MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma

Department of Gynaecological Oncology, Westmead Hospital, University of Sydney at Westmead Millennium Institute, WESTMEAD, NSW 2145, Australia.
Gynecologic Oncology (Impact Factor: 3.77). 03/2006; 100(2):239-46. DOI: 10.1016/j.ygyno.2005.08.046
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The ABC transporter MRP2 (ABCC2) can mediate cisplatin efflux, and over-expression of MRP2 has been associated with cisplatin resistance in cancer cell lines. The aim of this study was to determine the role of MRP2 in modulating cisplatin cytotoxicity in normal cells as well as the relationship between MRP2 expression and clinical response to platinum-based agents in ovarian cancer.
The effect of absence of MRP2 expression on cisplatin sensitivity was investigated using primary hepatocyte cultures from the TR- rat strain, which is deficient in Mrp2. We also examined MRP2 expression immunohistochemically in human ovarian tumors exhibiting extremes of clinical response to platinum-based chemotherapy, either absolute platin resistance or patients with residual disease after surgery who experienced extremely long complete response to primary platinum-based chemotherapy.
Primary hepatocyte cultures from Mrp2-deficient TR- rats were over threefold more sensitive to cisplatin and accumulated a twofold greater amount of platinum on DNA that wild-type rat hepatocytes. In human ovarian carcinomas, MRP2 was detected by immunohistochemistry in 3/13 (23%) tumors from patients with absolute platin resistance compared with 5/9 (56%) tumors from patients with prolonged survival following treatment including a platinum-based agent.
These studies indicate that MRP2 may play an important role in modulating normal tissue response to cisplatin. However, MRP2 expression occurred only in a subset of primary ovarian cancers, was frequently aberrant in location and was not correlated with clinical response to platinum-based chemotherapy.

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    • "e second member of the multidrug resistance protein (MRP; ABCC) family, MRP2, which is also designed as the canalicular multiorganic anion transporter (CMOAT), is involved in bilirubin glucuronide transport and confers resistance to MRP1 substrates and cisplatin [18]. e role of this protein in the resistance of ovarian cancer to cisplatin has been described in several studies [19] [20]. Another important MDR protein, breast cancer resistance protein BCRP (ABCG2), was cloned from a mitoxantrone-resistant subline of the breast cancer cell line MCF-7 [21]. "
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    ABSTRACT: Ovarian cancer is the leading cause of death among gynaecological malignancies. Multiple drug resistance makes cancer cells insensitive to chemotherapy. In this study, we developed six primary ovarian cancer cell lines (W1MR, W1CR, W1DR, W1VR, W1TR, and W1PR) resistant to drugs such as methotrexate, cisplatin, doxorubicin, vincristine, topotecan, and paclitaxel. A chemosensitivity assay MTT test was performed to assess drug cross-resistance. Quantitative real-time polymerase chain reaction and Western blot were also performed to determine mRNA and protein expression of genes involved in chemoresistance. We observed high cross-resistance to doxorubicin, vincristine, and paclitaxel in the cell lines resistant to these agents. We also found a significant correlation between resistance to these drugs and increased expression of P-gp. Two different mechanisms of topotecan resistance were observed in the W1TR and W1PR cell lines. We did not observe any correlation between MRP2 transcript and protein levels. Cell lines resistant to agents used in ovarian cancer treatment remained sensitive to methotrexate. The main mechanisms of drug resistance were due to P-gp expression in the doxorubicin, vincristine, and paclitaxel resistant cell lines and BCRP expression in the topotecan resistant cell line.
    03/2013; 2013(18, abstract lba5509):241763. DOI:10.1155/2013/241763
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    • "Materna et al. [43] revealed a distinct tendency in correlation between high MRP2 mRNA expression and poor prognosis in ovarian carcinoma patients, but due to the low case number, the difference was statistically not significant. Immunohistochemical evaluation of the MRP2 expression was performed on 24 specimens of ovarian carcinoma, but this study also demonstrated no correlation with clinical response to platinum-based chemotherapy [44]. Interestingly, Ma et al. [45] using short hairpin RNA (shRNA) observed that the knock down of MRP2 effected in an increased intracellular cisplatin accumulation. "
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    ABSTRACT: Objective To determine the prognostic value of the immunohistochemical evaluation of the multidrug resistance–associated protein 2 (MRP2) expression, together with its subcellular localization in primary fallopian tube carcinomas (PFTCs). Methods The immunohistochemical analysis was performed using samples originating from 70 patients with PFTCs. Results (1) We documented that MRP2 can be localized in the plasma membrane (MRP2c), as well as in the nuclear envelope (MRP2n) of the PFTC cells. (2) Patients with more advanced stage, with progression of the disease and patients who died, showed significantly higher expression of the MRP2n. (3) Univariate and multivariate analyses showed that MRP2n is an unfavorable prognostic factor in PFTCs. (4) The analysis of the classic clinicopathological data revealed that only the FIGO stage had prognostic value, both in the univariate, as well as in multivariate analysis. Conclusions (1) This study suggests that MRP2n is a new disadvantageous prognostic factor in PFTCs and (2) that expression in nuclear envelope can be associated with lower differentiation of cancer cells and their resistance to the cisplatin. (3) We have also confirmed independent prognostic value of FIGO stage in PFTCs.
    Archives of Gynecology and Obstetrics 11/2012; 287(3). DOI:10.1007/s00404-012-2589-7 · 1.36 Impact Factor
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    • "Previous studies confirmed that ABCC2 was localized in the nuclear membrane of CDDP-resistant cells, and nuclear membranous localization of ABCC2 correlated with resistance against CDDP in ovarian carcinoma cells [22, 27]. Furthermore, it had been reported that after treatment with RNAi targeting ABCC2, decreased nuclear membranous ABCC2 protein expression in the CDDP-resistant cancer cell lines was observed [28]. "
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    ABSTRACT: Cisplatin (CDDP) is one of the most active drugs to treat nasopharyngeal carcinoma (NPC) patients. To further understand the mechanisms of CDDP-resistance in NPC, two CDDP-resistant sublines (CNE2-CDDP and CNE2-CDDP-5Fu) derived from parental NPC cell line CNE2 were established. It was found that at the IC50 level, the resistance of CNE2-CDDP and CNE2-CDDP-5Fu against CDDP was 2.63-fold and 5.35-fold stronger than that of parental CNE2, respectively. Of the four ABC transporters (ABCB1, ABCC1, ABCC2 and ABCG2) related to MDR, only ABCC2 was found to be elevated both in CDDP-resistant sublines, with ABCC2 located in nucleus of CNE2-CDDP-5Fu but not in CNE2-CDDP and parental CNE2. Further research showed that compared to untreated CNE2, the intracellular levels of CDDP were decreased by 2.03-fold in CNE2-CDDP and 2.78-fold in CNE2-CDDP-5Fu. After treatment with PSC833, a modulator of MDR associated transporters including ABCC2, the intracellular level of CDDP was increased in CDDP-resistant sublines, and the resistance to CDDP was partially reversed from 2.63-fold to 1.62-fold in CNE2-CDDP and from 5.35-fold to 4.62-fold in CNE2-CDDP-5Fu. These data indicate that ABCC2 may play an important role in NPC resistant to CDDP.
    Journal of Oncology 06/2010; 2010:915046. DOI:10.1155/2010/915046
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