Upregulation of Multidrug Resistance-Associated Protein 1 by Allyl Isothiocyanate in Human Bronchial Epithelial Cell: Involvement of c-Jun N-Terminal Kinase Signaling Pathway

Wang, Shujun; Wang, Shanshan; Wang, Chenyin; Chen, Yajun; Li, Jie; Wang, Xueqi; Wang, Dianlei; Li, Zegeng; Peng, Zhaoliang

doi:10.1155/2015/903782

Cited by 8 publications

(7 citation statements)

References 35 publications

(43 reference statements)

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“…This upregulation was also functionally confirmed as the MRP1 substrate CFDA was effluxed in greater magnitude the more the cells were exposed to allyl isothiocyanate (5–40 μM). The authors connected the upregulation of MRP1 to the c‐Jun‐ N ‐terminal kinase (JNK) signaling pathway, as it could be reversed using the JNK inhibitor SP600125 (Figure ) . An increase in MRP1 expression was also observed for the isothiocyanate alyssin (10 μM; Figure ) in combination with either 250 μM verapamil or furosemide (Figure 37) .…”

Section: Natural Product Drugs and Synthetic Analogsmentioning

confidence: 97%

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Stefan

Wiese

2018

Medicinal Research Reviews

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Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.

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Section: Natural Product Drugs and Synthetic Analogsmentioning

confidence: 97%

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Stefan

Wiese

2018

Medicinal Research Reviews

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“…Rho-123 was a special substrate for P-gp which contains yellow-green fluorophores. CFDA was used as a model MRP1 substrate to evaluate the function of MRP1 (25).…”

Section: Multidrug Resistance Determination In K562/adm Cells Cellmentioning

confidence: 99%

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

Chen

Xing

Wang

et al. 2016

International Journal of Oncology

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One of the major causes of failure in chemotherapy for patients with human chronic myelogenous leukemia (CML) is the acquisition of multidrug resistance (MDR). MDR is often associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, has previously demonstrated the ability to suppress certain human tumor processes and the potential to be developed as an anticancer agent. Nevertheless, the ability of TAIII to reverse MDR has not yet been explored. In this study, the adriamycin (ADM) resistance reversal effect of TAIII in human CML K562/ADM cells and the underlying mechanism was investigated. The Cell Counting Kit-8 (CCK-8) assay showed that TAIII had a reversal effect on the drug resistance of K562/ADM cells. Flow cytometry assay showed increased intracellular accumulation of ADM after cells were pretreated with TAIII, and the changes in the accumulation of rhodamine-123 (Rho-123) and 5(6)-carboxyfluorescein diacetate (CFDA) dye in K562/ADM cells were determined to be similar to the changes of intracellular accumulation of ADM. After pretreatment of cells with TAIII, the decreasing expression of P-gp and MRP1 mRNA was examined by reverse transcription polymerase chain reaction (RT-PCR). Western blotting showed TAIII inhibiting P-gp and MRP1 expression depended on the PI3K/Akt signaling pathway by decreasing the activity of p-Akt. Moreover, wortmannin an inhibitor of PI3K/Akt signaling pathway has a strong inhibitory effect on the expression of p-Akt, P-gp and MRP1. Besides, the combined treatment with TAIII did not have an affect on wortmannin downregulation of p-Akt, P-gp and MRP1. Taken together, our findings demonstrate, for the first time, that TAIII induced MDR reversal through inhibition of P-gp and MRP1 expression and function with regained adriamycin sensitivity which might mainly correlate to the regulation of PI3K/Akt signaling pathway.

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“…The results were consistent with the previous study of our research group. Our previous results indicated that AITC upregulated the expression levels of MRP1 in 16HBE cells via the JNK signaling pathway in a concentration-dependent manner ( 15 , 16 ). MRP1 plays a protective role in the COPD process, whereas the JNK pathway also plays an important role in the treatment of COPD ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Benzyl-ITC and phenethyl isothiocyanate have been revealed to play an antitumor effect via regulation of the expression of MRP1( 14 ). Preliminary studies indicated that AITC increased the expression and activity of MRP1 in 16HBE14o-cells in a concentration-dependent manner via the JNK signaling pathway ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Allyl isothiocyanate increases MRP1 expression in cigarette smoke extract‑stimulated human bronchial epithelial cells via the JNK/Nrf2 pathway

Zhang

Wang

et al. 2021

Exp Ther Med

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Multidrug resistance-related protein 1 (MRP1) is involved in the biological transport of several molecules with diverse structural characteristics outside of the cell. In addition to its transport activity, MRP1 exhibits multiple defense mechanisms in vivo . MRP1 is highly expressed in normal lung tissues and plays a protective role in the process of chronic obstructive pulmonary disease. In the present study, human bronchial epithelial cells (16HBE14o-cells) were stimulated by cigarette smoke extract (CSE) in vitro to simulate a smoking environment. On this basis, the mechanism of Allyl isothiocyanate (AITC) administration on the expression of MRP1 in CSE-stimulated 16HBE14o-cells was investigated. The effects of CSE on the viability of 16 HBE14o-cells were investigated by an MTT assay. The changes in the mRNA expression levels of nuclear erythroid factor 2 (Nrf2) and MRP1 were investigated in CSE-stimulated 16HBE14o-cells using western blotting and reverse transcription quantitative PCR (RT-qPCR). Immunofluorescence analysis was used to detect Nrf2 nuclear translocation. Incubation of the cells with 5% CSE for 24 h had minor effects on cell viability and resulted in the activation of the JNK and p38MAPK signaling pathways. AITC activated the JNK pathway, inhibited the activation of the p38MAPK pathway in 16HBE14o-cells stimulated by 5% CSE and upregulated the expression levels of Nrf2 and MRP1 in a time-dependent manner. The upregulation of Nrf2, MRP1 and of Nrf2, and MRP1 mRNA expression levels in CSE-stimulated cells was inhibited by pretreatment with SP600125 (a JNK pathway inhibitor). Furthermore, the fluorescence intensity in the nucleus was significantly enhanced following AITC pretreatment and the analysis indicated nuclear translocation of Nrf2 in the cells. These results indicated that Nrf2 and MRP1 expression levels in CSE-stimulated cells were altered following AITC pretreatment. Thus demonstrating that the primary mechanism may be associated with activation of the JNK pathway, while the p38MAPK pathway may not be involved.

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Upregulation of Multidrug Resistance-Associated Protein 1 by Allyl Isothiocyanate in Human Bronchial Epithelial Cell: Involvement of c-Jun N-Terminal Kinase Signaling Pathway

Cited by 8 publications

References 35 publications

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

Allyl isothiocyanate increases MRP1 expression in cigarette smoke extract‑stimulated human bronchial epithelial cells via the JNK/Nrf2 pathway

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