Abstract
The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many anticancer agents. We recently showed that a Forkhead box-containing protein of the O subfamily 1 (FoxO1) is a key regulator of MDR1 gene transcription. Because nuclear localization of FoxO1 is regulated by silent information regulator two ortholog 1 (SIRT1) deacetylase, we wondered whether SIRT1 dominates MDR1 gene expression in breast cancer cells. Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. In addition, SIRT1 inhibition reduced both nuclear FoxO1 levels and MDR1 expression in doxorubicin-resistant breast cancer cells (MCF-7/ADR) cells. A potent SIRT1 inhibitor, amurensin G (from Vitis amurensis), was identified by screening plant extracts and bioassay-guided fractionation. The compound suppressed FoxO1 activity and MDR1 expression in MCF-7/ADR cells. Moreover, pretreatment of MCF-7/ADR cells with 1 μg/ml amurensin G for 24 h increased cellular uptake of doxorubicin and restored the responsiveness of MCF-7/ADR cells to doxorubicin. In xenograft studies, injection of 10 mg/kg i.p. amurensin G substantially restored the ability of doxorubicin to inhibit MCF-7/ADR-induced tumor growth. These results suggest that SIRT1 is a potential therapeutic target of MDR1-mediated chemoresistance and that it may be possible to develop amurensin G as a useful agent for chemoresistance reversal.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Research Foundation of Korea, funded by the Korean government [Grants 2009-0083757, 2010-0001707, R13-2008-010-01001-0].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.065961.
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ABBREVIATIONS:
- MDR
- multidrug resistance
- ABC
- ATP-binding cassette
- MRP
- multidrug resistance-associated protein
- FoxO
- Forkhead box-containing protein, O subfamily
- SIRT1
- silent information regulator two ortholog 1
- siRNA
- small-interfering RNA
- FBS
- fetal bovine serum
- PMSF
- phenylmethylsulfonyl fluoride
- PBS
- phosphate-buffered saline
- MS
- mass spectrometry
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide
- PCNA
- proliferating cell nuclear antigen
- PI3
- phosphatidylinositol 3
- FHRE
- forkhead-response element
- R-123
- Rhodamine-123
- MCF-7/ADR
- doxorubicin-resistant breast cancer cells
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling.
- Received April 29, 2010.
- Accepted August 16, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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