RETRACTED: ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles establishes MRP as a broad specificity transporter.

Paul, Saptarshi; Breuninger, Lisa M.; Tew, Kenneth D.; Shen, Hongxie; Kruh, Gary D.

doi:10.1073/pnas.93.14.6929

Cited by 75 publications

(42 citation statements)

References 36 publications

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“…The precise mechanism by which MRP renders cells resistant to cytotoxic insults has not been de®nitively established, but it is believed to act as an eZux pump for GSH conjugates of xenobiotics [28], although recent results support the possibility of unconjugated drug export [8]. Using inside-out vesicles prepared from the plasma membrane of HL60/ADR, which overexpress MRP, or DKLP cells, active NSAIDs (sulindac, indomethacin and tolmetin) have been shown to inhibit the uptake of LTC 4 , a MRP substrate.…”

Section: Discussionmentioning

confidence: 99%

“…MRP can act as an eZux pump for glutathione conjugates and it was originally thought that glutathione conjugation was an important step in the eZux of cytotoxic drugs from cells [7]. Recent reports have observed that unaltered cytotoxic drugs can be transported into inverted vesicles prepared from a MRP-overexpressing cell line, suggesting that glutathione conjugation may not be essential for eZux via MRP [8]. MDR due to P-170 expression can be circumvented by a variety of chemical agents, e.g.…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs)

Duffy

Elliott

O’Connor

et al. 1998

European Journal of Cancer

227

151

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The eVect on cytotoxicity of combining a range of clinically important non-steroidal anti-in¯amma-tory drugs (NSAIDs) with a variety of chemotherapeutic drugs was examined in the human lung cancer cell lines DLKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/ADR. A speci®c group of NSAIDs (indomethacin, sulindac, tolmetin, acemetacin, zomepirac and mefenamic acid) all at non-toxic levels, signi®cantly increased the cytotoxicity of the anthracyclines (doxorubicin, daunorubicin and epirubicin), as well as teniposide, VP-16 and vincristine, but not the other vinca alkaloids vinblastine and vinorelbine. A substantial number of other anticancer drugs, including methotrexate, 5-¯uorouracil, cytarabine, hydroxyurea, chlorambucil, cyclophosphamide, cisplatin, carboplatin, mitoxantrone, actinomycin D, bleomycin, paclitaxel and camptothecin, were also tested, but displayed no synergy in combination with the NSAIDs. The synergistic eVect was concentration dependent. The eVect appears to be independent of the cyclo-oxygenase inhibitory ability of the NSAIDs, as (i) the synergistic combination could not be reversed by the addition of prostaglandins D 2 or E 2 ; (ii) sulindac sulphone, a metabolite of sulindac that does not inhibit the cyclooxygenase enzyme, was positive in the combination assay: and (iii) many NSAIDs known to be cyclo-oxygenase inhibitors, e.g. meclofenamic acid, diclofenac, naproxen, fenoprofen, phenylbutazone,¯ufenamic acid,¯urbi-profen, ibuprofen and ketoprofen, were inactive in the combination assay. The enhancement of cytotoxicity was observed in a range of drug sensitive tumour cell lines, but did not occur in P-170-overexpressing multidrug resistant cell lines. However, in the HL60/ADR and COR L23R cell lines, in which multidrug resistance is due to overexpression of the multidrug resistance-associated protein MRP, a signi®cant increase in cytotoxicity was observed in the presence of the active NSAIDs. Subsequent Western blot analysis of the drug sensitive parental cell lines, DLKP and A549, revealed that they also expressed MRP and reverse-transcription±polymerase chain reaction studies demonstrated that mRNA for MRP was present in both cell lines. It was found that the positive NSAIDs were among the more potent inhibitors of [ 3 H]-LTC 4 transport into inside-out plasma membrane vesicles prepared from MRP-expressing cells, of doxorubicin eZux from preloaded cells and of glutathione-Stransferase activity. The NSAIDs did not enhance cellular sensitivity to radiation. The combination of speci®c NSAIDs with anticancer drugs reported here may have potential clinical applications, especially in the circumvention of MRP-mediated multidrug resistance. #

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs)

Duffy

Elliott

O’Connor

et al. 1998

European Journal of Cancer

227

151

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“…Intracellular glutathione (GSH) can be conjugated to these agents by glutathione-S-transferase. Multidrug resistance protein 1 transports GSH, GSH conjugates and unconjugated cytotoxic drugs to the extracellular compartment (Cole et al, 1994;Müller et al, 1994;Zaman et al, 1994;Paul et al, 1996;Ballatori et al, 2005). Glutathione is required for several other cellular functions such as protein and DNA synthesis, cell cycle regulation, protection against oxidative damage and detoxification of toxins (Wang and Ballatori, 1998).…”

mentioning

confidence: 99%

Indomethacin induces apoptosis via a MRP1-dependent mechanism in doxorubicin-resistant small-cell lung cancer cells overexpressing MRP1

Groot

Deen

et al. 2007

Br J Cancer

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Small-cell lung cancers (SCLCs) initially respond to chemotherapy, but are often resistant at recurrence. The non-steroidal anti-inflammatory drug indomethacin is an inhibitor of multidrug resistance protein 1 (MRP1) function. The doxorubicin-resistant MRP1-overexpressing human SCLC cell line GLC 4 -Adr was highly sensitive for indomethacin compared with the parental doxorubicin-sensitive line GLC 4 . The purpose of this study was to analyse the relationship between hypersensitivity to indomethacin and MRP1 overexpression. The experimental design involved analysis of the effect of MRP1 downregulation on indomethacininduced cell survival and apoptosis in GLC 4 -Adr and GLC 4 , using siRNA. In addition the effect of indomethacin on glutathione levels and mitochondrial membrane potential was investigated. Small interfering RNAs directed against MRP1 reduced MRP1 mRNA levels twofold and reduced efflux pump function of MRP1, which was reflected by a 1.8-fold higher accumulation of MRP1 substrate carboxyfluorescein, in si-MRP1 versus si-Luciferase-transfected GLC 4 -Adr cells. Multidrug resistance protein 1 downregulation decreased initial high apoptosis levels 2-fold in GLC 4 -Adr after indomethacin treatment for 24 h, and increased cell survival (IC 50 ) from 22.8±2.6 to 30.4±5.1 mM following continuous indomethacin exposure. Multidrug resistance protein 1 downregulation had no effect on apoptosis in GLC 4 or on glutathione levels in both lines. Although indomethacin (20 mM) for 2 h decreased glutathione levels by 31.5% in GLC 4 -Adr, complete depletion of cellular glutathione by L-buthionine (S,R)-sulphoximine only resulted in a small increase in indomethacin-induced apoptosis in GLC 4 -Adr, demonstrating that a reduced cellular glutathione level is not the primary cause of indomethacin-induced apoptosis. Indomethacin exposure decreased mitochondrial membrane potential in GLC 4 -Adr cells, suggesting activation of the mitochondrial apoptosis pathway. Indomethacin induces apoptosis in a doxorubicin-resistant SCLC cell line through an MRP1-dependent mechanism. This may have implications for the treatment of patients with MRP1-overexpressing tumours.

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“…P-glycoprotein, MRP1), belonging to the ATP-binding cassette protein family (Gottesman and Pastan, 1993;Germann, 1996;Marie et al, 1996;Borst et al, 2000). These transporters are responsible for the active ATP-dependent efflux of drugs out of resistant cells resulting in the decreased intracellular accumulation insufficient to inhibit resistant cell proliferation (Zaman et al, 1994;Paul et al, 1996). Different mechanisms have been proposed for anthracycline antitumour effects including DNA intercalation with consequent inhibition of DNA biosynthesis, free radical formation with induction of DNA damage, alkylation of DNA and DNA crosslinking, inhibition of topoisomerase II, activation of signalling pathways and apoptosis (for a recent review, see Gewirtz, 1999).…”

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confidence: 99%

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells.

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RETRACTED: ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles establishes MRP as a broad specificity transporter.

Abstract: Biochemistry. In the article ''A protein encoded by a group I intron in Aspergillus nidulans directly assists RNA splicing and is a DNA endonuclease'' by

Cited by 75 publications

References 36 publications

Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs)

Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs)

Indomethacin induces apoptosis via a MRP1-dependent mechanism in doxorubicin-resistant small-cell lung cancer cells overexpressing MRP1

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

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