to a single anticancer agent, become resistant to a range of chemically diverse anticancer agents. These MDR cells show a decrease in intracellular drug accumulation due to active efflux by transporter proteins. The transporter best characterized is P-glycoprotein (Pgp). This protein has been identified in many cancers and has been the target for agents able to inhibit its action, thereby reversing resistance. 2. More recently, another transporter, multidrug resistance-associated protein (MRP) has been identified in a number of MDR human tumor cell lines that do not apparently express Pgp. The presence of MRP at the cell surface of these cells is associated with alterations in drug accumulation and distribution. 3. The gene-encoding MRP has been cloned and sequenced and shown by transfection studies to be able to confer resistance and changes in drug accumulation in sensitive tumor cells. The profile of anticancer drugs expelled in the presence of MRP is similar, but not identical, to that of Pgp. 4. MRP has been identified in a number of different types of cancers, but it is not yet clear to what extent it is involved with clinical resistance. Furthermore, resistance modulators useful against Pgp are less effective in reversing MRP-mediated resistance. 5. It is not fully understood how MRP brings about drug efflux, but it is clear that the underlying mechanisms are different from those responsible for Pgp-mediated drug efflux. In particular, glutathione (GSH) is required for the effective expulsion of the anticancer agents. 6. Unlike Pgp, MRP is able to transport metallic oxyanions and glutathione and other conjugates, including peptidyl leukotrienes. Agents that inhibit organic anion transport, such as probenecid, can block MRP activity. 7. Like Pgp, MRP is expressed not only in resistant tumor cells, but also in normal human tissues. These include the epithelial cells lining the airways and the gastrointestinal tract. In cells in normal tissues, MRP appears to be located within the cytoplasm, which may mean that it functions here in a manner slightly different to that in malignant cells. It is now also recognized in cells and tissues from other species, such as the rat and mouse.
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PMID:Multidrug resistance-associated protein: a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion. 918 95

Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.
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PMID:Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin. 921 35

Human KB carcinoma C-A120 cells that express multidrug resistance-associated protein (MRP) were cross-resistant to trivalent and pentavalent antimonials and arsenicals. Intracellular glutathione (GSH) content was higher in C-A120 than its parental KB-3-1 cell line. Glutathione-S-transferase (GST) was similar in both cell lines. Depletion of cellular GSH by treatment of the cells with the inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), buthione sulfoximine (BSO), significantly increased the sensitivity of both KB-3-1 and C-A120 cells to heavy metals. A pyridine analog, PAK-104P, almost completely reversed the resistance to antimonials and arsenicals in C-A120 cells. BSO at 100 microM or PAK-104P at 10 microM enhanced the accumulation of antimony potassium tartrate in C-A120 cells to the level of that in KB-3-1 cells without the agents. PAK-104P inhibited the ATP-dependent efflux of antimony potassium tartrate. These findings suggest that MRP transports antimony conjugated with GSH ATP-dependently outside the cells and PAK-104P inhibits the transporting activity of MRP.
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PMID:Reversal of heavy metal resistance in multidrug-resistant human KB carcinoma cells. 924 93

Resistance to chemotherapy is a major problem in the treatment of patients with head and neck squamous cell carcinoma (HNSCC). Important factors involved are drug detoxification by glutathione (GSH) and reduced drug accumulation due to active transport out of the cell by so-called 'multidrug resistance-related proteins'. We have studied a panel of eight HNSCC cell lines showing differences in sensitivity to the anti-cancer drug cisplatin. Our previous studies indicated that the IC50 values were inversely correlated with the intracellular accumulation of platinum (Pt). In the present study, cellular GSH levels were found not to be related to the IC50 values. The expression levels of the enzymes glutathione S-transferase (GST) alpha, mu, and pi, the multidrug resistance-related proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP) were determined semiquantitatively by means of immunocytochemistry. The levels of the GSTs, P-gp and LRP were not found to be correlated with the IC50 values of the HNSCC cell lines. Surprisingly, however, an inverse correlation was found between MRP levels and IC50 values. The MRP expression levels were in agreement with the results of the MRP functional assay, based on the transport of calcein across the cell membrane as performed for two of the cell lines. Further studies should prove whether other pump mechanisms or DNA repair are involved in the cisplatin accumulation and the subsequent HNSCC cell growth inhibition.
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PMID:Role of glutathione, glutathione S-transferases and multidrug resistance-related proteins in cisplatin sensitivity of head and neck cancer cell lines. 948 11

Glutathione conjugation and transport of glutathione conjugates of anticancer drugs out of cells have been shown to work as a system in the detoxification of many anticancer drugs. The major components of this system include glutathione (GSH), GSH-related enzymes and glutathione conjugate export pump (GS-X pump). GSH can combine with anticancer drugs to form less toxic and more water soluble GSH conjugates, the conjugation reaction is catalysed by glutathione S-transferases (GSTs). The GSH conjugates of anticancer drugs can be exported from cells by GS-X pump or multidrug resistance-associated protein (MRP). GSH, glutathione-related enzymes and GS-X pump or MRP have been found to be increased or overexpressed in many drug resistant cells. Increased detoxification of anticancer drugs by this system may confer drug resistance. Inhibition of this detoxification system is a strategy for modulation of drug resistance.
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PMID:Glutathione-related mechanisms in cellular resistance to anticancer drugs. 949 49

Eisai hyperbilirubinemic (EHB) rats, a new mutant strain inbred from Sprague-Dawley (SD) rats, show no inherent expression of the canalicular multidrug resistance protein (cMrp) and lack canalicular multispecific organic anion transporter (cMOAT) activity. A sample of 203Hg (40 microCi with 40 microg Hg/kg) was injected intravenously (i.v.) into four male SD and EHB rats. Biliary excretion of reduced-glutathione (GSH) was 426 and 2 microg/bile for 15 min in the SD and EHB rats, respectively. Biliary excretion of 203Hg for 45 min in EHB rats significantly decreased to 1/4 of that of the SD rats. However, there was no difference in the hepatic uptake of 203Hg between the two strains. Other rats were injected subcutaneously (s.c.) with HgCl2 solution (at 0.2 and 1.6 mg/kg) containing 203Hg. Some 4 days after the injection of 0.2 mg/kg, about 3 and 13% of the total dose was found in the liver in SD and EHB rats, respectively. The hepatic supernatant Hg was recovered mainly in the void volume of a Sephadex column. Some 2 days after the injection of 1.6 mg/kg, these values were 3 and 23% in SD and EHB rats, respectively. The increased retention stimulated hepatic metallothionein (MT) induction and increased the proportion of Hg in the MT region on the Sephadex column. On the other hand, biliary excretion of 203Hg for 15 min in EHB rats was about 1/6-1/4 of that in SD rats. With the injection of 1.6 mg/kg, hepatic and renal functions worsened in EHB rats. In particular, severe necrosis was found in the renal tubules. Our results suggest that biliary secretion of inorganic Hg may be partly regulated by the ATP-dependent transport system, the glutathione S-conjugate export pump (GS-X pump) composed of Mrp and MOAT. Significantly decreased excretion stimulates hepatic retention of inorganic Hg. However, the hepatic lesions are less predictive. The MT induction may reduce the toxicity of metal to the liver cells.
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PMID:Decreased hepatobiliary secretion of inorganic mercury, its deposition and toxicity in the Eisai hyperbilirubinemic rat with no hepatic canalicular organic anion transporter. 958 89

The mechanism for cisplatin resistance in cisplatin-resistant KCP-4 cells was studied. Although multidrug resistance-associated protein (MRP) was not detected in KCP-4 cells, the cells were more resistant to heavy metals than multidrug-resistant C-A120 cells that overexpressed MRP. KCP-4 cells expressed metallothionein, but it was scarcely involved in cisplatin resistance in these cells. KCP-4 cells did not express canalicular multispecific organic anion transporter (cMOAT). The glutathione (GSH) level was 4.7-fold higher in KCP-4 cells than in KB-3-1 cells. When the GSH level in KCP-4 cells was decreased by treating the cells with buthionine sulfoximine and nitrofurantoin, the accumulation of and sensitivity to cisplatin in the cells were increased. C-A120 cells were only 3.0-fold more resistant to cisplatin than KB-3-1 cells and this resistance was not affected by the increased glutathione level. The accumulation of platinum in C-A120 and KCP-4 cells was 68.5 and 20.4% of that in KB-3-1 cells, respectively, while the intracellular levels of antimony potassium tartrate in C-A120 and KCP-4 cells were 13.2 and 9.9% of that in KB-3-1 cells, respectively. The ATP-dependent efflux of antimony was enhanced in both C-A120 and KCP-4 cells. These results, taken together, suggest an efflux pump for heavy metals different from MRP and cMOAT is involved in cisplatin resistance in KCP-4 cells.
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PMID:An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells. 959 4


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