Functional analysis of P-glycoprotein and multidrug resistance associated protein related multidrug resistance in AML-blasts

Brügger, Dorothee; Hebart, Holger; Gekeler, Volker; Seitz, Guido; Liu, C.; Klingebiel, Thomas; Orlikowsky, T.; Einsele, H.; Denzlinger, Claudio; Bader, Peter; Niethammer, D.; Beck, James F.

doi:10.1016/s0145-2126(98)00192-1

Cited by 14 publications

(13 citation statements)

References 14 publications

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“…The first of such arrays contains 38 human ABC transporter genes (DualChip human ABC low-density microarray) and it has been validated using three MDR cell lines, CEM/ADR5000, HL60/AR, and MCF7/AdVp1000 in comparison with their respective parental CEM, HL60, and MCF7 cells [24]. Using this array it was found that CEM/ADR5000, HL60/AR, and MCF7/AdVp1000 over-expressed ABCB1, ABCC1, and ABCG2, respectively, as previously demonstrated [5,31,32], thus validating the usefulness of this low density array. In this study, several other ABC transporters were also found to be over-expressed in the drug resistant cell lines ( Table 4), suggesting that they may also contribute to the resistance selected in these cells.…”

Section: Identification Of Abc Transporter Genes In Drug-selected Celmentioning

confidence: 58%

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

Zhang

2007

Cell Res

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Multidrug resistance (MDR) is a major problem in cancer chemotherapy. One of the best known mechanisms of MDR is the elevated expression of ATP-binding cassette (ABC) transporters. While some members of human ABC transporters have been shown to cause drug resistance with elevated expression, it is not yet known whether the over-expression of other members could also contribute to drug resistance in many model cancer cell lines and clinics. The recent development of microarrays and quantitative PCR arrays for expression profiling analysis of ABC transporters has helped address these issues. In this article, various arrays with limited or full list of ABC transporter genes and their use in identifying ABC transporter genes in drug resistance and chemo-sensitivity prediction will be reviewed.

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Section: Identification Of Abc Transporter Genes In Drug-selected Celmentioning

confidence: 58%

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

Zhang

2007

Cell Res

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“…The inhibition concentration 50% (IC 50 ) values for drugs are included in the Standard Agents Database of the Developmental Therapeutics Programme of the NCI. 6 The mRNA expression values of 60 cell lines of 31 ABC transporter genes (represented by 68 different clones with individual GenBank accession numbers) were selected from the NCI's database. The other 18 members of the ABC transporter gene family were not represented in the database.…”

Section: Methodsmentioning

confidence: 99%

“…The expression of the genes in the parental line was very low, making the ratio calculation to be qualitative. The multidrug-resistant HL60/AR subline overexpresses the ABCC1 (MRP1) gene (6). This gene was indeed found to be overexpressed by a factor of 10.46 compared with the parental line with the DualChip human ABC.…”

Section: Characterization Of Abc Gene Expression Pattern Of Threementioning

confidence: 99%

“…The overexpression was found for ABCA7 to be 2.15 on the microarray and 2.7 by real-time RT-PCR. 6 Internet address: http://dtp.nci.nih.gov. The data obtained for the parental promyelocytic HL60 cell line and its drug-resistant subline HL60/AR are summarized in Fig.…”

Section: Characterization Of Abc Gene Expression Pattern Of Threementioning

confidence: 99%

“…To investigate the usefulness of such a new tool, we investigated three multidrugresistant sublines that are known to express three different ABC transporter genes, e.g., ABCB1 (MDR1), ABCC1 (MRP1), and ABCG2 (MXR/BCRP; refs. [5][6][7]. The parental sensitive cell lines are used as reference and their corresponding drug-resistant subline as test.…”

Section: Introductionmentioning

confidence: 99%

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Microarray-based Detection of Multidrug Resistance in Human Tumor Cells by Expression Profiling of ATP-binding Cassette Transporter Genes

et al. 2004

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Different mechanisms of drug resistance, including ATP-binding cassette (ABC) transporters, are responsible for treatment failure of tumors. We developed a low-density DNA microarray which contains 38 genes of the ABC transporter gene family. This tool has been validated with three different multidrug-resistant sublines (CEM/ADR5000, HL60/AR, and MCF7/CH1000) known to overexpress either the ABCB1 (MDR1), ABCC1 (MRP1), or ABCG2 (MXR and BCRP) genes. When compared with their drug-sensitive parental lines, we observed not only the overexpression of these genes in the multidrug-resistant cell lines but also of other ABC transporter genes pointing to their possible role in multidrug resistance. These results were corroborated by quantitative real-time reverse transcription-PCR. As the microarray allows the determination of the expression profile of many ABC transporters in a single hybridization experiment, it may be useful as a diagnostic tool to detect drug resistance in clinical samples.

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Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines

Efferth¹,

Sauerbrey

Halatsch

et al. 2003

Naunyn-Schmiedeberg's Arch Pharmacol

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Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.

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Functional analysis of P-glycoprotein and multidrug resistance associated protein related multidrug resistance in AML-blasts

Cited by 14 publications

References 14 publications

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

Microarray-based Detection of Multidrug Resistance in Human Tumor Cells by Expression Profiling of ATP-binding Cassette Transporter Genes

Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines

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