Chemosensitisation and drug accumulation effects of cyclosporin A, PSC-833 and verapamil in human MDR large cell lung cancer cells expressing a 190k membrane protein distinct from P-glycoprotein

Barrand, Margery A.; Rhodes, Teresa; Twentyman, Peter R.

doi:10.1016/0959-8049(93)90397-x

Cited by 134 publications

(73 citation statements)

References 18 publications

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“…The mouse monoclonal antibody to MRP1 (MRPl m6) was kindly provided by Professor R Scheper, Amsterdam. The doxorubicin-resistant human large-cell lung cancer cell line COR-L23/R previously shown to overexpress MRPI (Barrand et al, 1993) was used as the positive control.…”

Section: Western Blotmentioning

confidence: 99%

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Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

Sharp

Smith²,

Hobbs³

et al. 1998

Br J Cancer

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Summary The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any of the cell lines. In addition, we have transfected the MRP1 gene into an intrinsically cisplatin-resistant cell line SKOV3, previously shown to have elevated levels of glutathione (GSH). The MRP1 -transfected line SKOV3-S2 was shown to be cross-resistant to doxorubicin, vincristine and etoposide but not to paclitaxel, vinblastine and platinum agents, such as cisplatin, JM216 [bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II)]. No cross-resistance to any of the platinum agents was observed in a MRP1 -overexpressing human lung cancer cell line with acquired doxorubicin resistance. Reduction of GSH levels (80-90%) by buthionine sulphoximine (BSO) produced significant potentiation in cisplatin sensitivity in the parental SKOV3, the vector-alone control SKOV3-puro and the MRP1 -transfected line SKOV3-S2. The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4.1-fold) but not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV3-puro and the SKOV3-S2 cells, although both these transfected lines accumulated significantly more than the parental line. Our results suggest that MRP1 does not play a significant role in platinum resistance in the human tumour cell lines investigated in this study.

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Section: Western Blotmentioning

confidence: 99%

“…CORL23 and CORL23/R, in which the resistant line has been previously shown to overexpress MRP (Barrand et al, 1993).…”

mentioning

confidence: 99%

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

Sharp

Smith²,

Hobbs³

et al. 1998

Br J Cancer

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“…46 In cell lines, Vp changed the intracellular distribution of DNR and doxorubicin resulting in an increased nuclear/cytoplasmic ratio of these drugs. 9,47,48 The modulators may also lower the intracellular pH which may enhance the protonation and cytotoxicity of DNR. 49 More detailed studies are necessary to establish the nature of the sensitizing effect on DNR cytotoxicity in childhood ALL.…”

Section: Discussionmentioning

confidence: 99%

“…12 Both P-gpand non-P-gp-mediated MDR may be affected by PSC 833, although the effect on the latter may be less pronounced. 9 In the present study we determined the modulating effect of PSC 833, CsA, Vp and genistein on the cytotoxicity of DNR in childhood ALL. The nature of the modulating effect was studied by analyzing the effect on the accumulation and retention of DNR and the expression of P-gp, MRP and LRP in these samples.…”

Section: Introductionmentioning

confidence: 97%

“…Presently, these modulators were also demonstrated to modulate MRPmediated drug resistance. 9,10 A more specific MRP/LRP modulator may be genistein, an isoflavone with protein tyrosine kinase inhibitory activity. Genistein has been found to increase the accumulation and retention of the anthracycline daunorubicin (DNR) in non-P-gp but not in P-gp expressing cell lines.…”

Section: Introductionmentioning

confidence: 99%

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The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 M PSC 833 (P = 0.025), 1.5-fold using 4 M CsA (P = 0.003) and 1.6-fold using 6 M Vp (P = 0.012) whereas the adverse effect of 25 M genistein was median 1.8-fold (P Ͻ 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of Pgp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

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DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux

et al. 1996

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Multidrug resistance (MDR) is often related to expression of P‐glycoprotein (Pgp) or Multidrug Resistance Protein (MRP). Pgp‐mediated MDR can be evaluated by determining cellular retention of fluorescent substrates by flow cytometry. This study determined if agents used to evaluate Pgp function also can be used to evaluate MRP function. Cellular retention of doxorubicin (Dox), Rhodamine‐123 (Rh‐123), and 3,3′‐diethyloxacarbocyanine iodide (DiOC2(3)) were studied in MRP‐expressing cell lines (HL60/Adr and HT1080/DR4), whereas a Pgp expressing cell line (A2780/Dx5) served as a positive control. Overexpression of Pgp correlated inversely with retention of Dox, Rh‐123, and DiOC2(3); however, under identical experimental conditions (1 h reincubation in drug‐free medium), no retention difference of the three agents was detected between parental and MRP‐expressing resistant cells. Upon extending the reincubation time to 4 h, an efflux of Rh‐123 and Dox in the resistant lines became apparent and even more pronounced after 24 h; however, still no efflux was detectable for DiOC2(3). Incubation of the cells with a modulator of MDR, PAK‐104P, negated the observed drug efflux in Pgp and MRP expressing cells, which correlated with increased sensitivity of the MDR lines to doxorubicin. Thus both Dox and Rh‐123 can be used to evaluate MRP‐function, but DiOC2(3) can not. © 1996 Wiley‐Liss, Inc.

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Chemosensitisation and drug accumulation effects of cyclosporin A, PSC-833 and verapamil in human MDR large cell lung cancer cells expressing a 190k membrane protein distinct from P-glycoprotein

Cited by 134 publications

References 18 publications

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux

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