Abstract:
: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 indomethacin-induced 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 microM 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 microM) 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.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
de Groot DJ,van der Deen M,Le TK,Regeling A,de Jong S,de Vries EGdoi
10.1038/sj.bjc.6604010subject
Has Abstractpub_date
2007-10-22 00:00:00pages
1077-83issue
8eissn
0007-0920issn
1532-1827pii
6604010journal_volume
97pub_type
杂志文章abstract::A multicentric, prospective phase III study was carried out with the aim of testing the so-called 'worst drug rule' hypothesis, which suggests the use of an effective but 'less active' regimen that first eradicates tumoral cells resistant to a second effective and 'more active' regimen. With respect to this hypothesis...
journal_title:British journal of cancer
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1038/bjc.1997.586
更新日期:1997-01-01 00:00:00
abstract:BACKGROUND:Lymphovascular invasion (LVI) is associated with the development of metastasis in invasive breast cancer (BC). However, the complex molecular mechanisms of LVI, which overlap with other oncogenic pathways, remain unclear. This study, using available large transcriptomic datasets, aims to identify genes assoc...
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pub_type: 杂志文章
doi:10.1038/s41416-019-0486-6
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pub_type: 杂志文章,随机对照试验
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abstract:BACKGROUND:Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on ce...
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doi:10.1038/bjc.2015.412
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journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1993.187
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journal_title:British journal of cancer
pub_type: 杂志文章
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journal_title:British journal of cancer
pub_type: 杂志文章
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journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1977.112
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journal_title:British journal of cancer
pub_type: 杂志文章,meta分析
doi:10.1038/bjc.1992.341
更新日期:1992-10-01 00:00:00
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journal_title:British journal of cancer
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1038/sj.bjc.6603214
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journal_title:British journal of cancer
pub_type: 杂志文章,meta分析,评审
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更新日期:2017-06-06 00:00:00
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journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1991.419
更新日期:1991-11-01 00:00:00
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journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/sj.bjc.6600598
更新日期:2002-11-04 00:00:00
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pub_type: 杂志文章
doi:10.1038/sj.bjc.6604410
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/sj.bjc.6600755
更新日期:2003-03-10 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
doi:10.1038/bjc.1994.338
更新日期:1994-09-01 00:00:00
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journal_title:British journal of cancer
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:British journal of cancer
pub_type: 临床试验,杂志文章
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journal_title:British journal of cancer
pub_type: 杂志文章
doi:10.1038/bjc.1976.67
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