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

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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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Acknowledgments

This work was supported, in part, by grants from the Ministry of Science and Technology, Korea, and the Korea Science and Engineering Foundation through the Research Center for Resistant Cells (R13-2003-009). The authors would like to thank Dr. B. C. Choi of the CL Women’s Hospital for his helpful advice.

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Authors and Affiliations

  1. Department of Pharmacology, Research Center for Resistant Cells, Chosun University Medical School, 375 Seosuk-dong Dong-gu, Gwangju, 501-759, Korea

    H. Bark & Cheol-Hee Choi

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  1. H. Bark
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Correspondence to Cheol-Hee Choi.

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Bark, H., Choi, CH. PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB. Cancer Chemother Pharmacol 65, 1131–1136 (2010). https://doi.org/10.1007/s00280-009-1121-7

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  • DOI: https://doi.org/10.1007/s00280-009-1121-7

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