Drug Efflux Transporter Multidrug Resistance-Associated Protein 5 Affects Sensitivity of Pancreatic Cancer Cell Lines to the Nucleoside Anticancer Drug 5-Fluorouracil

Nambaru, Praveen K.; Hübner, Tobias; Köck, Kathleen; Mews, Steffen; Grube, Markus; Payen, Léa; Guitton, Jérôme; Sendler, Matthias; Jedlitschky, Gabriele; Rimmbach, Christian; Rosskopf, Dieter; Kowalczyk, Dariusz W.; Kroemer, Heyo K.; Weiss, Frank Ulrich; Mayerle, Julia; Lerch, Markus M.; Ritter, Christoph A.

doi:10.1124/dmd.110.033613

Cited by 60 publications

(47 citation statements)

References 41 publications

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“…Therefore, amino acid and dipeptide prodrugs of chemotherapeutic agents might have another advantage transporting drugs into cancer cells via influx transporters such as LATs, and PEPTs except ENTs [7,11,16,87]. It has been reported that the chemoresistance is attributed to the up-regulation of MRPs, especially MRP5 [80,81,88,89,90]. Numerous studies have been conducted to overcome this resistance to treat cancers but clinically successful approaches have not been established [91,92,93,94,95].…”

Section: Resultsmentioning

confidence: 99%

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

2014

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Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5′-l-phenylalanyl-l-tyrosyl-floxuridine and 5′-l-phenylalanyl-l-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

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Section: Resultsmentioning

confidence: 99%

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

2014

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“…Cancer cells are more dependent on the glycolytic pathway for ATP generation, compared with normal cells, and they eventually acquire drug resistance, typically due to the aberrant expression of drug-expelling ABC transporters (12). The ATP-dependence of drug transporters for activity (40,41) suggests that glycolysis inhibition may increase the concentration of chemotherapeutic agents in cancer cells (42,43). The most widely studied transporters, including MRP1, BCRP and P-gp, are able to transport a variety of structurally-unassociated chemotherapeutic compounds from cancer cells, thereby inducing MDR (44).…”

Section: Discussionmentioning

confidence: 99%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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Abstract. Shikonin (SHK) is a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, that has been reported to suppress the growth of a number of cancer cell types. Adriamycin (AD) is typically used as an effective anticancer agent; however, it has the propensity to induce drug resistance. The aim of the present study was to investigate the effects of SHK alone and in combination with AD on lung adenocarcinoma cells and the underlying molecular mechanisms of their effects. Colony formation, MTT and propidium iodide staining assays demonstrated that the co-treatment of A549 cells with SHK and AD significantly decreased cell viability and potently induced apoptosis. The mitochondrial membrane potential was assessed using 5,5', 6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide staining and fluorescence microscopy. Cells co-treated with SHK and AD exhibited marked mitochondrial membrane damage. In addition, co-treatment with SHK and AD significantly reduced ATP levels in A549 cells compared with the control. Western blot analysis revealed that SHK enhanced the antitumor effects of AD by inhibiting the expression of ATP-binding cassette transporters. These results suggest that the inhibition of glycolysis could be an effective approach for lung cancer treatment. Therefore, SHK has the potential to be used as an anticancer agent in the treatment of lung adenocarcinoma, and thus warrants further investigation and development.

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“…Indeed, such MRP5-silenced Capan-1 cells in which MRP5 mRNA expression was downregulated to about 25% of that in control cells [26] showed an increased sensitivity to 5-FU as compared to parental or vector-transfected Capan-1 cells (Table 1) [26]. The contribution of MRP5 to 5-FU resistance was confirmed in a more recent study using Patu-02 pancreatic cancer cells where knock down of MRP5 also significantly increased cellular cytotoxicity of 5-FU [76]. …”

Section: Resultsmentioning

confidence: 89%

Membrane Drug Transporters and Chemoresistance in Human Pancreatic Carcinoma

Hagmann

Faissner

Schnölzer

et al. 2010

Cancers

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Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

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Drug Efflux Transporter Multidrug Resistance-Associated Protein 5 Affects Sensitivity of Pancreatic Cancer Cell Lines to the Nucleoside Anticancer Drug 5-Fluorouracil

Cited by 60 publications

References 41 publications

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Membrane Drug Transporters and Chemoresistance in Human Pancreatic Carcinoma

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