A 190-Kilodalton Protein Overexpressed in Non-P-Glycoprotein-Containing Multidrug-Resistant Cells and Its Relationship to the MRP Gene

Barrand, Margery A.; Heppell-Parton, A.; Wright, Karen A.; Rabbitts, Pamela; Twentyman, Peter R.

doi:10.1093/jnci/86.2.110

Cited by 127 publications

(75 citation statements)

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“…Our in vitro studies utilised doses significantly below the IC 50 of doxorubicin for MCF-7 cells; concentrations were kept constant over a 10-day period to mimic the release characteristics from a liposomal carrier. In contrast to multistep exposure to doxorubicin, where either ABCB1 or ABCC1 is the dominant ABC transporter causing MDR (Shen et al, 1986;Barrand et al, 1994;Mehta, 1994), we show here that following single-step selection other transporters, including ABCC4 and ABCG2, are overexpressed. Importantly, ABCG2 was found to confer resistance to doxorubicin in breast, ovarian and colon cancer cell lines.…”

contrasting

confidence: 77%

“…Although doxorubicin can work through various mechanisms, it is still not immune to the MDR phenotype and, consequently, the development of resistance to doxorubicin has been well documented in a broad range of cell lines (Shen et al, 1986;Barrand et al, 1994;Mehta, 1994). To more closely examine the regulation of ABC transporter expression at concentrations similar to those in vivo, we established several single-step doxorubicin-selected clones with three different cancer cell lines and found that these clones did not express ABCB1 (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

112

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Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.

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confidence: 77%

Section: Discussionmentioning

confidence: 99%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

112

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“…Another form of multidrug resistance is non-Pgp-mediated multidrug resistance. This type of multidrug resistance has been reported in doxorubicin-selected lung carcinoma cell lines (Mirski et al, 1987;Scheper et al, 1993;Barrand et al, 1994) and a leukaemia cell line (Marsh et al, 1987) among others. Expression of a 190 kDa vesicular glycoprotein (Krishnachary et al, 1993) and a 110 kDa membrane glycoprotein (Scheper et al, 1993) appears to be associated with the non-P-gp-mediated multidrug resistance in some of these cell lines.…”

mentioning

confidence: 64%

Expression of multidrug resistance-associated protein (MRP), MDR1 and DNA topoisomerase II in human multidrug-resistant bladder cancer cell lines

Hasegawa

Abe²,

Naito³

et al. 1995

Br J Cancer

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S_ry The acquisition of the mulidrug resistance phenotype in human tumours is associated with an overexpression of the 170 kDa P-glycoprotein encoded by the multidrug resistance I (MDR1) gene, and also with a 190 kDa membrane ATP-binding protein encoded by a multidrug resistance-associated protein (MRP) gene. Human bladder cancer is a highly malignant neoplasm which is refractory to anti-cancer chemotherapy. In order to understand the hanism underying multidrug resistance in bladder cancer, we established three doxorubicin-resistant cel lines, T24/ADM-1, T24/ADM-2 and KK47/ADM, and one vincristine-resistant cell line, T24/VCR, from human bladder cancer T24 and KK47 cells respectively. Both T24/ADM-1 and T24/ADM-2 cells which had elevated MRP mRNA levels showed both a cross-resistance to etoposide and a decreased intracellular accumulation of etoposide. T24/VCR cells which had elevated levels of MDR1 mRNA and P-glycoprotein but not of MRP mRNA, showed cross-resistce to doxorubicin. On the other hand, KK47/ADM cells, which had elevated levels of both MRP and MDR1 mRNA and a decreased level of topoisomerase II mRNA, were found to be cross-resistant to etoposide, vincristine and a camptothecin derivative, CT-1I 1. Our present study demonstrates a concomitant induction of increased levels of MRP mRNA, decreased levels of topoisomerase II mRNA and decreased drug accumulation during development of multidrug resistance in human bladder cancer cells. The enhanced expression of the MRP gene is herein discussed in a possible correlation with the decreased expression of the topoisomerase II gene.

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“…42,43 MRP1 has shown to be expressed in many non-Pgp/ MDR1 cell lines. 44,45 MRP1 transfection experiments, however, did not confer resistance to cisplatin. 44 Using the NCI 60 drug screening cell lines, Fojo et al 46,47 demonstrated a positive correlation between MDR1/MRP1 gene expression level and chemical compound sensitivity.…”

Section: Mrp1 Mrp2mentioning

confidence: 87%

Copper‐transporting P‐type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: Comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP

Nakayama

Kanzaki

Ogawa

et al. 2002

Intl Journal of Cancer

131

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Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorlydifferentiated ovarian carcinomas treated with cisplatinbased chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy.

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A 190-Kilodalton Protein Overexpressed in Non-P-Glycoprotein-Containing Multidrug-Resistant Cells and Its Relationship to the MRP Gene

Abstract: Though associated with drug resistance, enhanced drug efflux, and decreased drug accumulation in cell lines, the role of this protein in clinical resistance has yet to be determined.

Cited by 127 publications

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Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Expression of multidrug resistance-associated protein (MRP), MDR1 and DNA topoisomerase II in human multidrug-resistant bladder cancer cell lines

Copper‐transporting P‐type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: Comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP

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