Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

Kowalski, Petra; Stein, Ulrike; Scheffer, George L.; Lage, Hermann

doi:10.1038/sj.cgt.7700471

Cited by 48 publications

(32 citation statements)

References 26 publications

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“…Modulation of the BCRP multidrug-resistant phenotype by a hammerhead ribozyme directed against the transporter has recently been reported (Kowalski et al, 2002(Kowalski et al, , 2001. When the anti-BCRP hammerhead ribozyme was introduced into the human gastric carcinoma cell line EPG85-257RNOV, the levels of BCRP mRNA and protein were greatly reduced and cellular accumulation of BCRP substrate drugs was increased.…”

Section: Gene Therapy Approaches To Modulating Bcrpmentioning

confidence: 99%

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Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

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Section: Gene Therapy Approaches To Modulating Bcrpmentioning

confidence: 99%

“…Another way of revising BCRP-mediated resistance is to cleave the protein specifically using hammerhead ribozymes. A specific high-activity ribozyme directed at BCRP has recently been developed and found to cleave BCRP mRNA efficiently in a cell-free system (Kowalski et al, 2001(Kowalski et al, , 2002.…”

Section: Unanswered Questions and Pending Studiesmentioning

confidence: 99%

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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“…The latter, a known Pgp inhibitor, also inhibits ABCG2 at concentrations as low as 100 nm. In addition, as for Pgp and MRP1, a hammerhead ribozyme directed against ABCG2 has been shown to reverse drug resistance (Kowalski et al, 2002).…”

Section: Overcoming Drug Resistance Mediated By Abc Transportersmentioning

confidence: 99%

Strategies for reversing drug resistance

2003

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“…The relative cellular accumulation of mitoxantrone was determined by flow cytometry as described previously (Lage et al, 2001b;Kowalski et al, 2002). To examine efflux of mitoxantrone, the cells were incubated with 10 mg/ml for 1 h as described above.…”

Section: Drug Accumulation and Efflux Assaysmentioning

confidence: 99%

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

et al. 2003

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Elevated expression of the heparan sulphate proteoglycan glypican-3 (GPC3) was found on mRNA and protein levels in the atypical multidrug-resistant gastric carcinoma cell line EPG85-257RNOV, which was established by in vitro selection against mitoxantrone. In order to elucidate a putative role of GPC3 in the drug-resistant phenotype, the mitoxantrone-resistant cell line EPG85-257RNOV was transfected with an expression vector construct carrying an anti-GPC3 hammerhead ribozyme. It could be demonstrated that in anti-GPC3 ribozymetransfected cell clones, the GPC3-specific mRNA and corresponding protein expression levels were decreased to levels that are similar to those observed in nonresistant, parental cells. The anti-GPC3 ribozyme-containing clones reduced the mitoxantrone resistance level up to 21% of the original resistance and the crossresistance against etoposide to 33% of the original value. This reversal of drug resistance was accompanied by an increased cellular mitoxantrone accumulation in the anti-GPC3 ribozymeexpressing cells. In conclusion, it was verified that GPC3 is involved in the cellular protection against mitoxantrone in the atypical multidrug-resistant gastric carcinoma cell line EPG85-257RNOV. Oncogene (2004) 23, 945-955.

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Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2

Cited by 48 publications

References 26 publications

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Strategies for reversing drug resistance

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

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