Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs

Folmer, Y; Schneider, Matthias; Blum, Hubert E.; Hafkemeyer, Peter

doi:10.1038/sj.cgt.7701082

Cited by 46 publications

(31 citation statements)

References 16 publications

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“…Chloromethylfluorescein reacts with intracellular glutathione to form glutathione methylfluorescein. Calcein, doxorubicin, CDF, and glutathione methylfluorescein are substrates of MRP2 (Evers et al, 2000;Tian et al, 2004;Folmer et al, 2007;Förster et al, 2008). After the loading period, the transport buffer was aspirated, and the cells were rinsed 3ϫ (200 l each) with ice-cold PBS.…”

Section: Methodsmentioning

confidence: 99%

“…These include vincristine, etoposide, cisplatin, and doxorubicin, used to treat retinoblastoma, and methotrexate and piroxicam, used to treat uveitis (Hooijberg et al, 1999;El-Sheikh et al, 2007;Folmer et al, 2007). MRP2 is an ATP-dependent efflux transporter that shifts, in addition to many therapeutic drugs, endogenous metabolites, such as estradiol 17␤-D-glucuronide, and environmental toxins, such as ochratoxin A (van Aubel et al, 1998;Leier et al, 2000).…”

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confidence: 99%

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Localization of Multidrug Resistance-Associated Protein 2 in the Nonpigmented Ciliary Epithelium of the Eye

Pelis¹,

Shahidullah²,

Ghosh³

et al. 2009

J Pharmacol Exp Ther

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The nonpigmented epithelium (NPE) of the ciliary body represents an important component of the blood-aqueous barrier of the eye. Many therapeutic drugs penetrate poorly across the NPE into the aqueous humor of the eye interior. Several of these therapeutic drugs, such as methotrexate, vincristine, and etoposide, are substrates of the multidrug resistance-associated protein 2 (MRP2). Abundant MRP2 protein was detected by Western blot in homogenates of human ciliary body and freshly dissected porcine NPE. In cultured porcine NPE, the intracellular accumulation of the MRP2 substrates calcein (1.8-fold), 5-(and-6)-carboxy-2Ј,7Ј-dichlorofluorescein (22.1-fold), and doxorubicin (1.9-fold) was significantly increased in the presence of 50, an MRP inhibitor. In addition, the intracellular accumulation of the MRP2 substrate glutathione methylfluorescein was increased by 50 M MK571 (4.3-fold), 500 M indomethacin (2.6-fold), and 50 M cyclosporin A (2.1-fold) but not by 500 M sulfinpyrazone. These data are consistent with MRP2-mediated transport activity in cultured NPE, and MRP2 mRNA (reverse transcriptase-polymerase chain reaction) and protein (Western blot) were detected in the cultured cells. Immunolocalization studies in native human and porcine eyes showed MRP2 protein at the apical interface of the NPE and pigmented cell layers. Close examination of MRP2 immunoreactivity supported the conclusion that MRP2 is localized in the apical membrane of the NPE. MRP2 at the apical membrane of NPE cells may be involved in protecting intraocular tissues from exposure to potentially harmful toxins.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Localization of Multidrug Resistance-Associated Protein 2 in the Nonpigmented Ciliary Epithelium of the Eye

Pelis¹,

Shahidullah²,

Ghosh³

et al. 2009

J Pharmacol Exp Ther

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“…Multidrug resistance (MDR) to chemotherapeutic agents plays a major role in the failure of cancer therapy [5] . MDR phenotype, an intrinsic or acquired cross-resistance to a variety of structurally and functionally unrelated drugs, is almost constantly expressed in HCC and represents one of the major problems in cancer eradication by limiting the efficacy of chemotherapy [6] . Resistance to therapy can result from decreased drug uptake, increased DNA repair or drug inactivation [7] .…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells

Feng¹,

Wang²,

Pan³

et al. 2009

WJG

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AIM:To study the expression and phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2 in multidrug resistant (MDR) hepatocellular carcinoma (HCC) cells. METHODS:MDR HCC cell lines, HepG2/adriamycin (ADM) and SMMC7721/ADM, were developed by exposing parental cells to stepwise increasing concentrations of ADM. MTT assay was used to determine drug sensitivity. Flow cytometry was employed to analyze cell cycle distribution and measure cell P-glycoprotein (P-gp) and multidrug resistant protein 1 (MRP1) expression levels. ERK1 and ERK2 mRNA expression levels were measured by quantitative real-time PCR (QRT-PCR). Expression and phosphorylation of ERK1 and ERK2 were analyzed by Western blot. RESULTS:MTT assay showed that HepG2/ADM and SMMC7721/ADM were resistant not only to ADM, but also to multiple anticancer drugs. The P-gp expression was over 10-fold higher in HepG2/ADM cells than in HepG2 cells (8.92% ± 0.22% vs 0.88% ± 0.05%, P < 0.001) and over 4-fold higher in SMMC7721/ADM cells than in SMMC7721 cells (7.37% ± 0.26% vs 1.74% ± 0.25%, P < 0.001). However, the MRP1 expression was not significantly higher in HepG2/ADM and SMMC7721/ADM cells than in parental cells. In addition, the percentage of MDR HepG2/ADM and SMMC7721/ADM cells was significantly decreased in the G0/G1 phase and increased in the the S phase or G2/M phase. QRT-PCR analysis demonstrated that the ERK1 and ERK2 mRNA expression increased apparently in HepG2/ADM cells and decreased significantly in SMMC7721/ADM cells. Compared with the expression of parental cells, ERK1 and ERK2 protein expressions were markedly decreased in SMMC7721/ADM cells. However, ERK2 protein expression was markedly increased while ERK1 protein expression had no significant change in HepG2/ADM cells. Phosphorylation of ERK1 and ERK2 was markedly decreased in both HepG2/ADM and SMMC7721/ADM MDR cells.CONCLUSION: ERK1 and ERK2 activities are downregulated in P-gp-mediated MDR HCC cells. ERK1 or ERK2 might be a potential drug target for circumventing MDR HCC cells.

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“…In the current study, half of the tumor samples showed MRP2 overexpression, irrespective of administration of cisplatin (Table III). Since HCCs often produce bile, the intrinsic expression of MRP2 in HCC may partly explain their low sensitivity to some MRP2-dependent anti-cancer agents including cisplatin, doxorubicin, etoposide, and vincristine (7,28). Bonin et al documented that MRP2 mRNA expression level significantly increases in HCC compared to non-neoplastic liver tissue (14).…”

Section: Discussionmentioning

confidence: 99%

Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma

Korita

Wakai²,

Shirai³

et al. 2010

Oncol Rep

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Abstract.We hypothesized that expression of multidrug resistance-associated protein 2 (MRP2), a major cisplatin transporter, may determine the efficacy of cisplatin as a treatment for patients with hepatocellular carcinoma (HCC). A prospective analysis was conducted of 49 consecutive patients who underwent resection for HCC (16 patients treated with cisplatin-based neoadjuvant chemotherapy and 33 patients treated without neoadjuvant chemotherapy). Expression of MRP2 in resected specimens was assessed by immunohistochemical and Western blot analyses. The extent of tumor necrosis was assessed histologically in the greatest dimension of the tumor specimen from each patient. The median percentage of tumor necrosis was 81% (range: 0-100%) and complete tumor necrosis was found in 3 patients. Overexpression of MRP2 was detected in 24/46 (52%) tumor specimens. In 16 patients treated with cisplatin, tumor size and dose of cisplatin did not correlate with tumor necrosis of the resected specimens (P=0.706 and P=0.555, respectively). Of 13 tumor specimens containing vivid tumor from 16 patients treated with cisplatin, 8 had overexpression of MRP2. Tumor specimens with overexpression of MRP2 showed a lower percentage of tumor necrosis than those with non-overexpression (median percentage of tumor necrosis, 19% vs. 99%, P=0.003). In conclusion, overexpression of MRP2 correlates with a lower percentage of tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy for HCC, whereas either tumor size or dose of cisplatin does not. Expression of MRP2 determines the efficacy of cisplatinbased chemotherapy in patients with HCC.

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Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs

Cited by 46 publications

References 16 publications

Localization of Multidrug Resistance-Associated Protein 2 in the Nonpigmented Ciliary Epithelium of the Eye

Localization of Multidrug Resistance-Associated Protein 2 in the Nonpigmented Ciliary Epithelium of the Eye

Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells

Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma

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