Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line

Taylor, Charles W.; Dalton, William S.; Parrish, Pamela R.; Gleason, Mary C.; Bellamy, William; Thompson, Floyd H.; Roe, Denise J.; Trent, Jeffrey M.

doi:10.1038/bjc.1991.202

Cited by 138 publications

(71 citation statements)

References 24 publications

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“…Thus far at least two mechanisms have been shown to be operative in drug resistance in non-Pgp MDR cells. The first mechanism is a decreased drug concentration at target due to a decreased cellular accumulation of drugs (McGrath et al, 1989;Kuiper et al, 1990;Coley et al, 1991;Slovak et al, 1988;Taylor et al, 1991) and/or an altered distribution of drugs (Schuurhuis et al, 1991;Takeda et al, 1991). We have previously shown by using a digitonin based assay that the decrease in DNR accumulation occurred against a concentration gradient in a number of Pgp and non-Pgp MDR cell lines (Versantvoort et al, 1992a).…”

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confidence: 99%

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Versantvoort

Schuurhuis²,

Pinedo³

et al. 1993

Br J Cancer

126

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In tumour cells the pharmacological basis for multidrug resistance (MDR) often appears to be a reduced cellular cytostatic drug accumulation caused by the drug efflux protein, P-glycoprotein (Pgp MDR), or by other drug transporters (non-Pgp MDR). Here we report the reversal of the decreased daunorubicin (DNR) accumulation in five non-Pgp MDR cell lines (GLC4/ADR, SW-1573/2R120, HT1080/DR4, MCF7/Mitox and HL60/ADR) by genistein. Genistein inhibited the enhanced DNR efflux in the GLC4/ADR cells. In these cells the decreased VP-16 accumulation was also reversed by genistein. Three other (iso)flavonoids biochanin A, apigenin and quercetin also increased the DNR accumulation in the GLC4/ADR cells. In contrast to the effects on non-Pgp MDR cells, 200 microM genistein did not increase the reduced DNR accumulation in three Pgp MDR cell lines (SW-1573/2R160, MCF7/DOX40 and KB8-5) or in the parental cell lines. In conclusion the use of genistein provides a means to probe non-Pgp related drug accumulation defects. Images Figure 1 Figure 6

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mentioning

confidence: 99%

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Versantvoort

Schuurhuis²,

Pinedo³

et al. 1993

Br J Cancer

126

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“…The cells are parental, doxorubicin-sensitive human breast carcinoma cells. The doxorubicin-resistant variant MCF7/AdrR was generated in vitro by successive culturing of parental MCF7/WT cells in slowly increasing concentrations of doxorubicin in a multiple-step procedure [29]. Fresh drug was added when the medium was changed three times a week.…”

Section: Cell Linesmentioning

confidence: 99%

Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin

Liu

Stevenson

Barrett

et al. 2005

Nuclear Medicine and Biology

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Background-99m Tc-sestamibi (MIBI) and 99m Tc-tetrofosmin (TF) are avid transport substrates recognized by the multidrug resistance (MDR) P-glycoprotein (Pgp). This study was designed to compare the properties of MIBI and TF in assessing the inhibition of Pgp by PSC833 in severe combined immunodeficient mice bearing MCF7 human breast tumors using SPECT imaging.Methods-Animals with drug-sensitive (MCF/WT) and drug-resistant (MCF7/AdrR) tumors were treated by PSC833 and by carrier vehicle 1 h before imaging, respectively. Dynamic images were acquired for 30 min after intravenous injection of MIBI/TF using a SPECT system, FastSPECT. The biodistribution of MIBI and TF was determined at the end of the imaging session.Results-MCF7/WT in the absence and presence of PSC833 could be visualized by MIBI and TF imaging within 5 min and remained detectable for 30 min postinjection. MCF7/AdrR could be visualized only 2-5 min without PSC833 treatment but could be detected for 30 min with PSC833, very similar to MCF7/WT. MCF7/AdrR without PSC833 showed significantly greater radioactive washout than MCF7/WT and MCF7/AdrR with PSC833 treatment. PSC833 increased the accumulation (%ID/g) in MCF7/AdrR 3.0-fold (1.62 ± 0.15 vs. 0.55 ± 0.05, P <.05) for TF and 1.9-fold (1.21 ± 0.04 vs. 0.64 ± 0.05, P <.05) for MIBI but did not affect MCF7/WT.Conclusions-The feasibility of MIBI and TF for assessment of MDR expression and inhibition was demonstrated in mice through FastSPECT imaging. The results indicate that TF may be at least comparable with MIBI in recognizing Pgp expression and modulation.

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“…Effective modulation of multidrug resistance is possible in Pglycoprotein containing cells with compounds which exhibit different structural features (Zamora et al, 1988) and it is attributed to increases in cellular drug accumulation resulting from inhibition of drug efflux (Bradley et al, 1988). Modulation of non-P-glycoprotein mediated MDR and accumulation defects by verapamil and other Pgp modulators, however, seems to be less efficient than for P-glycoprotein mediated MDR (Cole et al, 1989;Coley et al, 1991;Harker et al, 1989;Kuiper et al, 1990;Schuurhuis et al, 1991;Slovak et al, 1988;Taylor et al, 1991).…”

mentioning

confidence: 99%

“…Reduced drug accumulation may also be a parameter of drug resistance for some (Coley et al, 1991;Haber et al, 1989;Hindenburg et al, 1989;Kuiper et al, 1990;McGrath & Center, 1988;Slapak et al, 1990;Slovak et al, 1988;Taylor et al, 1991) but not for all (Cole et al, 1991;Danks et al, 1987;Harker et al, 1989;McGrath et al, 1989) MDR cells which do not overexpress P-glycoprotein. Effective modulation of multidrug resistance is possible in Pglycoprotein containing cells with compounds which exhibit different structural features (Zamora et al, 1988) and it is attributed to increases in cellular drug accumulation resulting from inhibition of drug efflux (Bradley et al, 1988).…”

mentioning

confidence: 99%

Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells

Schuurhuis¹,

Heijningen²,

Cervantes³

et al. 1993

Br J Cancer

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Summary Doxorubicin accumulation defects in multidrug reistant tumour cells are generally small in comparison to the resistance factors. Therefore additional mechanisms must be operative. In this paper we show by a quantitative approach that doxorubicin resistance in several P-glycoprotein-positive non-small cell lung cancer and breast cancer multidrug resistant cell lines can be explained by a summation of accumulation defect and alterations in the efficacy of the drug once present in the cell. This alteration of efficacy was partly due to changes in intracellular drug localisation, characterised by decreased nuclear/cytoplasmic doxorubicin fluorescence ratios (N/C-ratios). N/C-ratios were 2.8-3.6 in sensitive cells, 0.1-0.4 in cells with high (>70-fold) levels of doxorubicin resistance and 1.2 and 1.9 in cells with low or intermediate (7.5 and 24-fold, respectively) levels of doxorubicin resistance. The change of drug efficacy was reflected by an increase in the total amount of doxorubicin present in the cell at equitoxic (IC50) concentrations. N/C ratios in highly resistant P-glycoprotein-containing cells could be increased with the resistance modifier verapamil to values of 1.3-2.7, a process that was paralleled by a decrease of the cellular doxorubicin amounts present at IC50. At the low to moderate residual levels of resistance, obtained with different concentrations of verapamil, a linear relationship between IC50 and cellular doxorubicin amounts determined at IC50 was found. This shows that at this stage of residual resistance, extra reversal by verapamil should be explained by further increase of drug efficacy rather than by increase of cellular drug accumulation. A similar relationship was found for Pglycoprotein-negative MDR cells with low levels of resistance. Since in these cells N/C ratios could not be altered, verapamil-induced decrease of IC50 must be due to increased drug efficacy by action on as yet unidentified targets. Although the IC50 of sensitive human cells cannot be reached with resistance modifiers, when using these relationships it can be shown by extrapolation that cellular and nuclear doxorubicin amounts at IC50 at complete reversal of resistance were the same as in sensitive cells. It is concluded that doxorubicin resistance factors for multidrug resistant cells can for a large part, and in the case of P-glycoprotein-containing cells probably fully, be accounted for by decreased amounts of drug at nuclear targets, which in turn is characterised by two processes only: decreased cellular accumulation and a shift in the ratio nuclear drug/cytoplasmic drug.

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Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line

Cited by 138 publications

References 24 publications

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin

Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells

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