RT Journal Article
SR Electronic
T1 Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.065961
DO 10.1124/mol.110.065961
A1 Won Keun Oh
A1 Kyoung Bin Cho
A1 Tran T Hien
A1 Tae Hyung Kim
A1 Hyung Sik Kim
A1 Trong T Dao
A1 Hyo-Kyung Han
A1 Seong-Min Kwon
A1 Sang-Gun Ahn
A1 Jung-Hoon Yoon
A1 Tae Hyun Kim
A1 Yoon Gyoon Kim
A1 Keon Wook Kang
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/08/16/mol.110.065961.abstract
AB The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multi-drug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many anti-cancer 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 adriamycin-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, intraperitoneal injection of 10 mg/kg 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 it may be possible to develop amurensin G as a useful agent for chemoresistance reversal.