Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade

Chen, Zhaolin; Shi, Tianlu; Zhang, Lei; Zhu, Pengli; Mingying, D; Huang, Cheng; Hu, Tingting; Jiang, Ling; Li, Jun

doi:10.1016/j.canlet.2015.10.010

Cited by 637 publications

(450 citation statements)

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“…However, its clinical applicability is considerably impeded by dose-limiting toxicity (5) and by primary or secondary drug-resistance (6,7). As acquired drug resistance can be mediated by enhanced efflux transporter expression (8,9), it is essential to determine whether anti-myeloma drugs are transported by certain proteins. It has previously been demonstrated that bortezomib is a substrate of the well-known ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp); however, the clinical relevance of this finding remains unclear (10).…”

Section: Introductionmentioning

confidence: 99%

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

et al. 2017

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Abstract. In order to optimize the clinical application of an increasing number of proteasome inhibitors, investigations into the differences between their respective pharmacodynamic and pharmacokinetic profiles, including their ability to act as a perpetrator in drug-drug interactions, are warranted. Therefore, in the present in vitro study, it was investigated whether bortezomib, carfilzomib and ixazomib are able to alter the expression, and/or the activity, of specific drug transporters generally relevant for pharmacokinetic drug-drug interactions. Through induction experiments, the current study demonstrated that the aforementioned three proteasome inhibitors do not induce mRNA expression of the transporter genes ATP binding cassette (ABC)B1, C1, C2 and G2 in the LS180 cell line, which was used as a model for systemic induction. By contrast, in certain myeloma cell lines, ixazomib provoked minor alterations in individual transporter gene expression. None of the proteasome inhibitors tested relevantly inhibited drug transporters within the range of physiological plasma concentrations. Taken together, transporter-based drug-drug interactions are unlikely to be a primary concern in the clinical application of the tested compounds.

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Section: Introductionmentioning

confidence: 99%

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

et al. 2017

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“…The classical mechanism of MDR is associated with the overexpression of the ATP binding cassette subfamily B member 1 (ABCB1) gene enco ding P-glycoprotein (P-gp), which contributes to the reduction of the effective drug concentration in the cell by transporting the drug out of the cell (14,15,(17)(18)(19)(20). In addition to the classical MDR mechanism associated with overexpression of P-gp, there are atypical mechanisms (21)(22)(23). Examples of these atypical mechanisms include the overexpression of Annexin A1 (ANXA1) and thioredoxin (TXN) proteins.…”

Section: Introductionmentioning

confidence: 99%

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

et al. 2018

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Abstract. Multidrug resistance (MDR) is a notable problem in the use of chemotherapy. Therefore, studies aimed at identifying substances capable of overcoming resistance of cancer cells are required. Examples of these compounds are polyphenols, including resveratrol, that exert a range of various biological activities. The aim of the present study was to demonstrate the effect of 3,5,4'-trihydroxy-trans-stilbene (resveratrol) on the expression of ATP binding cassette subfamily B member 1, Annexin A1 (ANXA1) and thioredoxin (TXN) genes, and the proteins encoded by these genes, which are associated with MDR. The experiments were performed in human gastric cancer cell lines EPG85-257RDB (RDB) and EPG85-257RNOV (RNOV), which are resistant to daunorubicin and mitoxantrone, respectively, in addition to EPG85-257P (control), which is sensitive to cytostatic drugs. Cells were treated with 30 or 50 µM resveratrol for 72 h and changes in the expression levels of the genes were analysed with the use of a reverse transcription-quantitative polymerase chain reaction. The cellular levels of P-glycoprotein (P-gp), ANXA1 and TXN were evaluated using immunofluorescence and western blot analysis. Resveratrol in both concentrations has been shown to have a statistically significant influence on expression of the mentioned genes, compared with untreated cells. In RDB cells, resveratrol reduced the expression level of all analyzed genes, compared with untreated cells. Similar results at the protein level were obtained for P-gp and TXN. In turn, in the RNOV cell line, resveratrol reduced TXN expression at mRNA and protein levels, compared with untreated cells. The results of the present study indicate that resveratrol may reduce the resistance of cancer cells by affecting the expression of a number of the genes and proteins associated with MDR. IntroductionResveratrol belongs to the stilbenoid group of polyphenols, possessing two phenol rings linked to each other by an ethylene bridge (1). In 1940, resveratrol was isolated from the root of Veratrum grandiflorum (1,2). A primary dietary source of resveratrol is red wine, as a very high resveratrol concentration is present in the skin of red grapes (50-100 µg/g) (3). In natural conditions, resveratrol is synthesized by plants in response to external environmental factors, including ultraviolet radiation and heavy metals (3,4). Resveratrol is identified in two isomeric forms, cis and trans-resveratrol ( Fig. 1) (5,6).The trans form is dominant in terms of its prevalence and biological activity (7). The hydrophobic nature of resveratrol considerably contributes to its limited bioavailability (8).Owing to the varied biological activity of resveratrol, it has been the subject of numerous studies aimed at revealing its health-enhancing properties, and its use in prevention and treatment of many diseases (1,3,5,9). The results of in vitro and in vivo studies have proved that resveratrol exhibits anticancer activity at all three stages of the oncogenic process: initiation, promotion and progr...

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confidence: 99%

“…Therapy of cancer, if not completely effective, results in the overexpression of genes that code for efflux pumps that extrude the noxious agent (anticancer drug) before it reaches its intended target of the cancer cell (1). The overexpressed efflux pump renders the cancer cell immune to not only the initial drug used in therapy but to a wide range of unrelated noxious compounds (1).…”

mentioning

confidence: 99%

“…The overexpressed efflux pump renders the cancer cell immune to not only the initial drug used in therapy but to a wide range of unrelated noxious compounds (1). The arising of this multidrugresistant (MDR) phenotype makes therapy highly problematic and the end result is that the patient succumbs to the disease (1). Therefore, it is the consensus of many that therapy of MDR cancer may succeed if the responsible efflux pump is inhibited from its activity, therefore, affording the increased concentration of anticancer drug to a level consistent with its toxic targeted action needed to kill the cancer cell.…”

mentioning

confidence: 99%

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Identification of Important Compounds Isolated from Natural Sources that Have Activity Against Multidrug-resistant Cancer Cell Lines: Effects on Proliferation, Apoptotic Mechanism and the Efflux Pump Responsible for Multi-resistance Phenotype

Amaral

Spengler

Molnár

2016

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Abstract. The focus of this mini-review is to identify non-toxic compounds isolated from natural sources (plants) that exhibit specific activity against efflux pumps of specific multidrugresistant (MDR) cancer cell lines, inhibit proliferation of the MDR cancer cell lines and inhibit the activity of overexpressed efflux pumps of the MDR cancer cell line.Therapy of cancer, if not completely effective, results in the overexpression of genes that code for efflux pumps that extrude the noxious agent (anticancer drug) before it reaches its intended target of the cancer cell (1). The overexpressed efflux pump renders the cancer cell immune to not only the initial drug used in therapy but to a wide range of unrelated noxious compounds (1). The arising of this multidrugresistant (MDR) phenotype makes therapy highly problematic and the end result is that the patient succumbs to the disease (1). Therefore, it is the consensus of many that therapy of MDR cancer may succeed if the responsible efflux pump is inhibited from its activity, therefore, affording the increased concentration of anticancer drug to a level consistent with its toxic targeted action needed to kill the cancer cell. To this extent, over 100,000 synthetic compounds for activity against the known efflux pumps of cancer cell types have been screened by the National Cancer Institute (USA) and, to date, not a single inhibitor has found its way toward successful therapy of MDR cancer. In fact, because normal counter type cells have a fully functional efflux pump, albeit at a much lower level of activity, clinical trials with selected efflux pump inhibitors have produced high toxicity and even death.During the past two decades, traditional medicine has become a source for the identification of plants that harbor compounds that may have important potential for the therapy of cancer. With respect to the laboratory of one of the authors of this mini-review (JM), literally, hundreds of plants have been studied for their activity against specific targets of the cancer cell and it is the focus of this mini-review to identify selected compounds that have no toxicity at the level of their in vitro study and which have activity against proliferation or induction of the apoptotic mechanism or the efflux pump responsible for the phenotype of the MDR cancer cell. Targets of MDR Cancer CellsProliferation. Proliferation is affected by many drugs and, although the search for non-toxic compounds that inhibit proliferation was initiated more than 60 years ago, remains the focus of most studies; however, the inhibition of proliferation by compounds isolated from natural sources will not be discussed here at the level of its mechanism. Rather, suffice to say that our observations for antiproliferative activity as presented in the text remain, for the 5665

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Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade

Cited by 637 publications

References 152 publications

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

Identification of Important Compounds Isolated from Natural Sources that Have Activity Against Multidrug-resistant Cancer Cell Lines: Effects on Proliferation, Apoptotic Mechanism and the Efflux Pump Responsible for Multi-resistance Phenotype

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