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Cancer Chemotherapy and Pharmacology

Published in:

01-05-2010 | Original Article

PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB

Authors: H. Bark, Cheol-Hee Choi

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2010

Abstract

Purpose

Multidrug resistance (MDR) is one of the major causes of clinical cancer chemotherapy failure. PSC833 is well known as a non-immunosuppressant cyclosporine analogue that functionally inhibits P-glycoprotein (Pgp), a product of the MDR1 gene. We investigated whether PSC833 could also alter MDR1 expression and, if so, which mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-κB) pathways were involved in this event.

Methods

MTT assay and flow cytometry were used for the analysis of cytotoxicity and intracellular drug accumulation, respectively. RT-PCR and Western blot assays for analysis of gene expression and electrophoretic mobility shift assays for determination of DNA-binding activity of transcription factors were used.

Results

The doxorubicin-resistant lung cancer cell subline (SK-MES-1/DX1000), selected from SK-MES-1/WT cells, upregulated MDR1 expression, thereby showing MDR phenotypes. PSC833 sensitized SK-MES-1/DX1000 cells to doxorubicin. PSC833 (5 μM) also decreased the intracellular accumulation of fluorescent Pgp substrates such as rhodamine 123 and daunorubicin in SK-MES-1/DX1000 cells. PSC833 downregulated MDR1 mRNA and Pgp expression in a time- and concentration-dependent manner. PSC833 activated c-Jun NH2-terminal kinase (JNK)/c-Jun and enhanced AP-1 DNA-binding activity, but suppressed nuclear translocation of NF-κB, all of which were prevented by pretreatment with a JNK inhibitor SP600125.

Conclusions

These results indicate that PSC833 not only sensitizes SK-MES-1/DX1000 cells to doxorubicin by enhancing drug accumulation, but also downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB.

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Title: PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB
Authors: H. Bark
Cheol-Hee Choi
Publication date: 01-05-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1121-7

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Abstract

Purpose

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Conclusions

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