Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport.

Müller, Michael; Meijer, Coby; Zaman, Guido J.R.; Borst, Piet; Scheper, Rik J.; Mulder, Nanno; Vries, Elisabeth G.E. de; Jansen, Petér L. M.

doi:10.1073/pnas.91.26.13033

Cited by 534 publications

(338 citation statements)

References 48 publications

(54 reference statements)

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“…Studies have shown that MRPl can act as a GS-X pump that is capable of transporting glutathione conjugates (Ishikawa et al, 1994;Muller et al, 1994;Jedlitschky et al, 1996). In addition, Zaman et al (1995), Schneider et al (1995) and Versantvoort et al (1995) have demonstrated that drug transport in MRPl-but not in P-glycoprotein-overexpressing cells can be regulated by manipulating intracellular GSH levels by BSO.…”

Section: Discussionmentioning

confidence: 99%

“…Transfected clones surviving selection with puromycin are therefore biased towards expression of the upstream gene (Rees et al, 1996). A cDNA containing the complete coding sequence for MRP1 (Zaman et al, 1994) was cloned into the multiple cloning site of F250 as an N/eI-Notl fragment, resulting in the vector F253 (Figure 1). …”

Section: Vector Construction and Transfectionmentioning

confidence: 99%

“…This is mainly achieved by transporting drugs that are conjugated or co-transported with GSH (Muller et al, 1994;Jedlitschky et al, 1996). One of the main mechanisms of cisplatin resistance is increased cellular detoxification via elevated GSH (Andrews and Howell, 1990).…”

mentioning

confidence: 99%

“…Moreover, Ishikawa et al (1994) have shown overexpression of the GS-X pump in cisplatin-resistant human promyelocytic leukaemia HL-60 (HL-60/R-CP) cells, in which GSH was elevated. Conversely, other reports have suggested that MRPI is not the major pump responsible for cisplatin resistance through studies in which the MRP] gene was transfected into a cervical cell line, HeLa (Cole et al, 1994), and into a non-small-cell lung cancer cell line (SW-1573) (Zaman et al, 1994), or using a pair of cisplatin-sensitive and acquired resistant sublines (De Vries et al, 1995).…”

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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: Discussionmentioning

confidence: 99%

Section: Vector Construction and Transfectionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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“…Overexpression of MRP1 is associated with an increased transport rate of a range of substrates that are conjugated to glutathione (GSH), glucuronide, or sulfate (Leier et al, 1994;Müller et al, 1994;Jedlitschky et al, 1997). Transporters with these characteristics are known as glutathione conjugate (GS-X) pumps (Ishikawa, 1992), or multispecific organic anion transporters .…”

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confidence: 99%

Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export

et al. 2000

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SummaryThe multidrug resistance proteins MRP1 and MRP2 are members of the same subfamily of ATP-binding cassette transporters. Besides organic molecules conjugated to negatively charged ligands, these proteins also transport cytotoxic drugs for which no negatively charged conjugates are known to exist. In polarized MDCKII cells, MRP1 routes to the lateral plasma membrane, and MRP2 to the apical plasma membrane. In these cells MRP1 transports daunorubicin, and MRP2 vinblastine; both transporters export reduced glutathione (GSH) into the medium. We demonstrate that glutathione transport in MDCKII-MRP1 cells is inhibited by the inhibitors of organic anion transporters sulfinpyrazone, indomethacin, probenecid and benzbromarone. In MDCKII-MRP2 cells, GSH export is stimulated by low concentrations of sulfinpyrazone or indomethacin, whereas export is inhibited down to control levels at high concentrations. We find that unmodified sulfinpyrazone is a substrate for MRP2, also at concentrations where GSH export is inhibited. We also show that GSH export in MDCKII-MRP2 cells increases in the presence of vinblastine, and that the stochiometry between drug and GSH exported is between two and three. Our data indicate that transport of sulfinpyrazone and vinblastine is associated with GSH export. However, at high sulfinpyrazone concentrations this compound is transported without GSH. Models of MRP action are discussed that could explain these results.

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Multidrug resistance-associated protein expression in clinical gastric carcinoma

Endo

Maehara

Ichiyoshi

et al. 1996

Cancer

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Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport.

Cited by 534 publications

References 48 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

Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export

Multidrug resistance-associated protein expression in clinical gastric carcinoma

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