Journal Article


M Clynes
R Nicamhlaoibh
C M O'Loughlin
S Verhaegen
K Kavanagh
I M Cleary
S Coyle
M M Heenan
R A O'Connor
C J Elliott
and 1 others



glutathione transferase lung neoplasms humans drug synergism therapeutic use drug resistance neoplasm human cells dose response relationship drug drug therapy drug toxicity cancer cell lines drug resistance multiple non steroidal hl 60 cells anti inflammatory agents non steroidal anti inflammatory tumor cells cultured adenocarcinoma chemotherapeutic drugs leukemia carcinoma squamous cell drug combinations antineoplastic agents polymerase chain reaction

Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs). (1998)

Abstract The effect on cytotoxicity of combining a range of clinically important non-steroidal anti-inflammatory 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 specific group of NSAIDs (indomethacin, sulindac, tolmetin, acemetacin, zomepirac and mefenamic acid) all at non-toxic levels, significantly 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-fluorouracil, 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 effect was concentration dependent. The effect 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 D2 or E2; (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, flufenamic acid, flurbiprofen, 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 significant 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 [3H]-LTC4 transport into inside-out plasma membrane vesicles prepared from MRP-expressing cells, of doxorubicin efflux from preloaded cells and of glutathione-S-transferase activity. The NSAIDs did not enhance cellular sensitivity to radiation. The combination of specific NSAIDs with anticancer drugs reported here may have potential clinical applications, especially in the circumvention of MRP-mediated multidrug resistance.
Collections Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Biology
Ireland -> Maynooth University -> Type = Article
Ireland -> Dublin City University -> PubMed
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering
Ireland -> Maynooth University -> Status = Published
Ireland -> Maynooth University -> Open Access DRIVERset

Full list of authors on original publication

M Clynes, R Nicamhlaoibh, C M O'Loughlin, S Verhaegen, K Kavanagh, I M Cleary, S Coyle, M M Heenan, R A O'Connor, C J Elliott and 1 others

Experts in our system

Martin Clynes
Dublin City University
Total Publications: 232
Kevin Kavanagh
Maynooth University
Total Publications: 183
Shirley Coyle
Dublin City University
Total Publications: 86
Robert O'Connor
Dublin City University
Total Publications: 74